Gut microbiota in health and disease

Yangziyi Li; Xueyan Xiao; Xin Jiang; Xinyi Li; Weijun Wang; Rong Lin

doi:10.1186/s43556-026-00512-6

. 2026 Jul 20;7:116. doi: 10.1186/s43556-026-00512-6

Gut microbiota in health and disease

Yangziyi Li ¹, Xueyan Xiao ¹, Xin Jiang ¹, Xinyi Li ¹, Weijun Wang ^1,^✉, Rong Lin ^1,^2,^✉

PMCID: PMC13385334 PMID: 42474869

Abstract

The gut microbiota is integral to host physiology, contributing to metabolic homeostasis, epithelial barrier integrity, immune balance, and bidirectional communication along gut–organ axes. Disruption of this ecosystem, commonly referred to as dysbiosis, is increasingly implicated in a wide range of gastrointestinal and extra-intestinal diseases. Rather than reflecting isolated compositional changes, microbiota-related pathology often involves interconnected disturbances in barrier function, microbial metabolism, immune regulation, genotoxicity, inflammatory and oncogenic signaling, and long-range communication with distal organs. However, key challenges remain, particularly in resolving causality, accounting for interindividual heterogeneity, and translating complex microbiome data into robust clinical tools. In this review, we summarize the role of the gut microbiota in maintaining host homeostasis and outline the concept, drivers, and consequences of dysbiosis. We then discuss the major mechanisms through which the gut microbiota contributes to disease development and progression, using colorectal cancer as a representative gastrointestinal example and gut–organ axes as a framework for extra-intestinal disorders. We further highlight current translational advances in microbiota-based biomarkers, dietary modulation, biotic and postbiotic strategies, fecal microbiota transplantation, and emerging precision microbiota therapies. By integrating mechanistic insights with translational perspectives, this review offers an updated framework for interpreting the gut microbiota in health and disease and may help inform the future development of more precise, mechanism-informed diagnostic and therapeutic strategies.

Keywords: Gut microbiota, Dysbiosis, Colorectal cancer (CRC), Gut-organ axis, Microbiota-based biomarker, Microbiota-based therapy

Introduction

The gut microbiota is a complex microbial ecosystem inhabiting the human gastrointestinal tract and maintaining dynamic interactions with the host [1, 2]. It regulates diverse physiological processes, including nutrient metabolism, epithelial integrity, immune function, and systemic signaling [1, 2]. With the rapid development of high-throughput sequencing, multi-omics profiling, and functional experimental approaches, our understanding of how the gut microbiota shapes both local intestinal homeostasis and systemic physiology has substantially expanded [2–4].

Increasing evidence links gut microbiota dysbiosis to numerous disorders, including gastrointestinal diseases such as colorectal cancer (CRC), inflammatory bowel disease (IBD), and irritable bowel syndrome (IBS), as well as extra-intestinal conditions affecting the liver, metabolism, nervous, and endocrine systems [1, 2]. The relationship between the gut microbiota and disease is complex and often bidirectional. A healthy gut microbiota cannot be defined by a single compositional pattern [5, 6], while dysbiosis may function as either a driver or consequence of disease [7, 8]. Moreover, the effects of specific microbes and metabolites are highly context-dependent, shaped by host background, environmental factors, and disease stage [9, 10].

These complexities present a major challenge for the field. Although many studies have identified disease-associated microbial signatures, compositional changes alone are often insufficient to explain pathogenesis or to support their reliable clinical translation. As a result, increasing attention has shifted toward functional mechanisms, including metabolic remodeling, barrier disruption, immune reprogramming, genotoxic damage, and inter-organ communication through gut–organ axes [1, 2]. These mechanistic advances have also increased interest in the clinical applicability of microbiota-based biomarkers and targeted interventions [11, 12].

Because host–microbiota interactions are complex and context-dependent, disease-associated microbial changes cannot be fully interpreted through composition alone. This review integrates current evidence on microbial homeostasis, dysbiosis, disease mechanisms, and translational applications, with an emphasis on how mechanistic insights can inform microbiota-based biomarkers and therapeutic strategies.

Gut microbiota and health

A healthy gut microbiota is not simply defined by a fixed microbial composition, but rather by its ability to sustain host homeostasis across changing physiological and environmental conditions. Its key ecological features, including diversity, stability, and resilience, help maintain a functionally balanced microbial ecosystem. By mediating metabolic regulation, barrier protection, immune balance, and gut–organ axis communication, this ecosystem supports both intestinal and systemic health, making microbial homeostasis an important basis of host physiology.

Definition of a healthy gut microbiota

The gut microbiota is a complex microbial community colonizing the human gastrointestinal tract, where it establishes a relatively stable symbiotic relationship with the host [1, 3]. Bacteria, commonly dominated by Firmicutes, Bacteroidetes, and Actinobacteria [13], predominate in the gut microbiota, although fungi, viruses, and archaea are also present [3, 5, 14]. By contrast, the gut microbiome refers more broadly to this microbial community together with its collective genetic material and microbially derived metabolites and functional molecules [3, 15, 16]. Through sustained host–microbe interactions, the gut microbiota exerts broad regulatory effects on host physiological homeostasis and health. Its composition and function are shaped by multiple host-related and environmental factors, including genetics, diet, age, lifestyle, medication exposure, external environment and so on, which together drive substantial interindividual variability [1, 3, 5]. Nevertheless, a healthy gut microbiota is commonly characterized by relatively high diversity, overall stability, and resilience to perturbations [1, 5, 17] (Fig. 1). Rather than representing a fixed taxonomic configuration, a healthy gut microbiota is better understood as a functionally balanced ecological state. Gut microbiota diversity extends beyond taxonomic composition to functional diversity, enabling a wide range of activities in nutrient processing, metabolism, and immune modulation [5, 17]. Notably, many key functions can be maintained by multiple microbial taxa, a phenomenon known as functional redundancy [18, 19]. This allows functional compensation across alternative community structures and thereby promotes stability and resilience. Stability describes a dynamic equilibrium in core community functions under daily fluctuations [17, 20], while resilience refers to the ability to recover from stronger perturbations, such as antibiotics or inflammation [17, 20].

Fig. 1 — Healthy gut microbiota and host homeostasis. A healthy gut microbiota is generally characterized by diversity, stability, and resilience, and contributes to host homeostasis through metabolic homeostasis, barrier protection, immune regulation, and gut–organ axis communication

Role of gut microbiota in maintaining host health

By producing bioactive metabolites, strengthening the intestinal barrier, modulating immune responses, and communicating along gut–organ axes, the gut microbiota supports metabolic homeostasis, barrier protection, and immune balance while extending its regulatory effects to distal organs [1, 3] (Fig. 1).

Metabolic homeostasis

There is extensive metabolic crosstalk between the gut microbiota and the host, mainly through two major mechanisms [21]. First, the microbiota acts as a metabolic organ that supplies energy substrates to the host. Second, microbiota-derived metabolites function as signaling molecules that regulate host metabolic homeostasis.

A substantial fraction of dietary components is not directly digested by the host. Instead, gut microbes ferment substrates such as dietary fiber, resistant starch, and other complex carbohydrates into host-accessible metabolites, particularly short-chain fatty acids (SCFAs) [21, 22]. More than 90% of SCFAs are absorbed by the intestinal epithelium via transporters such as solute carrier family 26 member 3 (SLC26A3) and monocarboxylate transporter 1 (MCT1) [22, 23]. Once absorbed, these metabolites may be used for lipid and carbohydrate synthesis or enter the tricarboxylic acid cycle, contributing about 5%–10% of daily energy requirements [22–24]. Among SCFAs, butyrate is the main fuel for colonocytes [25], whereas acetate and propionate primarily enter the portal circulation to support hepatic lipogenesis and cholesterol biosynthesis [26]. Acetate can also be detected in peripheral blood as a systemic energy substrate [27]. The gut microbiota broadens host metabolic capacity by contributing to vitamin synthesis, particularly vitamin K and B vitamins [28, 29], and by modulating amino acid metabolism [30].

Gut microbiota-derived metabolites also have regulatory roles beyond their use as substrates. Many of them engage host receptors, regulate hormone secretion, and influence epigenetic programs, thereby reshaping host metabolic networks. SCFAs and secondary bile acids provide well-established examples of this signaling role, as they connect microbial metabolism with host endocrine and metabolic regulation. For instance, SCFAs activate G protein-coupled receptors (GPCRs) such as GPR41 and GPR43, promoting the release of enteroendocrine hormones, including glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), thereby improving insulin sensitivity, appetite regulation, and glycemic homeostasis [22, 31, 32]. Butyrate can also function as a histone deacetylase (HDAC) inhibitor and modulate transcriptional programs involved in lipid metabolism [22, 33]. Secondary bile acids signal through the nuclear receptor farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) to regulate lipid absorption, hepatic lipid handling, and glucose homeostasis [34, 35]. More recent studies have expanded this view beyond classical SCFA and bile acid pathways, identifying additional microbiota-derived metabolites, such as 3-succinylcysteine [36] and mesaconate [37], as regulators of host metabolic homeostasis. Overall, the gut microbiota contributes to host metabolism not only by extracting nutrients, but also by producing signaling molecules that help coordinate metabolic regulation.

Barrier protection

The gut microbiota helps maintain intestinal barrier function at several levels. It supports the physical barrier formed by the epithelial layer and intercellular junctions, the chemical barrier composed of mucus and soluble defensive effectors, and the biological barrier provided by colonization resistance [38, 39]. Together, these mechanisms form an intestinal defense system against pathogen invasion and the translocation of harmful substances.

For the physical barrier, the gut microbiota restricts the translocation of luminal contents by promoting epithelial cell homeostasis and maintaining tight junction integrity [22, 38, 39]. Commensal bacteria and their metabolites provide energy substrates and regulatory signals that support epithelial metabolism and proliferation, thereby helping epithelial cells resist injury and repair damage [38–40]. Microbial signals also regulate the expression and function of tight junction proteins [38, 39]. For example, butyrate [22] and spermidine [41] can upregulate proteins such as Occludin, Claudin-1, and ZO-1, while specific strains such as Bifidobacterium bifidum [42] have also been shown to strengthen tight junction barrier function through microbe–host interactions. Together, these actions preserve epithelial integrity and limit increased intestinal permeability, often referred to as a “leaky gut”.

The gut microbiota also reinforces the chemical barrier through its effects on mucus, antimicrobial peptides (AMPs), and secretory IgA (sIgA) [38]. Microbial metabolites stimulate goblet cells to secrete mucin 2 (MUC2), which contributes to the formation of the double-layered mucus structure [43–45]. This structure supports commensal colonization while keeping the inner layer relatively sterile [43–45]. The microbiota also promotes AMP production by intestinal epithelial cells, including enterocytes, goblet cells, and Paneth cells. For example, microbial signals induce Paneth cells to secrete α-defensins and RegIIIγ, which help eliminate bacteria that penetrate the mucus layer [46, 47]. The microbiota further induces plasma cells to produce sIgA, which is transported into the intestinal lumen and limits bacterial adhesion to and invasion of the epithelium by coating microbial surfaces [48, 49].

The microbiota also provides biological antagonism through colonization resistance [50, 51]. A healthy gut microbiota suppresses potential pathogens by competing for limited nutrients, such as monosaccharides, amino acids, and iron, and by occupying attachment sites within the epithelial and mucus layers [52, 53]. In addition, commensal bacteria can directly inhibit invading pathogens by producing antimicrobial substances, including bacteriocins [54] and hydrogen peroxide [55]. Microbiota-derived metabolites, particularly SCFAs and secondary bile acids, also exert antimicrobial effects [22, 51, 56]. These metabolites can further restrict pathogen growth, especially that of environmentally sensitive pathogens, by lowering local pH [57] and oxygen levels [50] in the gut. Through these mechanisms, the microbiota helps maintain a community structure that resists pathogen overgrowth and supports long-term barrier stability.

Immune regulation

Beyond maintaining intestinal barrier integrity, the gut microbiota is also a key exogenous regulator of the immune system, shaping immune development and sustaining immune homeostasis [58].

The gut microbiota provides the initial driving force for immune maturation. Early-life colonization and subsequent continuous microbial exposure supply essential antigenic and signaling inputs that shape immune development via mechanisms such as microbe-associated molecular pattern (MAMP)–pattern recognition receptor (PRR) signaling, including Toll-like receptor (TLR)- and NOD-like receptor (NLR)-mediated pathways [59, 60]. On the one hand, the microbiota and its metabolites promote the development of gut-associated lymphoid tissue (GALT), including isolated lymphoid follicles and Peyer’s patches, thereby providing an organized niche for immune cell localization and crosstalk [61]. On the other hand, commensal microbes provide tonic signals that support the maturation and differentiation of both innate and adaptive immune cells [58]. For example, segmented filamentous bacteria (SFB) can induce T helper 17 (Th17) cell differentiation and thereby enhance host resistance to infection [62, 63]. In infants, Bifidobacterium can also promote CD4+ T cell polarization toward regulatory T (Treg) and Th1 lineages through indole-3-lactic acid (ILA), helping restrain mucosal inflammation [64]. Consistently, germ-free animal studies show that the absence of microbiota-driven immune education results in structural and functional immune defects, with lasting consequences for immune homeostasis and susceptibility to infectious and inflammatory diseases [58, 59].

In addition, the gut microbiota sustains immune homeostasis through dynamic regulatory networks that calibrate inflammatory intensity, effector programs, and response duration [58]. This allows the host to mount protective immunity when needed while limiting excessive inflammation and maintaining tolerance to commensals. Microbial metabolites are central mediators of this regulation. SCFAs promote the induction and stability of Treg cells through HDAC inhibition and/or GPCR-mediated signaling [22, 65, 66], and also modulate antigen-presenting and myeloid-cell function by reshaping cellular metabolism and cytokine production [67, 68], thereby restraining inflammatory amplification and promoting resolution. In parallel, microbiota-derived tryptophan metabolites regulate innate and adaptive effector pathways, including innate lymphoid cell 3 (ILC3)/Th17-IL (Interleukin)-22-linked responses, through activation of the aryl hydrocarbon receptor (AhR), promoting barrier restitution and coordinating immune responses [69, 70]. Secondary bile acids and their derivatives also regulate myeloid-cell inflammatory set-points and effector functions, such as chemotaxis and phagocytosis, through receptors including TGR5 and FXR [71–73]. Thus, microbiota-dependent immune regulation should not be viewed simply as immune activation or suppression, but as an integrated process that supports immune maturation, maintains tolerance, and calibrates inflammatory responses.

Gut–organ axis communication

The gut–organ axis refers to a bidirectional and dynamic communication network between the intestine and extraintestinal organs, mediated through multiple pathways, primarily including neural, endocrine, immune, and metabolic routes [74, 75]. This network enables intestinal states to modulate distal organ function while allowing distal organs to reciprocally influence gut physiology [74, 75]. Major gut–organ axes include the gut–liver, gut–brain, gut–kidney, gut–lung, gut–heart axes and so on. Through these axes, the gut microbiota functions not only as a local intestinal community, but also as a systemic regulator linking microbial ecology to distal organ physiology.

One major route involves the direct dissemination of gut microbes and their components, products, and metabolites through the circulation [74, 75]. SCFAs are representative examples. Along the gut–liver axis, butyrate supports hepatocyte metabolism [76], whereas propionate can suppress hepatic gluconeogenesis via GPR43, which contributes to glycemic homeostasis [32, 77]. In the gut–lung axis, SCFAs regulate pulmonary immune equilibrium by metabolically reprogramming alveolar macrophages [78]. In the gut–kidney axis, they participate in blood pressure regulation through receptor-mediated effects on renin secretion and vascular tone [79]. SCFAs can also influence blood–brain barrier function and microglial maturation, thereby supporting central nervous system homeostasis [80, 81].

Another route operates indirectly through the remodeling of host metabolic, immune, endocrine, and neural pathways [74, 75]. At the metabolic level, the microbiota can modulate carbohydrate, lipid, and protein metabolism across organs, as well as calcium absorption and vitamin metabolism, especially vitamins B, D, and K [82]. These effects are relevant to the gut–bone axis and bone remodeling [82]. Immunologically, the gut microbiota and its metabolites influence systemic immune homeostasis by affecting immune cells, including ILCs, Tregs, and Th17 cells, and related cytokines [58]. This has particular relevance for the respiratory tract as part of the mucosal immune system [83, 84]. In the endocrine system, the microbiota influences incretin secretion, including GLP-1, PYY, and glucose-dependent insulinotropic polypeptide (GIP), contributing to glycemic stability [85, 86]. The microbiota is also linked to sex hormone homeostasis. Microbial β-glucuronidases can deconjugate estrogens and affect circulating active estrogen levels [87, 88], while gut bacteria can convert tetrahydrodeoxycorticosterone (THDOC) into the progesterone derivative tetrahydroprogesterone (THP) through microbiota-dependent 21-dehydroxylation [89]. Through neural routes, the microbiota can signal through the vagus nerve or enteric nervous system and modulate neurotransmitter production, such as γ-aminobutyric acid (GABA) and serotonin, thereby influencing the nervous system and consequently other organs [90–92]. Taken together, these routes make gut–organ axis communication a link between local microbial activity and systemic homeostasis, and show how the gut microbiota helps coordinate intestinal and extraintestinal physiological functions.

Gut microbiota dysbiosis

Gut microbiota dysbiosis is generally viewed as a dynamic disruption of the intestinal microbial ecosystem rather than a single compositional abnormality. It involves related changes in microbial structure, composition, function, and ecological stability, shaped by external exposures, host-related factors, and disease-associated feedback. These disturbances can impair barrier integrity, alter microbial metabolism, reshape immune regulation, and perturb gut–organ communication, thereby linking microbial imbalance to disease susceptibility and progression.

Definition and features of gut microbiota dysbiosis

Gut microbiota dysbiosis refers to alterations in the structure, composition, and function of the intestinal microbial community, which can disrupt the symbiotic balance established through long-term co-evolution between the host and its microbes [93–95]. The concept extends beyond simple compositional imbalance to encompass functional perturbations, including shifts in microbial metabolite profiles and disturbances in the host–microbe interaction network [93–95]. Although some dysbiosis indices have been studied, substantial individual variability in the gut microbiota driven by factors such as host genetics, diet, and geography makes it difficult to define a single diagnostic criterion [96–98]. As a result, dysbiosis is better understood through an integrated assessment that combines diversity metrics, specific taxonomic changes, and functional parameters.

Although there is no unified quantification standard, gut microbiota dysbiosis commonly manifests as a multidimensional disturbance involving microbial structure, function, and ecological stability (Fig. 2). The most prominent characteristic is a reduction in microbial α-diversity, which can be assessed using indices such as the Shannon diversity index [96, 99]. This is often accompanied by taxonomic imbalance, characterized by the depletion of beneficial commensals and the enrichment of disease-associated taxa. For example, SCFA-producing microbes, including Faecalibacterium prausnitzii, Roseburia spp., and Eubacterium rectale, are frequently reduced [99, 100], whereas disease-associated taxa such as Fusobacterium nucleatum, Escherichia coli, Bacteroides fragilis, Enterococcus faecalis, and Streptococcus gallolyticus show marked increases in abundance [101, 102]. However, these taxonomic changes should not be interpreted in isolation, as their biological relevance largely depends on the functional consequences they produce. Structurally altered microbial communities can lead to functional disturbances, particularly changes in microbial metabolic capacity. These include a decline in protective metabolites, especially SCFAs, and increased production of harmful microbial products, such as lipopolysaccharide (LPS) [21, 22]. Another feature of functional dysbiosis is the enrichment of antimicrobial resistance genes [103, 104]. Furthermore, dysbiosis is associated with reduced stability and resilience, which can lead to persistent or difficult-to-reverse imbalances in the microbiota, thereby increasing disease susceptibility [20, 99, 105].

Fig. 2 — Gut microbiota dysbiosis. Gut microbiota dysbiosis can be driven by multiple factors, including lifestyle, medication and environmental exposure, infection and inflammation, host-related factors, and disease-associated disturbances. It is characterized by reduced diversity, altered microbial composition, functional disturbance, and impaired stability and resilience, ultimately leading to barrier dysfunction, metabolic imbalance, immune dysregulation, and perturbed gut–organ communication

Causes and consequences of gut microbiota dysbiosis

Gut microbiota dysbiosis is rarely driven by a single cause, rather, it often emerges from interactions among external perturbations, host-intrinsic factors, and disease-related feedback loops [7, 94, 99] (Fig. 2). Lifestyle habits, such as diet, smoking, alcohol consumption, and sleep patterns, represent major exogenous contributors [94, 99, 106, 107]. For example, a Western diet high in fat and sugar but low in fiber has been associated with reduced microbial diversity and an expansion of Proteobacteria [108, 109]. Medications and environmental exposures are also key contributors [94, 110, 111]. Antibiotics can markedly reshape community composition [105, 112, 113], and early-life exposure to macrolides has been linked to long-lasting reductions in microbial diversity [114]. Several non-antibiotic drugs, such as proton pump inhibitors [115] and metformin [116], can also alter the gut microbiota [117]. Infection and inflammation serve as additional triggers [94, 118]. Pathogen invasion can directly disrupt community structure, while the ensuing inflammatory environment may further favor the outgrowth of certain pathobionts, thereby reinforcing and sustaining dysbiosis [94, 118]. In addition, host-related factors contribute substantially to dysbiosis. Genetic background and innate host traits can exert specific influences on microbiota composition [119], and advancing age is often accompanied by lower microbial diversity [120, 121]. Moreover, dysbiosis can act both as a “driver” of disease and as a “passenger” phenomenon. Disease-associated disturbances in metabolism, immunity, and other host processes can feed back to worsen microbial imbalance [122]. This bidirectional relationship suggests that dysbiosis is not merely an upstream disturbance, but may also be amplified by the disease environment itself.

The consequences of gut microbiota dysbiosis can be characterized as a synergistic disruption of barrier integrity, metabolic homeostasis, and immune regulation [3, 94] (Fig. 2). In terms of barrier function, dysbiosis is typically accompanied by impaired intestinal barrier integrity and diminished colonization resistance [38, 56]. This not only increases the risk of pathogen infection but also facilitates the translocation of harmful bacterial products, such as LPS, into the circulation through increased intestinal permeability, which can trigger systemic inflammatory responses [123, 124]. Metabolically, dysbiosis is associated with imbalances in key microbial pathways [125], including reduced SCFA availability, altered bile acid biotransformation, and disturbed tryptophan metabolism, alongside increased generation of deleterious metabolites such as the pro-atherogenic molecule trimethylamine N-oxide (TMAO) [126]. These alterations can impair the energy metabolism of intestinal epithelial cells and change the availability of specific signaling molecules [127, 128]. At the immune level, dysbiosis-driven shifts in microbial metabolites and products can reshape host immune responses, resulting in aberrant immune cell function and differentiation as well as activation of inflammatory pathways [129, 130]. The effects of dysbiosis can also extend beyond the intestine. Through metabolic, immune, endocrine, and neural pathways, dysbiosis can perturb gut–organ axis communication and thereby influence distal organs [3, 94, 131]. These barrier, metabolic, immune, and systemic alterations are closely interconnected, forming a self-reinforcing network through which dysbiosis can increase disease susceptibility and promote disease progression.

Gut microbiota in disease development and progression

Although the causal direction between dysbiosis and disease often remains difficult to define, the gut microbiota is increasingly recognized as a key disease regulator, exerting both pathogenic and protective effects. Dysbiosis can promote pathology by disrupting barrier integrity, driving chronic inflammation and immune dysregulation, producing bioactive metabolites, modulating host signaling pathways, and, in some cases, generating genotoxins that directly damage host DNA. Conversely, commensal microbes can protect the host by regulating signaling, shaping the immune microenvironment, and producing beneficial metabolites. In the following sections, we first focus on gastrointestinal diseases, using colorectal cancer (CRC) as a representative example to illustrate major microbiota-related pathogenic and protective mechanisms, and then extend the discussion to gut–organ axes to summarize how the gut microbiota influences extra-intestinal diseases (Fig. 3).

Fig. 3 — Gut microbiota in gastrointestinal and extra-intestinal diseases. Gut microbiota dysbiosis contributes to the development and progression of gastrointestinal diseases and multiple extra-intestinal disorders through microbial signals and products, barrier integrity, immune regulation, and neuroendocrine-metabolic communication across gut–organ axes

Gut microbiota in gastrointestinal diseases: colorectal cancer as a representative example

Colorectal Cancer (CRC)

CRC development involves complex genetic and environmental interactions. Although the causal relationship between gut microbiota dysbiosis and colorectal cancer remains incompletely defined, microbiota from CRC patients can promote intestinal carcinogenesis in mice [132, 133], supporting the involvement of microbes in CRC initiation and progression. The mechanisms can be broadly categorized into genotoxicity, signaling modulation, immune regulation, and metabolic pathways (Fig. 4).

Genotoxicity

Microbial genotoxicity provides a direct mechanistic link between CRC-associated dysbiosis and epithelial genomic instability (Fig. 4a). Gut microbes can produce genotoxic substances, primarily including cytolethal distending toxin (CDT), colibactin, and indoleamine, which damage colorectal epithelial DNA and may contribute to driver mutation accumulation, including alterations in APC (adenomatous polyposis coli), thereby facilitating the adenoma–carcinoma sequence.

CDT, produced by pathogenic Escherichia coli and Campylobacter jejuni, induces DNA double-strand breaks via deoxyribonuclease activity [134]. The reduced carcinogenic and metastatic potential of cdtB-mutant strains underscores the role of CDT in tumorigenesis [135, 136]. Colibactin, produced by pks⁺ Escherichia coli (pks⁺ E. coli) [137], preferentially targets AAWWTT DNA motifs [138], forming adducts and crosslinks that cause double-strand breaks [139, 140]. Its pro-tumorigenic effects have been demonstrated in experimental models [141, 142], and it has also been linked to chemotherapy and immunotherapy resistance [143, 144]. Consistently, colibactin-related mutational signatures have been identified in human CRC genomes [145, 146], while inhibition of its biosynthesis or blockade of adhesin-mediated epithelial binding can attenuate its genotoxic and tumor-promoting effects [147, 148]. In addition, Morganella morganii produces indolimines, which contain functional imine groups that can also mediate DNA damage and promote CRC development [149]. Some pathogens may further induce genomic instability indirectly by triggering host reactive oxygen species (ROS) production. For example, Bacteroides fragilis toxin (BFT) from enterotoxigenic Bacteroides fragilis (ETBF) induces ROS accumulation and DNA damage in colonic cells [150, 151], and Enterococcus faecalis exerts similar effects [152]. Collectively, these findings suggest that microbial genotoxicity contributes to CRC by inducing direct DNA damage and ROS-associated genomic instability, thereby promoting mutational accumulation during tumor development.

Signal transduction

Colorectal cancer commonly involves oncogenic pathways such as Wnt/β-catenin, NF-κB (nuclear factor kappa B), and PI3K (phosphoinositide 3-kinase)/AKT, with additional pathways identified in recent years (Fig. 4b). CRC-associated microbes can influence tumor development by converging on these host signaling networks, thereby promoting epithelial proliferation, resistance to apoptosis, invasion, metastasis, and therapy resistance. Fusobacterium nucleatum (F. nucleatum) is one of the best-studied examples and acts through several virulence factors. Its adhesin FadA (Fusobacterium adhesin A) binds E-cadherin to activate Wnt/β-catenin signaling and upregulate downstream proliferative genes such as cyclin D1 [153, 154]. FadA also enhances E-cadherin–KLF4 (Krüppel-like factor 4) signaling in a Ca²⁺-dependent manner, resulting in KLF4 phosphorylation and nuclear translocation, which drives integrin α5 transcription and metastatic progression [155]. Another virulence factor, RadD (radiation resistance protein D), facilitates F. nucleatum enrichment and colonization in tumor tissues through CD147 binding and activates PI3K/AKT signaling [156]. Beyond these effects, F. nucleatum can also promote chemoresistance by modulating the YAP/BCL2/Caspase-3/GSDME (Yes-associated protein/B-cell lymphoma-2/Caspase-3/gasdermin E) pathway [157] and promote metastatic dissemination through the ALPK1/NF-κB/ICAM1 (alpha-kinase 1/nuclear factor kappa B/intercellular adhesion molecule 1) axis [158].

Other CRC-associated bacteria also modulate host signaling pathways involved in tumor progression. Parvimonas micra activates the miR-218-5p/RAS (rat sarcoma viral oncogene)/ERK (extracellular signal-regulated kinase)/c-Fos axis [159], whereas Peptostreptococcus anaerobius stimulates PI3K/AKT signaling through integrin α2β1 binding mediated by its PCWBR2 (putative cell wall binding repeat 2) protein [160]. In addition, Desulfovibrio vulgaris promotes epithelial-mesenchymal transition (EMT) through flagellin-mediated interaction with LRRC19 (leucine-rich repeat containing 19) and activation of the TRAF6/TAK1 (tumor necrosis factor receptor-associated factor 6/transforming growth factor-β-activated kinase 1) signaling pathway [161]. Beyond direct bacterial signaling, microbial metabolites can also reshape oncogenic programs. Agmatine enhances Wnt/β-catenin signaling by inhibiting Rnf128-mediated β-catenin ubiquitination, thereby upregulating targets such as Cyclin D1, Lgr5, CD44, and c-Myc [162], while 5-aminovaleric acid (5-AVA) derived from Fusobacterium mortiferum similarly activates this pathway through suppression of the tumor suppressor DKK2 [163]. These examples suggest that CRC-associated microbes do not act through a single signaling route. Instead, they may reshape tumor-promoting signaling through bacterial adhesion, virulence factor–host receptor interactions, and microbiota-derived metabolites.

Conversely, selected commensals and microbiota-derived metabolites can also restrain CRC progression by modulating signaling pathways. For example, Clostridium butyricum suppresses CRC progression by inhibiting the Wnt/β-catenin pathway and altering microbial composition [164]. Indole acetic acid (IAA) from Acinetobacter radioresistens activates AhR in intestinal stem cells to inhibit Wnt/β-catenin signaling, reducing cellular proliferation, intestinal stem cell (ISC) turnover, and tumorigenesis [165]. The peptidoglycan fragment N-acetylmuramic acid (NAM) binds AKT1, inhibits its phosphorylation, and suppresses the oncogenic AKT1–FoxO3a pathway, thereby impeding tumor progression [166]. Thus, microbiota-mediated signaling regulation in CRC is bidirectional rather than uniformly tumor-promoting. Dysbiotic microbes may activate oncogenic pathways, whereas selected commensals or metabolites may restrain tumor-promoting signaling and preserve epithelial homeostasis.

Immune modulation

The microbiota shapes the tumor microenvironment through immune modulation with dual effects, promoting CRC progression by driving inflammation and immune suppression while also supporting anti-tumor immunity (Fig. 4c).

Inflammation is a recognized risk factor for CRC, and dysbiosis is closely linked to intestinal inflammation [167]. Both microbiota from CRC patients [132, 133] and individual tumor-promoting pathogens [168, 169] can induce colonic inflammation and upregulate pro-inflammatory mediators in mice. A key mechanism is the activation of Th17 cells [169, 170]. For example, ETBF disrupts the intestinal barrier through BFT, which then rapidly induces Th17 activation and IL-17 secretion [169, 171]. IL-17 then acts on colonic epithelial cells to activate STAT3 (signal transducer and activator of transcription 3) and NF-κB signaling, thereby promoting inflammation and carcinogenesis [172, 173]. The gut microbiota can also modulate the tumor immune microenvironment through direct interactions with epithelial cells. F. nucleatum, for instance, activates the pattern recognition receptor TLR4 through LPS to trigger NF-κB-driven inflammation [174]. Its virulence factor Fap2 can also bind to galactose-N-acetyl-D-galactosamine (Gal-GalNAc), inducing tumor cells to secrete IL-8 and CXCL1, which further recruits immune cells to secrete pro-inflammatory cytokines [175, 176]. Moreover, the F. nucleatum metabolite ADP-heptose can also activate NF-κB through the ALPK1/TIFA/TRAF6 pathway, leading to increased IL-8 expression [177]. These processes reinforce tumor-associated inflammation.

Beyond promoting inflammation, CRC-associated bacteria can also foster an immunosuppressive tumor microenvironment. Th17-driven signaling can induce CXC chemokine production and recruit myeloid cells, including myeloid-derived suppressor cells (MDSCs), into the tumor microenvironment [178, 179]. MDSCs suppress effector T cells through mechanisms such as arginase production and induction of Treg cell differentiation, thus fostering immunosuppression [180, 181]. F. nucleatum further protects tumor cells from immune-mediated killing through Fap2- and CbpF-mediated binding to the inhibitory receptors TIGIT (T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain) [182] and CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1) [183] on natural killer (NK) cells and T cells. Another adhesin, RadD, can bind Siglec-7 (sialic-acid-binding immunoglobulin-like lectin 7) on NK cells and exert immunosuppressive effects as well [184]. In addition, F. nucleatum promotes TLR4-dependent M2 macrophage polarization [185, 186] and selectively recruits immunosuppressive myeloid-derived cells, including MDSCs, tumor-associated neutrophils (TANs), tumor-associated macrophages (TAMs), and immature dendritic cells (DCs) [168], thereby further shaping a pro-tumor microenvironment [187]. These mechanisms allow CRC-associated microbes to weaken anti-tumor immune surveillance and promote immune evasion.

Conversely, the gut microbiota can also enhance anti-tumor immunity. A high abundance of Lachnospiraceae is associated with higher immune scores in advanced CRC [188] and preserves CD8+ T cell immune surveillance by degrading inhibitory lysoglycerophospholipids [189]. L-arginine from Bifidobacterium pseudolongum promotes memory CD8+ T cell formation and suppresses colorectal cancer progression [190]. Lactobacillus gallinarum enhances CD8 + T cell function and restrains CD4+ Treg differentiation by blocking the IDO1 (indoleamine 2,3-dioxygenase 1)/Kyn/AhR axis via indole-3-carboxylic acid (ICA) [191]. Faecalibacterium prausnitzii produces tyrosol to inhibit HIF-1α (hypoxia-inducible factor 1α)/NF-κB signaling, thereby reducing ROS and inflammatory cytokines and exerting anti-tumor effects [192]. In addition, Lactobacillus intestinalis induces tumor-derived CCL5 via NOD1/NF-κB signaling, thereby promoting dendritic cell recruitment and suppressing colorectal tumorigenesis [193]. Interestingly, even F. nucleatum, a bacterium more commonly linked to CRC progression, may under specific conditions contribute to anti-tumor immunity. Intratumoral F. nucleatum can enhance anti-PD-1 (programmed cell death 1) responses in microsatellite-stable CRC through butyrate-mediated relief of CD8+ T cell exhaustion [194], and may also promote neutrophil cytotoxicity by activating Siglec-14-dependent tumor cell killing in a host genotype-dependent manner [195]. These seemingly contradictory findings underscore that the effects of F. nucleatum in CRC are highly context-specific and may depend on its spatial and ecological niche within tumors, the tumor molecular and therapeutic setting, and host genetic regulation of immune responsiveness. More broadly, they suggest that microbiota-immune interactions in CRC are better understood as conditional and state-dependent rather than uniformly tumor-promoting or tumor-suppressive.

Metabolism

Gut microbiota can metabolize host-derived and dietary substrates into a wide range of bioactive compounds that influence CRC initiation and progression [196, 197] (Fig. 4d). Among these microbiota-derived metabolites, SCFAs and secondary bile acids (SBAs) are the most extensively studied classes.

SCFAs, such as acetate, butyrate, and propionate, are produced by bacterial fermentation of indigestible carbohydrates in the colon [198]. They are generally thought to protect against CRC through immune modulation, especially butyrate [199]. By engaging receptors such as FFAR2 (free fatty acid receptor 2, also called GPR43) and GPR109A on epithelial and immune cells, they reinforce barrier integrity and enhance anti-tumor immunity [164, 200, 201]. As HDAC inhibitors, SCFAs also regulate Tregs and CD8+ T cells while suppressing tumor proliferation and promoting apoptosis [66, 68, 202]. Consistently, butyrate-producing bacteria and fecal butyrate levels are reduced in CRC [203], and lower SCFA levels are associated with increased CRC risk [204]. Butyrate may also enhance anti-PD-1 efficacy [205] and potentiate the pro-ferroptotic effect of oxaliplatin [206]. However, butyrate can also exert context-dependent pro-tumorigenic effects. For example, enrichment of specific butyrate-producing bacteria such as Porphyromonas spp. may increase local butyrate exposure and induce epithelial senescence and a senescence-associated secretory phenotype, thereby creating a tumor-promoting inflammatory microenvironment [207]. This apparent paradox likely reflects differences in host genetic background, microbial source, and epithelial metabolic state, which together determine whether butyrate functions predominantly as a homeostatic metabolite or as a pro-tumorigenic signal [208, 209].

Most bile acids are reabsorbed at the end of the ileum, but about 5%–10% enter the colon for further microbial metabolism [71]. Through the sequential actions of bile salt hydrolase [210] and bai operon-encoded 7α-dehydroxylase [211], bile acids undergo dehydroxylation to form SBAs, such as deoxycholic acid and lithocholic acid [212]. SBAs can promote tumorigenesis [71, 213] by activating carcinogenic signaling pathways [214, 215], inducing DNA damage [216, 217], and inhibiting anti-tumor immunity [218, 219]. They also promote CRC-associated dysbiosis, which can be alleviated by antibiotic-mediated microbiota depletion [220, 221]. These effects are mediated in part by bile acid receptors, particularly FXR [222, 223]. Supporting this, high colonic SBA levels in individuals with high-fat diets have been associated with increased CRC risk [224], and fecal metagenomic analyses further support enrichment of bile acid metabolism-related microbial signatures in CRC [225]. In contrast, ursodeoxycholic acid (UDCA), produced by Ruminococcus gnavus [226], appears protective against CRC, mainly through activation of the bile acid receptor TGR5 [227, 228]. Recent evidence further shows that the microbial bile acid 3-oxo-LCA (3-oxo-lithocholic acid) activates FXR signaling to inhibit cancer stem cell proliferation and induce apoptosis, highlighting its therapeutic potential in intestinal tumorigenesis [229].

Additionally, other metabolites such as hydrogen sulfide [230, 231], tryptophan metabolites [232–234], and polyamines [235, 236] have also been implicated in CRC. These findings indicate that CRC-associated microbial metabolism extends beyond SCFAs and SBAs, pointing to a broader network that may influence tumor initiation, progression, and therapeutic response.

Other gastrointestinal diseases

Inflammatory Bowel Disease (IBD)

Inflammatory bowel disease (IBD), a heterogeneous group of inflammatory diseases including ulcerative colitis (UC) and Crohn’s disease (CD) [237], is characterized by gut microbiota dysbiosis. This dysbiosis is typically marked by depletion of protective SCFA-producing bacteria, such as Faecalibacterium prausnitzii and Roseburia spp., and enrichment of pathobionts, including Enterobacteriaceae, Enterococcus spp., and Fusobacterium spp. [238, 239]. Transfer of microbiota from patients with CD to germ-free mice can induce colitis, further supporting a contributory role of the gut microbiota in IBD [240].

Under physiological conditions, commensal microbes maintain epithelial homeostasis and barrier integrity by regulating mucus secretion, preserving tight junctions, and producing beneficial metabolites. In IBD, disruption of these functions impairs barrier defense and promotes disease progression. In particular, depletion of SCFA-producing commensals reduces butyrate availability, which can compromise epithelial energy supply and tight junction stability [241–243]. Meanwhile, expansion of pathobionts can directly damage the epithelial barrier. Adherent-invasive Escherichia coli (AIEC) can adhere to and invade intestinal epithelial cells through adhesin-mediated interactions, such as FimH binding to cell adhesion molecule 6 receptor, and persist intracellularly, thereby increasing intestinal permeability [244, 245], whereas Enterococcus faecalis impairs epithelial integrity through gelatinase-mediated cleavage of E-cadherin [246].

Dysbiosis also amplifies intestinal inflammation and sustains disease activity through immune dysregulation [247]. AIEC can persist within macrophages and induce pro-inflammatory cytokine production [245, 248], and Ruminococcus gnavus has been linked to TNFα induction [249]. F. nucleatum can further exacerbate epithelial injury and inflammatory responses by inducing acetyl-CoA accumulation and activating STAT3 signaling [250]. The Th17/Treg imbalance observed in IBD is another important immune feature. It is characterized by increased Th17 responses and reduced Treg-mediated regulation, contributes to exaggerated mucosal immune activation, and is closely linked to microbial alterations. Reduced abundance of Clostridium spp. and Bacteroides fragilis has been implicated in impaired Treg regulation [251, 252], while segmented filamentous bacteria promote Th17 differentiation and IL-17/IL-22 production [62]. Oral-derived pathobionts such as Porphyromonas gingivalis can reshape gut microbial composition and suppress linoleic acid metabolism, thereby promoting Th17 differentiation while constraining Treg differentiation [253]. Conversely, Roseburia intestinalis promotes dendritic cell-mediated Treg differentiation through TLR5 signaling, suggesting that its depletion may likewise contribute to immune imbalance and intestinal injury [254].

Notably, dysbiosis-associated metabolic disturbances, including alterations in SCFAs, bile acids, and tryptophan metabolites, also play important roles in shaping immune responses and promoting inflammation [125, 247]. For example, microbiota-derived indole-3-propionic acid (IPA) is reduced in patients with IBD and can limit mucosal inflammation by promoting apoptosis of Th1/Th17 cells [255]. Likewise, depletion of Odoribacter splanchnicus in colitis may impair microbial secondary bile acid transformation, thereby reducing the suppression of neutrophil extracellular trap formation and aggravating mucosal inflammation [256]. In addition, recent studies suggest that gut microbes can generate bioactive H₂S from sulfur-containing substrates via assimilatory sulfate reduction, linking disordered microbial sulfur metabolism to epithelial injury and chronic intestinal inflammation [257]. Together, barrier dysfunction and excessive immune activation drive the onset, persistence, and recurrence of chronic intestinal inflammation.

Irritable Bowel Syndrome (IBS)

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized by recurrent abdominal pain associated with altered bowel frequency and/or stool form in the absence of overt structural abnormalities [258, 259]. Accumulating evidence suggests that gut microbiota dysbiosis is involved in IBS pathophysiology, with IBS-associated dysbiosis generally characterized by reduced microbial diversity, depletion of protective commensals, and enrichment of symptom-associated taxa [260]. However, compared with other inflammatory or structural gastrointestinal diseases, IBS-related microbial alterations are more heterogeneous and lack disease-specific signatures, which may reflect differences across subtypes, including diarrhea-predominant IBS (IBS-D) and constipation-predominant IBS (IBS-C), as well as marked interindividual variability [260–262].

Mechanistically, beyond mild barrier dysfunction and mucosal immune activation, the more distinctive microbiota-related features of IBS involve effects on visceral sensation, intestinal motility, and gut–brain axis signaling [263, 264]. Dysbiosis can impair barrier integrity, allowing translocation of bacterial products or components into the subepithelial compartment and trigger low-grade mucosal immune activation, particularly involving mast cells [265]. These immune mediators can sensitize enteric neurons and contribute to visceral hypersensitivity [265, 266]. At the same time, microbial metabolites and immune signals may alter bidirectional gut–brain communication by modulating enteric neural activity, vagal signaling, and central processing of visceral stimuli, which may further amplify symptom perception in IBS [267, 268]. Such pathophysiological alterations may persist for years [269]. Microbial metabolic disturbances also shape symptom onset and exacerbation in IBS [270]. Disordered bile acid metabolism is an important mechanism, particularly in IBS-D [261, 271]. Impaired conversion of primary to secondary bile acids and bile acid overproduction, associated with increased Escherichia coli and Clostridia and reduced Clostridium leptum and Bifidobacterium, may lead to the accumulation of primary bile acids in the intestinal lumen, thereby stimulating fluid secretion and accelerating intestinal transit [270–272]. In IBS-C, increased abundance of methanogens such as Methanobrevibacter smithii has been observed [262, 273]. Methane delays ileal and colonic transit and reduces contractile amplitude, thereby slowing peristalsis and contributing to constipation [262, 274]. In addition, other microbiota-related alterations, including disturbed tryptophan metabolism and abnormal fermentation, may further shape IBS symptom patterns [270, 275]. Overall, given the heterogeneity and complexity of IBS, the effects of gut microbiota are difficult to generalize. The microbiota in IBS is more appropriately viewed as a modulator of disease phenotype and symptom severity than as a primary driver of disease initiation.

Gut microbiota in extra-intestinal diseases: the gut–organ axis

Gut–liver axis

The gut and liver are intimately connected both anatomically and functionally, forming a bidirectional gut–liver axis [276–278]. From an anatomical perspective, intestinal blood drains into the liver through the portal venous system, which allows the liver to sense and process gut-derived nutrients, microbial metabolites, and bacterial components [276, 277, 279]. Functionally, enterohepatic bile acid circulation is central to this interaction. Primary bile acids synthesized in the liver are converted by the gut microbiota into secondary bile acids, which not only facilitate lipid digestion and absorption but also shape microbial composition and feed back to regulate intestinal and hepatic physiology [280, 281]. This tightly regulated crosstalk helps maintain metabolic homeostasis, immune balance, and barrier integrity, supporting the importance of gut microbial homeostasis for liver health. When gut microbiota dysbiosis develops, this communication can shift from a physiological to a pathological state.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

In metabolic dysfunction-associated steatotic liver disease (MASLD, also termed nonalcoholic fatty liver disease, NAFLD), the contribution of the gut microbiota is particularly evident in metabolic dysregulation and chronic inflammatory activation [282–284]. At the metabolic level, dysbiosis can disrupt bile acid metabolism by increasing hydrophobic toxic bile acids while suppressing intestinal FXR signaling and fibroblast growth factor 19 (FGF19) expression, thereby relieving the negative feedback inhibition of hepatic cholesterol 7α-hydroxylase (CYP7A1) and promoting bile acid pool expansion and hepatocellular lipotoxicity [285, 286]. Within this context, a recent study further showed that the microbial bile acid 3-sucCA (3-succinylated cholic acid), which mitigates metabolic dysfunction-associated steatohepatitis (MASH) by enriching Akkermansia muciniphila, is reduced in MASLD patients [36]. At the same time, depletion of SCFA-producing bacteria weakens the protective effects of short-chain fatty acids. However, when SCFAs exceed the host metabolic threshold, they may indirectly promote hepatic lipid deposition by serving as substrates for lipogenesis and activating GPR41/43 [287, 288]. Dysbiosis also alters other microbial metabolic pathways relevant to hepatic lipid accumulation and injury. LPS and pro-inflammatory cytokines can activate IDO, shifting tryptophan metabolism from the beneficial indole pathway toward the kynurenine pathway [289, 290]. In addition, anaerobic bacteria can produce substantial amounts of endogenous ethanol, directly inducing oxidative damage in hepatocytes [291, 292]. Trimethylamine (TMA)-producing bacteria can also metabolize choline into TMA, which is subsequently converted in the liver to TMAO, thereby reducing choline availability and promoting hepatic lipid accumulation [293, 294].

At the inflammatory level, barrier dysfunction further increases hepatic exposure to LPS and other pathogen-associated molecular patterns (PAMPs), thereby enhancing TLR-mediated inflammatory signaling, including NLRP3 inflammasome assembly and innate immune activation [295, 296]. Gut-derived high-density lipoprotein subspecies HDL3 normally restrains LPS-driven hepatic inflammation by preventing the interaction between LPS and LPS-binding protein (LBP), whereas this protective effect is weakened during MASLD progression [297]. Collectively, gut microbiota dysbiosis may contribute to MASLD progression from simple steatosis to steatohepatitis and fibrosis through metabolic dysregulation and chronic inflammatory activation.

Primary Sclerosing Cholangitis (PSC)

In primary sclerosing cholangitis (PSC), gut microbiota dysbiosis is closely linked to aberrant gut–liver immune crosstalk [298, 299]. The close association between PSC and IBD suggests that persistent activation of mucosal immunity can contribute to biliary injury through the gut–liver axis [298]. Following mucosal immune activation, dendritic cells process antigens and imprint gut-homing properties on T cells, including α4β7 integrin and CCR9 [300, 301]. In PSC, the liver aberrantly expresses the corresponding ligands, MAdCAM-1 and CCL25, thereby promoting the recruitment of gut-primed lymphocytes and contributing to peribiliary inflammation and tissue injury [300, 301]. This pathogenic process may be reinforced by PSC-associated dysbiosis, which is characterized by reduced microbial diversity and enrichment of potentially pro-inflammatory taxa such as Veillonella, Enterococcus, and Streptococcus [298, 299]. Such dysbiosis may sustain intestinal immune activation and enhance gut-derived inflammatory signaling [298, 299]. Upon exposure to gut-derived PAMPs, cholangiocytes respond through pattern recognition receptors and produce chemokines and cytokines, which further recruit and activate local immune cells and promote inflammation and periductal fibrosis [302, 303]. Moreover, shared T-cell clonotypes have been identified in the liver and intestine of patients with PSC, supporting the idea that antigen-driven adaptive immune responses may operate across both organs [298, 304]. Overall, these findings suggest that, in PSC, gut microbiota dysbiosis may promote biliary inflammation, fibrosis, and liver injury by sustaining abnormal immune communication between the intestine and liver.

Cirrhosis

Cirrhosis can be viewed as a more advanced stage of gut–liver axis dysfunction, in which dysbiosis is no longer confined to a local intestinal abnormality but is closely linked to decompensation and multiple complications [276, 305]. Typical features include depletion of commensals such as Lachnospiraceae and Ruminococcaceae, together with enrichment of potentially pathogenic taxa, including Enterobacteriaceae, Enterococcaceae, and Streptococcaceae [306, 307]. This dysbiotic state can weaken colonization resistance, promote small intestinal bacterial overgrowth, facilitate recurrent translocation of bacteria and their products, and maintain systemic exposure to endotoxins and other gut-derived harmful molecules [308]. At the same time, portal hypertension, intestinal edema, delayed transit, reduced bile flow, and impaired hepatic clearance further aggravate this imbalance, creating a self-reinforcing cycle between gut ecological disruption and worsening liver function [277, 309]. This cycle may drive progression from compensated to decompensated cirrhosis. In addition, cirrhosis-associated dysbiosis may contribute to the development of related complications. For example, it can disturb intestinal nitrogen and ammonia metabolism, increase the burden of hyperammonemia, and promote hepatic encephalopathy [310, 311].

Gut–brain axis

The intestinal microbiota and the central nervous system maintain continuous and dynamic bidirectional communication through the microbiota–gut–brain axis (MGBA), which is mediated by microbial metabolites, immune signaling, hormone-like signals released by enteroendocrine cells (EECs), and peripheral nerves, particularly vagal afferent pathways [90, 312]. Microbial metabolites can influence central nervous system function by acting on the blood–brain barrier and various target cells within the brain [80, 312]. Furthermore, the regulatory effects of the gut microbiota on local and peripheral immune systems can reshape the central neuroimmune environment through cytokines, chemokines, and other immune mediators [313]. Concurrently, EECs can sense microbial and metabolic signals and release diverse hormone-like molecules that modulate neural activity and behavioral responses [314]. Peripheral sensory nerves innervating the gut provide a rapid pathway for transmitting intraluminal signals to the central nervous system. Conversely, the central nervous system can regulate gut motility, secretion, barrier integrity, mucosal immunity, and microbial ecology via the hypothalamic–pituitary–adrenal (HPA) axis and peripheral efferent nerves [90]. When gut microbial homeostasis is disrupted, this finely tuned bidirectional physiological communication may progressively shift toward pathological imbalance, thereby contributing to neurological dysfunction and disease susceptibility.

Autism Spectrum Disorder (ASD)

In neurodevelopmental disorders, particularly autism spectrum disorder (ASD), the MGBA is closely involved in early-life immune programming [315]. Individuals with ASD commonly show reduced gut microbial diversity and lower levels of beneficial bacteria, which correlate with gastrointestinal symptoms and the severity of behavioral symptoms [315, 316]. Recent work has shown that ASD model mice (BTBR strain) display abnormal accumulation of brain-resident CD4+ T cells [317]. These cells can promote neuroinflammation through the production of pro-inflammatory cytokines [317]. Depletion of these T cells or maintenance of mice under germ-free conditions can ameliorate ASD-related behaviors, supporting a causal link along a gut microbiota–brain immune cell–behavior axis [317]. Metabolically, specific microbial metabolites, such as 4-ethylphenyl sulfate (4-EPS) and p-cresol sulfate (pCS), have been implicated in abnormal neurodevelopmental processes, including altered myelination and synaptic function [318]. Additionally, individuals with ASD often present with an imbalance in the glutamate/GABA ratio, reflecting an excitation–inhibition imbalance that is considered relevant to core ASD symptoms [319]. The gut microbiota may contribute to the maintenance of this balance by producing or modulating neurotransmitter precursors [320]. These MGBA-related mechanisms may be especially important during the perinatal period and early infancy, when patterns of microbial colonization may exert long-lasting programming effects on social behavior and stress responsiveness by shaping microglial maturation and the neuroimmune microenvironment [321].

Parkinson’s Disease (PD)

In neurodegenerative disorders, Parkinson’s disease (PD) provides a distinctive framework for understanding the role of the MGBA in the propagation of protein pathology [322, 323]. The pathological hallmarks of PD include the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the abnormal aggregation of α-synuclein into Lewy bodies [322, 323]. Gastrointestinal dysfunction, particularly constipation, often precedes motor symptoms by years or even decades [324], which is consistent with the Braak hypothesis that PD may, at least in part, originate in the gut [325, 326]. Unlike Alzheimer’s disease, where MGBA-related mechanisms are often discussed in the context of chronic inflammation-associated protein aggregation, the MGBA in PD is more specifically centered on the initiation of α-synuclein pathology in the gut and its subsequent retrograde spread along the gut–brain axis [316]. EECs, which are chemosensory cells within the intestinal epithelium, endogenously express α-synuclein and form synapse-like connections with enteric neurons and vagal afferent terminals, forming a potential anatomical interface between the intestinal environment and the central nervous system [314]. Gut microbial dysbiosis can increase exposure to bacterial components and inflammatory stimuli, which may promote local innate immune activation and oxidative stress, and create a permissive microenvironment for α-synuclein misfolding and aggregation [327, 328]. These aberrantly folded proteins may then spread retrogradely in a prion-like manner via the vagus nerve to the dorsal motor nucleus and subsequently to other brain regions, including the substantia nigra [322, 323, 329]. Under conditions of impaired intestinal and blood–brain barrier integrity, bacterial products and microbial metabolites may also activate microglia and astrocytes and interfere with α-synuclein clearance, further amplifying neuroinflammatory responses [330]. Overall, current evidence supports a model in which gut dysbiosis may promote early intestinal α-synuclein pathology, followed by gut-to-brain propagation and chronic neuroinflammation, and ultimately to progressive dopaminergic neurodegeneration. This framework helps explain why gastrointestinal symptoms often precede motor manifestations and provides a rationale for further exploration of microbiota-targeted strategies in PD.

Major Depressive Disorder (MDD)

Major depressive disorder (MDD) is a prototypical affective disorder in which microbiota dysbiosis has been linked to chronic low-grade inflammation, altered tryptophan metabolism, and dysregulation of the HPA axis [331, 332]. Dysbiosis can impair intestinal barrier homeostasis, promoting LPS translocation into the circulation and systemic pro-inflammatory signaling, thereby sustaining peripheral low-grade inflammation [80, 331]. This inflammatory state not only disrupts blood–brain barrier integrity and the central immune milieu, but also enhances IDO activity, diverting tryptophan metabolism from the relatively mood-supportive 5-hydroxytryptamine (5-HT) pathway toward the kynurenine pathway [333, 334]. As a result, the availability of neurotransmitter precursors is reduced, while potentially neurotoxic intermediates accumulate [335, 336]. In parallel, gut dysbiosis can further disrupt emotional regulation by altering the production, bioavailability, and signaling of GABA, dopamine, norepinephrine, and their precursors [320, 332]. In addition, the gut microbiota is increasingly recognized as an important regulator of HPA axis programming and stress reactivity [337]. Under inflammatory conditions, persistent HPA axis dysregulation may result in chronically elevated and poorly controlled cortisol levels [338]. Importantly, MGBA dysfunction in MDD is characterized by a bidirectional amplification loop in which chronic stress and heightened HPA axis reactivity further increase intestinal permeability, alter gut motility, and disrupt microbial composition, whereas persistent dysbiosis, in turn, exacerbates inflammatory burden and stress sensitivity [332, 339]. Together, these processes link immune activation, metabolic disturbance, and neuroendocrine dysregulation in a self-reinforcing cycle that may contribute to MDD pathophysiology.

Gut–endocrine axis

The gut–endocrine axis is a bidirectional communication network linking the gut microbiota, enteroendocrine cells, neural circuits, and peripheral endocrine organs. Within this axis, microbiota-derived metabolites, particularly SCFAs, bile acid derivatives, and tryptophan metabolites, act as important signaling mediators that regulate enteroendocrine hormone secretion and thereby influence systemic endocrine homeostasis [127, 340]. Enteroendocrine cells, such as L and K cells, sense luminal nutritional and microbial cues and secrete hormones including GLP-1, PYY, and GIP, linking the intestinal microbial environment to appetite regulation, insulin secretion, glucose metabolism, and energy homeostasis [341]. Gut-derived hormonal and metabolic signals can also be sensed through vagal and neuroendocrine pathways, extending the regulatory influence of the gut microbiota on host endocrine function through the hypothalamic–pituitary–adrenal (HPA), hypothalamic–pituitary–thyroid (HPT), and hypothalamic–pituitary–gonadal (HPG) axes [342].

Type 2 Diabetes Mellitus (T2DM)

In type 2 diabetes mellitus (T2DM), dysfunction of the gut–endocrine axis involves not only dysbiosis-induced impairment of intestinal barrier integrity and chronic inflammation, but more importantly a reduced capacity to convert luminal microbial and nutritional cues into endocrine regulatory signals [343]. T2DM-associated dysbiosis is often accompanied by depletion of butyrate-producing bacteria and reduced SCFA biosynthesis [344], which may weaken SCFA-mediated activation of GPR41/43 on L cells and thereby reduce GLP-1 secretion [86]. Concurrently, dysbiosis-related disturbances in bile acid metabolism may disrupt TGR5-dependent incretin release, further blunting postprandial gut hormone responses [345]. In contrast, certain microbial metabolites, such as high concentrations of acetate, may stimulate ghrelin release, thereby promoting appetite [346]. These alterations attenuate satiety signaling, impair gastric emptying control, accelerate postprandial glucose entry into the circulation, and weaken hormonal regulation of nutrient handling and postprandial energy metabolism [347]. As the major incretin hormones linking intestinal and pancreatic endocrine function, GLP-1 and GIP are essential for glucose-dependent insulin secretion [347]. Thus, reduced secretion or impaired action of these hormones compromises β-cell compensation in response to postprandial glucose stimulation [348]. Gut microbial metabolites may also directly influence glucose homeostasis. Because GPR41/43 receptors are expressed on β-cells, SCFAs may directly influence β-cell function [349]. Elevated branched-chain amino acid (BCAA) levels have been associated with insulin resistance and increased T2DM risk [350], while altered microbial carbohydrate metabolism, characterized by increased host-accessible monosaccharides in individuals with insulin resistance, may further contribute to metabolic dysfunction [351]. Moreover, dysbiosis may disturb bile acid-related signaling, thereby reducing adipose thermogenesis and white adipose tissue browning, while altering hepatic fatty acid oxidation and metabolic reprogramming [352]. These changes may reduce host energy expenditure, promote lipid accumulation, aggravate insulin resistance, and further contribute to the development and progression of T2DM [352].

Other gut–organ axes

Beyond the gut–liver, gut–brain, and gut–endocrine axes, gut microbiota dysbiosis has also been implicated in a broad range of extra-intestinal diseases through interconnected mechanisms [74]. Microbial-derived metabolites, including SCFAs, bile acid derivatives, tryptophan metabolites, trimethylamine N-oxide, and uremic toxins, can enter the portal or systemic circulation and influence metabolic homeostasis, inflammatory responses, and cellular function in distant organs [353]. These effects are especially relevant to the gut–heart and gut–kidney axes. TMAO has been linked to vascular inflammation, atherosclerosis, hypertension, and heart failure [354, 355], whereas uremic toxins such as indoxyl sulfate and p-cresyl sulfate may aggravate chronic kidney disease and reinforce the vicious cycle between intestinal and renal dysfunction [356, 357].

Dysbiosis may also weaken intestinal barrier integrity and facilitate the translocation of bacteria and microbial components such as lipopolysaccharide into the circulation, which can amplify systemic inflammation and worsen distant organ injury [38]. In the gut–kidney axis, barrier disruption may accelerate systemic toxin exposure and promote renal damage [356, 358], while in the gut–heart axis, it may contribute to endothelial dysfunction and chronic vascular inflammation [359]. Within the gut–lung axis, translocated microbial products may act as gut-derived inflammatory signals, sustaining pulmonary immune dysregulation and disease progression [360, 361].

These alterations are frequently accompanied by immune dysregulation and persistent low-grade inflammation, which further translate gut-derived perturbations into organ-specific pathology [58]. This is especially apparent in the gut–lung axis, where dysbiosis and reduced protective metabolites may impair immune tolerance and reshape pulmonary innate and adaptive immunity [362, 363]. Such changes can promote airway inflammation and increase susceptibility to asthma, chronic obstructive pulmonary disease, and respiratory infections [362, 363]. Comparable immune remodeling has also been implicated in the gut–skin [364] and gut–bone axes [365], contributing to psoriasis and atopic dermatitis, as well as osteoporosis and bone loss.

Gut–organ communication is further modulated by neuroendocrine–metabolic reprogramming, including changes in autonomic and vagal signaling, gut hormone secretion, nutrient sensing, and host metabolic pathways [366]. Beyond the gut–brain and gut–endocrine axes, such mechanisms may also operate along the gut–reproductive axis, where gut microbiota dysbiosis has been linked to hormonal imbalance, ovarian dysfunction, and reproductive metabolic disturbances, thereby contributing to disorders such as polycystic ovary syndrome and gynecological cancer [367, 368]. Taken together, these examples point to an interconnected gut–organ network through which dysbiosis may affect extra-intestinal organs via metabolic, inflammatory, immune, and neuroendocrine signals.

Clinical applications and translational perspectives of the gut microbiota in disease

Building on mechanistic evidence linking the gut microbiota to disease, recent research has increasingly shifted toward clinical translation, with particular emphasis on biomarker development, microbiota-targeted interventions, and their potential in precision medicine. Consistent with this trend, microbiota-related clinical trials have increased substantially in recent years, reflecting growing translational interest across multiple disease areas (Fig. 5).

Fig. 5 — Clinical trials of gut microbiota-related research. This figure summarizes the overall landscape of gut microbiota-related clinical trials registered in ClinicalTrials.gov. Data were updated through April 2026. a Cumulative number of registered studies. Cumulative number of registered studies over time. b Clinical trials by disease category and phase. Number of registered studies across disease categories and clinical phases.

Microbiota-based biomarkers

Microbiota-based biomarkers represent a major area of microbiome clinical translation [11, 369] (Fig. 6). Compared with conventional single-molecule biomarkers, microbiota-based biomarkers can capture disease-associated alterations at multiple levels, including microbial composition, functional potential, and metabolite profiles, and therefore provide richer biological information [370]. Many of these signatures are also accessible through noninvasive fecal samples, which makes them attractive for disease screening, adjunctive diagnosis, patient stratification, and longitudinal monitoring [11, 369]. Their clinical value, however, does not lie simply in describing increases or decreases in specific microbial taxa, but in whether such signatures reliably reflect disease-relevant biological processes and complement existing clinical assessment tools [12, 371].

The clinical utility of gut microbiota-based biomarkers is currently primarily evident in disease detection and classification, risk stratification and prognostic assessment, and prediction of therapeutic response. For disease detection and classification, gut microbial signatures have shown potential as noninvasive tools, particularly in disorders such as IBD and CRC. Patients with IBD exhibit marked alterations in microbial composition and function compared with healthy individuals, while UC and CD may also display partially distinct microbial features [371–373]. For example, IBD is often characterized by depletion of beneficial commensals and SCFA-related metabolic disturbances, with some microbial alterations showing subtype preference, such as a stronger association of Escherichia coli with CD in certain cohorts [371, 372]. These findings support the use of microbiota-related signatures as adjunctive tools alongside endoscopy, imaging, and conventional inflammatory markers. In CRC, carcinogenesis-associated microbes and metabolic disturbances also show potential as biomarkers for early screening and risk identification, and may improve detection efficiency when integrated with established screening approaches [225, 374, 375].

Beyond diagnosis, microbiota-based biomarkers may reflect disease activity and prognostic risk. Patterns of dysbiosis, altered functional pathways, or disturbed metabolite profiles may correlate with disease activity, relapse tendency, complication risk, disease progression, or stage-specific differences, thereby supporting patient stratification and management [376–378]. For example, microbiome alterations have been implicated in the predisease and progressive phases of IBD [376, 377]. Reproducible microbial signatures have also been linked to CRC progression and stage-specific stratification, with Parvimonas micra and Fusobacterium nucleatum increasing from stage I onward, whereas Akkermansia muciniphila and Parabacteroides distasonis appear to be more enriched in late-stage CRC [378].

Another important application is prediction of therapeutic response. Baseline microbial states and metabolic capacity may partly explain heterogeneous responses to dietary interventions, metabolic therapies, and cancer immunotherapy [379–382]. For instance, gut microbiome features may help predict personalized responses to dietary fiber intervention in prediabetes [379] and are also being explored as biomarkers of response to immune checkpoint inhibitors across multiple cancers [380–382]. Overall, microbiota-based biomarkers may provide complementary biological information to refine clinical interpretation and individualized disease management.

Microbiota-targeted interventions

Beyond biomarker applications, the gut microbiota has emerged as a promising therapeutic target (Fig. 6). Current microbiota-targeted interventions aim to restore microbial balance, recover beneficial microbial functions, and re-establish host–microbiota homeostasis. Representative completed clinical trials across different disease contexts and intervention strategies are summarized in Table 1, highlighting the translational potential of microbiota-based therapies.

Table 1.

Representative completed clinical trials of microbiota-targeted interventions

Study (NCT)	Disease	Microbiota intervention	Study design	Phase	Key clinical outcome	Main findings	Translational significance	Ref
Fresh vs frozen FMT for recurrent CDI (NCT01398969)	Recurrent Clostridioides difficile infection	Fresh FMT vs frozen-and-thawed FMT	Randomized, double-blind, noninferiority trial (n = 232)	PHASE2	Clinical resolution of diarrhea without relapse at 13 weeks and adverse events	Frozen FMT was non-inferior to fresh FMT for clinical resolution of CDI, with no significant differences in adverse events	Supports the transition from fresh to standardized FMT, advancing the clinical translation of microbiota-based therapies in rCDI	[383]
RBX2660 for recurrent CDI (PUNCHCD3) (NCT03244644)	Recurrent Clostridioides difficile infection	Microbiota-based therapy (RBX2660) vs placebo	Randomized, double-blind, placebo-controlled trial (n = 289)	PHASE3	Absence of CDI diarrhea within 8 weeks	RBX2660 improved treatment success compared with placebo and showed sustained response through 6 months, with an acceptable safety profile	Represents an FDA-approved standardized microbiota-based therapeutic for preventing rCDI recurrence, highlighting the clinical maturation of microbiota-based therapy	[384, 385]
SER-109 vs placebo for recurrent CDI (ECOSPOR III) (NCT03183128)	Recurrent Clostridioides difficile infection	Microbiota-based therapy (SER-109) vs placebo	Randomized, double-blind, placebo-controlled trial (n = 182)	PHASE3	Recurrence of CDI up to 8 weeks	SER-109 significantly reduced CDI recurrence compared with placebo, with an acceptable safety profile	Demonstrates the efficacy of an FDA-approved oral microbiota-based therapeutic for preventing rCDI recurrence, further advancing standardized microbiota therapy beyond conventional delivery approaches	[386]
VE303 for prevention of recurrent CDI (NCT03788434)	Recurrent Clostridioides difficile infection	Defined bacterial consortium (VE303) vs placebo	Randomized, double-blind, placebo-controlled, dose-ranging trial (n = 79)	PHASE2	Recurrence of CDI at 8 weeks using a combined clinical and laboratory definition	High-dose VE303 reduced CDI recurrence compared with placebo, while a further phase 3 validation is needed	Supports defined bacterial consortia as a standardized next-generation microbiota therapy for preventing CDI recurrence	[387]
FMT for ulcerative colitis (NCT01896635)	Ulcerative colitis	FMT vs placebo	Multicentre, randomized, double-blind, placebo-controlled trial (n = 85)	PHASE2	Steroid-free clinical remission with endoscopic remission or response (Mayo score-based) at week 8	FMT increased clinical remission and endoscopic response compared with placebo in active ulcerative colitis	Supports FMT as a potential microbiota-based therapy for UC	[388, 389]
Fecal biotherapy for induction of remission in ulcerative colitis (NCT01545908)	Ulcerative colitis	FMT vs placebo	Randomized, double-blind, placebo-controlled trial (n = 75)	PHASE2	remission of UC (Mayo score-based) at week 7	FMT induced remission in a higher proportion of patients with active ulcerative colitis than placebo, with similar adverse event rates	Supports FMT as an investigational microbiota-based therapy for UC, while highlighting the potential importance of donor- and disease-duration-related effects	[390]
FMT plus dietary fiber in ulcerative colitis (NCT03998488)	Ulcerative colitis	FMT vs placebo, with or without psyllium fiber	Randomized, triple-blind, crossover trial (n = 27)	PHASE2	Clinical response (Mayo score-based) at week 8	FMT improved clinical response, remission, and endoscopic outcomes compared with placebo, while psyllium fiber did not further improve clinical outcomes	Evaluates the transition from FMT alone to combined microbiota–dietary modulation strategies in UC, while highlighting donor-dependent engraftment as a key determinant of response	[391]
FMT to enhance immune checkpoint therapy in renal cell carcinoma (NCT04758507)	Renal cell carcinoma	FMT vs placebo, with pembrolizumab and axitinib	Randomized, double-blind placebo-controlled trial (n = 50)	PHASE2	12-month progression-free survival (PFS), with median PFS and median overall survival, objective response rate (ORR), safety and microbiome changes as secondary outcomes	Donor FMT from complete responders to immunotherapy did not significantly improve the primary endpoint of 12-month PFS but did significantly improve median PFS versus placebo FMT	Highlights the potential of microbiota modulation to improve immune checkpoint inhibitor therapy in cancer	[392]
FMT plus pembrolizumab in melanoma (NCT03341143)	Melanoma	FMT with Pembrolizumab	Single-arm clinical trial (n = 16)	PHASE2	Objective response rate (ORR) up to 3 years	FMT with pembrolizumab induced clinical responses in a subset of anti-PD-1–refractory melanoma patients, accompanied by donor microbiota engraftment and tumor immune remodeling	Suggests a potential role for FMT in improving anti-PD-1 responsiveness in selected patients, while supporting larger trials to define predictive biomarkers and responsive microbial consortia	[393]
Probiotic for prevention of irinotecan-induced diarrhea in CRC (NCT01410955)	Colorectal cancer	Probiotics vs placebo	Multicentre, randomized, double-blind, placebo-controlled trial (n = 46)	PHASE3	Prevention of grade 3–4 diarrhea up to 2 years	Probiotics in patients with CRC treated with irinotecan-based chemotherapy were safe and could lead to a reduction in the incidence and severity of gastrointestinal toxicity, while further phase 3 with adequate sample size is needed	Provides early randomized evidence for microbiota-based strategies to mitigate chemotherapy-induced gastrointestinal toxicity in colorectal cancer	[394]
Synbiotic therapy for radiation-induced gut injury in rectal cancer (NCT03420443)	Colorectal cancer	Prebiotic/synbiotic supplementation vs no supplementation	Randomized, triple-blind, parallel-group trial (n = 30)	N/A	Radiation-induced gastrointestinal mucosal response (assessed by microbial diversity and inflammation) at 2 weeks	Synbiotic supplementation reduced radiation-induced mucosal inflammation and microbiota disruption, with effects primarily localized to intestinal tissue	Supports synbiotic intervention as a preventive strategy to mitigate radiotherapy-induced intestinal injury through microbiota modulation in rectal cancer	[395]
Probiotic supplementation for inflammatory modulation in CRC (NCT03782428)	Colorectal cancer	Probiotics vs placebo	Randomized, double-blind, placebo-controlled trial (n = 52)	N/A	Changes in circulating inflammatory cytokine levels at 6 months	Probiotics were safe and reduced pro-inflammatory cytokine levels in CRC patients after surgery	Suggests a potential role for probiotics as a microbiota-based adjunct to modulate persistent inflammation in colorectal cancer	[396]
Akkermansia muciniphila supplementation in metabolic syndrome (NCT02637115)	Overweight/obesity with insulin resistance	Live or pasteurized Akkermansia muciniphila vs placebo	Randomized, double-blind, placebo-controlled trial (n = 40)	N/A	safety, tolerability and metabolic parameters (insulin resistance, circulating lipids, visceral adiposity and body mass) at 3 months	Akkermansia muciniphila supplementation was safe and well tolerated. Pasteurized A. muciniphila improved insulin sensitivity and reduced selected metabolic parameters	Supports next-generation probiotics as a potential microbiota-based strategy for metabolic syndrome	[397]
FMT and fiber supplementation in obesity and metabolic syndrome (NCT03477916)	Obesity and metabolic syndrome	Oral lean-donor FMT vs placebo FMT, with cellulose or prebiotic fiber	Randomized, double-blind, placebo-controlled trial (n = 70)	PHASE2	Change in insulin sensitivity at 6 weeks	Oral FMT followed by low-fermentable fiber improved insulin sensitivity at 6 weeks, with associated changes in enteroendocrine responses, microbial ecology, and donor-microbe engraftment	Supports rational combination strategies integrating FMT with dietary substrates to guide defined microbiota-based therapeutics for metabolic disease	[398]
Low-FODMAP diet in IBS (NCT02107625)	Irritable bowel syndrome	Low-FODMAP diet vs traditional IBS dietary advice	Multicenter, randomized, single-blind, parallel-group trial (n = 75)	N/A	Symptom alleviation through the questionnaire IBS-SSS at 4 weeks	A diet low in FODMAPs reduced IBS symptoms as well as traditional IBS dietary advice. And subsequent fecal bacterial profiling showed that low-FODMAP diet altered bacterial profiles and that microbiota patterns were associated with dietary response	Supports dietary counselling as a feasible IBS management strategy and highlights the potential to integrate microbiota profiling with individualized nutritional guidance	[399, 400]
Bifidobacterium longum CECT 7347 (ES1) in IBS-D (NCT05339243)	Irritable bowel syndrome with diarrhea	Live or heat-treated ES1 vs placebo	Randomized double-blind, placebo-controlled trial (n = 200)	N/A	Change in total IBS-Symptom Severity Scale (IBS-SSS) score at 12 weeks	Both live ES1 and heat-treated ES1 significantly reduced IBS symptom severity, with improvements in stool consistency, quality of life, abdominal pain and anxiety scores	Supports strain-specific probiotic and postbiotic approaches as standardized microbiota-modulating strategies for IBS-D symptom management	[401]
Probiotic therapy for prevention of hepatic encephalopathy (NCT01110447)	Hepatic encephalopathy	Probiotic VSL#3 vs placebo	Randomized, double-blind, placebo-controlled trial (n = 130)	PHASE2/PHASE3	Development of overt HE in 6 months	VSL#3 reduced the risk of hospitalization for HE, as well as Child-Turcotte-Pugh and model for end-stage liver disease scores in patients with cirrhosis	Supports probiotic modulation of the gut–liver–brain axis as a feasible adjunctive strategy to reduce clinically relevant complications in cirrhosis	[402]
Synbiotic therapy for NAFLD (NCT01680640)	Non-alcoholic fatty liver disease	Synbiotic vs placebo	Randomized, double-blind, placebo-controlled trial (n = 104)	PHASE2	Change in liver fat, fibrosis scores, and the composition of the fecal microbiome at 12 months	Synbiotic supplementation altered the fecal microbiome but did not reduce liver fat content or fibrosis biomarkers	Provides clinical evidence that synbiotics can modulate the gut microbiota in NAFLD, informing the design of more targeted microbiota-based strategies with functionally relevant liver and inflammatory endpoints	[403]
FMT for Parkinson’s disease (NCT03808389)	Parkinson's disease	Donor FMT vs autologous FMT	Randomized, double-blind, placebo-controlled trial (n = 46)	PHASE2	Changes in clinical symptoms as scored on the MDS-UPDRS (Movement Disorder Society—Unified Parkinson's Disease Rating Scale) at 12 months	Healthy-donor FMT produced a greater improvement in MDS-UPDRS motor score than autologous FMT, with adverse events limited mainly to transient abdominal discomfort	Provides early clinical evidence for microbiome modulation in Parkinson’s disease and supports further evaluation of FMT across larger and more diverse patient cohorts	[404]
Adjunctive probiotic in depression (NCT03893162)	Major depressive disorder	Multi-strain probiotic “BioKult” vs placebo	Randomized, double-blind, placebo-controlled trial (n = 50)	N/A	Retention, acceptability, tolerability, and depressive/anxiety symptom scores at 8 weeks	Adjunctive probiotic treatment was acceptable and well tolerated, with improvements in depressive and anxiety symptoms	Supports microbiota–gut–brain axis modulation as a feasible adjunctive strategy for depression	[405]
Engineered microbial therapy (SYNB1618/SYNB1934) for phenylketonuria (NCT04534842)	Phenylketonuria	Engineered E. coli Nissle synthetic biotics SYNB1618 or SYNB1934	Open-label dose-escalation trial (n = 20)	PHASE2	Changes from baseline in labeled Phe (D5-Phe) in plasma at day 14	Both SYNB1618 and SYNB1934 reduced plasma Phe levels, and SYNB1934 also reduced fasting plasma Phe, with no serious adverse events or infections	Supports the clinical translation of engineered probiotics as programmable, standardized microbiota-based therapeutics for metabolic disease	[406]

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This table summarizes representative completed microbiota-targeted clinical trials across different disease contexts and intervention types, providing an overview of their clinical outcomes, main findings, and translational implications

Dietary modulation

Dietary modulation is one of the most common and readily applicable microbiota-targeted interventions [407–409]. By changing luminal nutrient availability, diet can reshape microbial composition and function, thereby influencing intestinal barrier integrity, immune homeostasis, and microbiota-related metabolic pathways involved in disease [407–409]. Consistent with this, a recent large-scale population-based metagenomic study further demonstrated that diet is strongly associated with gut microbial composition, diversity, and functional pathways, and highlighted its potential to guide personalized nutritional intervention [410].

Dietary intervention has attracted increasing attention in diseases associated with gut microbial dysbiosis [411, 412]. In IBD, studies have shown that enteral nutrition, specific carbohydrate restriction, and dietary patterns characterized by high fiber intake and low consumption of processed foods may help alleviate intestinal inflammation and are accompanied by changes in microbial composition and metabolic profiles [413, 414]. In IBS, a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) can reduce fermentable substrate load and relieve bloating, abdominal pain, and altered bowel habits [415, 416]. In metabolic disorders, healthy dietary patterns such as the Mediterranean diet are generally associated with greater microbial diversity, enrichment of SCFA-producing bacteria, reduced inflammatory tone, and improvements in insulin sensitivity, lipid metabolism, and energy homeostasis [417–419]. This suggests that dietary intervention may have therapeutic effects not only by changing microbial composition, but also by reshaping microbial function and host metabolic responses. Functional dietary components such as resistant starch, polyphenols, and dietary fiber may further enhance the microbiota-modulating effects by promoting SCFA production and regulating metabolic pathways involving bile acids and tryptophan [420–422]. Overall, dietary modulation represents an accessible microbiota-targeted strategy with considerable translational potential. However, its clinical effects are still shaped by interindividual variability, dietary adherence, and disease context.

Probiotics, prebiotics, synbiotics, and postbiotics

Probiotics, prebiotics, synbiotics, and postbiotics represent widely used biotic and biotic-derived microbiota-targeted interventions [423, 424]. Compared with overall dietary management, these approaches generally have more clearly defined components, more standardized modes of administration, and greater feasibility for clinical implementation. For this reason, they have been widely studied in gastrointestinal, metabolic, and certain extraintestinal diseases [423, 424].

Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host, with commonly used genera such as Lactobacillus and Bifidobacterium [425]. Their most established clinical applications are in diarrhea-related conditions, particularly antibiotic-associated diarrhea and some post-infectious functional gastrointestinal disorders [426, 427]. In IBD, some probiotic formulations have shown potential for maintaining remission in mild-to-moderate UC, whereas their efficacy in CD appears more limited [428, 429]. In IBS, probiotics may also help alleviate symptoms such as bloating, abdominal pain, and altered bowel habits, although their effects vary considerably across strains and formulations [430].

Prebiotics are substrates that are selectively utilized by host microorganisms and confer health benefits [431]. Common examples include inulin, fructooligosaccharides, galactooligosaccharides, resistant starch, and other fermentable dietary fibers [431, 432]. By promoting beneficial microbes such as Bifidobacterium, prebiotics can improve the intestinal microenvironment and support bowel and metabolic function [431, 432]. In individuals with constipation or irregular bowel habits, certain prebiotic formulations may increase stool frequency and improve stool consistency [433]. In metabolic disorders, prebiotics have been investigated as adjunctive approaches for improving glucose and lipid metabolism and reducing low-grade inflammation [434, 435]. Their effects, however, vary substantially among individuals, and in patients with IBS, some highly fermentable substrates may exacerbate symptoms such as bloating.

Synbiotics combine probiotics and prebiotics with the aim of enhancing the colonization, survival, and functional activity of beneficial microbes by providing functional strains together with their growth substrates, which may generate synergistic effects [436]. They have been investigated in diseases such as IBD, IBS, MASLD, and metabolic syndrome, with some studies suggesting improvements in symptom scores, inflammatory markers, or metabolic parameters [437, 438]. Before broader clinical use, however, stronger evidence is still needed, especially because of the substantial heterogeneity in strain combinations, substrate composition, and intervention duration across studies.

Postbiotics are preparations of inanimate microorganisms and/or their components that confer a health benefit on the host [439]. Compared with live biotic preparations, postbiotics generally offer advantages in stability and standardization and may be particularly attractive in settings where the use of live microorganisms raises safety concerns [440]. Postbiotics have shown promise in areas such as infant nutrition, intestinal inflammation, infection prevention, and metabolic intervention, although they remain at a relatively early stage of translation into standardized clinical application [441–443].

Taken together, these approaches offer a more targeted way to modulate microbial composition and function than broad dietary approaches. Their clinical translation will depend on stronger evidence, standardized formulations, and better alignment among specific products, disease contexts, and patient populations.

Fecal Microbiota Transplantation (FMT)

Fecal microbiota transplantation (FMT) refers to the transfer of gut microbial communities and their associated components from rigorously screened healthy donors to recipients, with the aim of restoring microbial homeostasis, reinforcing colonization resistance, and modulating host immune and metabolic functions [444, 445]. Compared with relatively mild interventions such as dietary modulation, probiotics, and prebiotics, FMT provides a more direct and comprehensive reconstruction of a disrupted gut ecosystem [446]. As donor screening, manufacturing protocols, delivery routes, and quality control have improved, FMT has evolved from an empirical procedure into a more regulated microbiome-based therapeutic strategy across multiple diseases [444, 445, 447].

At present, the strongest evidence and clearest clinical application of FMT remain in recurrent Clostridioides difficile infection (rCDI). FMT can markedly reduce recurrence risk by restoring microbial diversity, reconstituting SCFA and bile acid metabolism, reinforcing colonization resistance, and suppressing pathogen expansion [448, 449]. The 2024 AGA guideline has incorporated fecal microbiota-based therapies in the management of recurrent CDI [447], and the U.S. FDA has approved REBYOTA and VOWST for prevention of recurrence following antibacterial treatment [450].

FMT has also been actively explored in IBD, particularly UC. In some patients, FMT can induce clinical remission and is accompanied by remodeling of microbial composition and function [451–453]. However, the durability of response, long-term maintenance effects, and improvements in endoscopic and histological outcomes remain inconsistent across studies [454, 455]. Heterogeneity in donors, recipients, and treatment protocols further limits cross-study comparability [454, 455]. Accordingly, FMT is not yet considered part of standard therapy for UC [447].

Beyond gastrointestinal diseases, FMT has been explored in several extra-intestinal conditions. In hepatic encephalopathy, FMT has been associated with improved cognitive function and related clinical outcomes in patients with cirrhosis, supporting a therapeutic role through modulation of the gut–liver–brain axis [456, 457]. FMT has also been explored in acute gastrointestinal graft-versus-host disease, where it may improve clinical manifestations and promote microbiota restoration in some steroid-refractory patients [458, 459]. In addition, FMT has been investigated as a strategy to improve insulin resistance and cardiometabolic abnormalities, although this application remains largely exploratory [398, 460].

In oncology, FMT has emerged as a potential strategy to enhance responsiveness to immune checkpoint inhibitors. In advanced melanoma, FMT from immunotherapy responders can restore anti-PD-1 responsiveness in a subset of resistant patients, alongside remodeling of the gut microbiota and tumor immune microenvironment [393, 461]. Its application is being extended to other solid tumors, including gastrointestinal cancers, reflecting the potential of microbiota remodeling in precision oncology [462].

Overall, FMT has clear clinical value in rCDI and broader therapeutic potential in selected disease settings. Although broader clinical implementation still requires progress in standardization, management of interindividual response variability, and safety evaluation, FMT is becoming increasingly established as a microbiota-based intervention.

Emerging precision microbiota therapies

With advances in microbiota-targeted therapeutics, gut microbiota interventions are shifting from broad microbial modulation toward more precise, controllable, and standardized strategies [11, 463]. Emerging precision microbiota therapies emphasize defined composition, focused targets, quality control, and reproducibility, making them better aligned with current drug development and clinical translation [463, 464].

Defined microbial consortia represent a characteristic form of emerging precision microbiota therapies [465]. Composed of selected commensal strains, they are designed to restore key microbiota functions with greater reproducibility [465]. rCDI remains the most mature clinical setting for this strategy, with VE303 serving as a representative example [387, 466]. This approach is also being explored in chronic inflammatory diseases, as illustrated by the clinical development of VE202 for UC [467]. In addition, selected commensal consortia may enable the targeted suppression of pathobionts such as Enterobacteriaceae, supporting their potential application in decolonization of antimicrobial-resistant organisms and in microbiota states associated with increased risk of infection or other adverse clinical outcomes [468].

In parallel, engineered live biotherapeutics further exemplify the programmable nature of microbiota-based therapy [469]. These strategies involve the modification of commensal or probiotic chassis to perform predefined therapeutic functions in the gut [469]. In phenylketonuria, SYNB1618 and its optimized successor SYNB1934 are both engineered Escherichia coli Nissle strains designed to metabolize phenylalanine in the intestinal lumen [406, 470]. These candidates represent examples of clinical translation in this field, highlighting the shift of engineered bacteria from proof-of-concept studies toward indication-driven clinical development [406, 470]. Beyond inherited metabolic disorders, engineered bacteria are being developed for inflammatory diseases, infections, and cancer [469, 471].

In addition, phage therapy and CRISPR-mediated microbiome editing offer new strategies for the targeted elimination of specific pathogens or pathobionts [472, 473]. Unlike broad-spectrum antibiotics, these approaches may selectively suppress pathobionts, antimicrobial-resistant organisms, or strains carrying specific virulence determinants while minimizing disruption to the broader commensal microbiota [472–474]. At the same time, personalized microbiota-directed interventions targeting specific metabolic or ecological functional deficits represent another important direction [475, 476]. Rather than merely altering microbial composition, these approaches aim to restore key microbiota-related functions more precisely according to the patient’s microbial profile, metabolic features, and disease context [475, 476].

Defined microbial consortia, engineered live biotherapeutics, phage- or CRISPR-based microbiome editing, and function-oriented personalized interventions together form the main framework of emerging precision microbiota therapies. Although most of these strategies remain at the preclinical or early clinical stage, their development marks a gradual shift from empirical microbiota modulation toward more precise, standardized, and clinically translatable therapeutic approaches.

Challenges and future perspectives in clinical translation

Although considerable progress has been made in elucidating disease mechanisms, developing microbiota-based biomarkers, and exploring microbiota-targeted interventions, the clinical translation of gut microbiota research still faces substantial challenges [11, 477] (Fig. 6). The key bottlenecks are no longer limited to identifying disease-associated microbial alterations, but lie in whether these findings have robust causal interpretability, are reproducible across populations and platforms, can be translated into standardized diagnostic or therapeutic strategies, and meet requirements for long-term safety and regulatory feasibility [11, 369, 478].

First, insufficient evidence for causality remains a major barrier to the clinical translation of gut microbiota research. Many existing studies, including those on CRC, IBD, and various extraintestinal diseases, are still based primarily on cross-sectional analyses or case–control comparisons, making it difficult to determine whether specific microbial alterations are drivers of disease, consequences of the disease state, or secondary changes related to diet, medication exposure, inflammation, or host behavior [478, 479]. This limitation not only weakens the robustness of microbiota-based biomarkers, but also increases the risk of target misidentification in microbiota-directed interventions [11, 478]. To address this issue, recent studies have increasingly emphasized multicenter, large-scale, longitudinal prospective cohorts, together with functional validation of candidate strains and metabolites using germ-free animal models, colonization models, culturomics, functional metagenomics, and metabolite complementation [11, 478, 480, 481]. Causal inference approaches, such as Mendelian randomization, are also being introduced into population-based studies to prioritize microbial features with greater potential pathogenic or protective relevance [479]. Together, these approaches are important for moving the field from association-based observations toward more actionable microbiome-based medicine [478].

In addition to causal uncertainty, marked interindividual heterogeneity and the lack of methodological standardization further limit the reproducibility and clinical generalizability of gut microbiota research. Age, genetic background, dietary patterns, lifestyle, medication exposure, and host immune status can all shape the baseline microbial ecosystem, causing the same microbial signal or intervention to perform differently across individuals [11, 369, 477]. Technical variation in sample collection, storage, DNA extraction, sequencing platforms, and bioinformatic workflows also compromises cross-study consistency [369, 482, 483]. To address this, recent international consensus statements, reporting guidelines, and reference materials have begun to promote a more standardized framework for microbiome testing, with increasing emphasis on both technical harmonization and standardized interpretation [369, 482, 483]. At the same time, growing efforts are being made to stratify patients according to baseline microbiota profiles, metabolomic features, and immune phenotypes, rather than relying on a universal standard [477, 484, 485]. These developments suggest that gut microbiota-based medicine is more likely to enter clinical practice through stratified and individualized approaches rather than universal application.

Beyond issues of evidence and standardization, current microbiota-based interventions still face major limitations, including colonization resistance, limited durability, and insufficient long-term safety evaluation. Although FMT has established clinical value in rCDI, its broader use in non-infectious indications remains constrained by unresolved issues related to donor screening, long-term safety, and potential transmission of antimicrobial resistance genes [486]. Likewise, many probiotics, prebiotics, and related products fail to achieve stable engraftment or durable functional effects, and the ecological effects of some substrates may be broader and less specific than intended [487, 488]. Emerging precision approaches, such as phages, engineered bacteria, and metabolite-based therapies, offer greater specificity, but their in vivo efficacy remains constrained by challenges related to stability, delivery, host compatibility, and potential long-term ecological effects [489]. In response, recent efforts have focused on developing next-generation probiotics with improved ecological fitness, optimizing delivery strategies such as sporulation, encapsulation, and sustained-release formulations, and exploring combination-based reconstruction approaches to enhance the durability and controllability of microbiota-directed interventions [469, 490]. In parallel, long-term follow-up registries and systematic assessment of delayed adverse events are increasingly recognized as important priorities [491].

More fundamentally, the gut microbiota exerts its effects through multilayered networks involving metabolism, immunity, barrier function, and neuroendocrine signaling, making single-taxon or single-pathway explanations and interventions inherently limited. This may explain why biomarker models based on individual microbes or metabolites often show limited external validity, and why interventions that alter microbial composition do not always yield consistent clinical benefit [485]. To address this limitation, recent research has increasingly emphasized multi-omics integration, combining metagenomics, metabolomics, proteomics, host transcriptomics, and immune phenotyping to identify functionally relevant nodes and regulatory pathways [492, 493]. Interpretable machine learning, causal inference, and network analysis are also being applied to improve the integration of complex multimodal data [494, 495]. These advances suggest that future microbiota-based medicine will likely depend less on simply adding or removing specific microbes and more on the precise and dynamic modulation of key functional networks.

In this context, progress in causal validation, methodological standardization, safety assessment, and precision intervention will be essential for translating gut microbiota research into clinically useful diagnostics and therapeutics.

Conclusion

The gut microbiota is now recognized as an important regulator of human health and disease, linking intestinal ecology to host metabolism, barrier integrity, immunity, and systemic organ function. Rather than acting through isolated taxa or single pathways, its effects are exerted through interconnected functional networks that can maintain homeostasis or, when disrupted, contribute to disease development and progression across both intestinal and extra-intestinal systems. The studies reviewed here indicate that microbiota dysbiosis is not simply a compositional abnormality, but a broader disturbance of host–microbe interactions with important mechanistic and clinical implications.

The field is also shifting from descriptive profiling toward clinical translation. Microbiota-based biomarkers, dietary modulation, biotic products, fecal microbiota transplantation, and emerging precision microbiota therapies are broadening the clinical application of microbiome research. Even so, several barriers still limit translation, including unresolved causality, marked interindividual heterogeneity, insufficient methodological standardization, and the need for durable efficacy and long-term safety evaluation. Future progress will likely depend on integrating longitudinal human studies with functional validation, multi-omics analysis, and more precise intervention strategies that target microbial functions and host–microbe networks rather than composition alone. Taken together, the gut microbiota represents not only an important determinant of health and pathophysiology, but also a promising entry point for more precise, mechanism-informed diagnostics and therapeutics.

Acknowledgements

The authors thank BioRender (https://BioRender.com) for assisting in figure creation.

Abbreviations

3-sucCA: 3-Succinylated cholic acid
4-EPS: 4-Ethylphenyl sulfate
5-AVA: 5-Aminovaleric acid
5-HT: 5-Hydroxytryptamine
AhR: Aryl hydrocarbon receptor
AIEC: adherent-invasive Escherichia coli
ALPK1: Alpha-kinase 1
AMP: Antimicrobial peptide
APC: Adenomatous Polyposis Coli
ASD: Autism spectrum disorder
BCAA: Branched-chain amino acid
BCL2: B-cell lymphoma-2
BFT: Bacteroides fragilis Toxin
CD: Crohn’s disease
CDT: Cytolethal distending toxin
CEACAM1: Carcinoembryonic antigen-related cell adhesion molecule 1
CRC: Colorectal cancer
CYP7A1: Cholesterol 7α-hydroxylase
DC: Immature dendritic cell
E. coli: Escherichia coli
EEC: Enteroendocrine cell
EMT: Epithelial–mesenchymal transition
ERK: Extracellular signal-regulated kinase
ETBF: Enterotoxigenic Bacteroides fragilis
F. nucleatum: Fusobacterium nucleatum
FadA: Fusobacterium Adhesin A
FFAR2: Free fatty acid receptor 2
FGF19: Fibroblast growth factor 19
FMT: Fecal microbiota transplantation
FODMAP: Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols
FXR: Farnesoid X receptor
GABA: γ-Aminobutyric acid
Gal-GalNAc: Galactose-N-acetyl-D-galactosamine
GALT: Gut-associated lymphoid tissue
GIP: Glucose-dependent insulinotropic polypeptide
GLP-1: Glucagon-like peptide-1
GPCR: G protein-coupled receptor
GSDME: Gasdermin E
HDAC: Histone deacetylase
HDL: High-density lipoprotein
HIF-1α: Hypoxia-inducible factor 1α
HPA: Hypothalamic–pituitary–adrenal
HPG: Hypothalamic–pituitary–gonadal
HPT: Hypothalamic–pituitary–thyroid
IAA: Indole acetic acid
IBD: Inflammatory bowel disease
IBS: Irritable bowel syndrome
IBS-C: Constipation-predominant IBS
IBS-D: Diarrhea-predominant IBS
ICA: Indole-3-carboxylic acid
ICAM1: Intercellular adhesion molecule 1
IDO: Indoleamine 2,3-dioxygenase
IL-22: Interleukin-22
ILA: Indole-3-lactic acid
ILC: Innate lymphoid cell
IPA: Indole-3-propionic acid
ISC: Intestinal stem cells
KLF4: Krüppel-like factor 4
LBP: LPS-binding protein
LCA: Lithocholic acid
LPS: Lipopolysaccharides
LRRC19: Leucine-rich repeat containing 19
MAMP: Microbe-associated molecular pattern
MASH: Metabolic dysfunction-associated steatohepatitis
MASLD: Metabolic dysfunction-associated steatotic liver disease
MCT1: Monocarboxylate transporter 1
MDD: Major depressive disorder
MDSC: Myeloid-derived suppressor cell
MGBA: Microbiota-gut-brain axis
miR: MicroRNA
MUC2: Mucin 2
NAFLD: Nonalcoholic fatty liver disease
NAM: N-acetylmuramic acid
NF-κB: Nuclear factor kappa B
NK: Natural killer cell
NLR: NOD-like receptor
PAMP: Pathogen-associated molecular pattern
pCS: P-cresol sulfate
PCWBR2: Putative cell wall binding repeat 2
PD: Parkinson’s disease
PD-1: Programmed cell death 1
PI3K: Phosphoinositide 3-kinase
PRR: Pattern recognition receptor
PSC: Primary sclerosing cholangitis
PYY: Peptide YY
RadD: Radiation resistance protein D
RAS: Rat sarcoma viral oncogene
rCDI: Recurrent Clostridioides difficile infection
ROS: Reactive oxygen species
SBA: Secondary bile acid
SCFA: Short-chain fatty acids
SFB: segmented filamentous bacteria
sIgA: Secretory IgA
Siglec: Sialic-acid-binding immunoglobulin-like lectin
SLC26A3: Solute carrier family 26 member 3
STAT3: Signal transducer and activator of transcription 3
T2DM: Type 2 diabetes mellitus
TAK1: Transforming growth factor-β-activated kinase 1
TAM: Tumor-associated macrophage
TAN: Tumor-associated neutrophil
TGR5: Takeda G protein-coupled receptor 5
Th17: T helper 17 cell
THDOC: Tetrahydrodeoxycorticosterone
THP: Tetrahydroprogesterone
TIGHT: T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain
TLR: Toll-like receptor
TMA: Trimethylamine
TMAO: Trimethylamine N-oxide
TRAF6: Tumor necrosis factor receptor-associated factor 6
Treg: Regulatory T cell
UC: Ulcerative colitis
UDCA: Ursodeoxycholic acid
YAP: Yes-associated protein

Authors' contributions

YZYL: Conceptualization, Investigation, Writing—Original Draft. XYX: Investigation. XJ: Investigation. XYL: Investigation. WJW: Conceptualization, Writing—Review & Editing, Supervision, Funding acquisition. RL: Supervision, Funding acquisition. All authors read and approved the final manuscript.

Funding

This study was supported by National Key Research and Development Program of the 14th Five-Year Plan (No: 2023YFC2307000), Noncommunicable Chronic Diseases-National Science and Technology Major Project (2024ZD0520800), Funds for basic scientific research operations in central universities (5003530167), National Natural Science Foundation of China (Nos. 82170571, 81974068, 82270586 and 81900580), and Natural Science Foundation of Hubei Province (No. 2022CFA009), the Ministry of Science and Technology of the People’s Republic of China (CN) (2022YFF1203300).

Data availability

No new data were generated in this study. Data used to generate Fig. 5 were retrieved from the publicly accessible ClinicalTrials.gov database.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Weijun Wang, Email: wangweijunct@sina.com.

Rong Lin, Email: linrong@hust.edu.cn.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

No new data were generated in this study. Data used to generate Fig. 5 were retrieved from the publicly accessible ClinicalTrials.gov database.

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PERMALINK

Gut microbiota in health and disease

Yangziyi Li

Xueyan Xiao

Xin Jiang

Xinyi Li

Weijun Wang

Rong Lin

Abstract

Introduction

Gut microbiota and health

Definition of a healthy gut microbiota

Fig. 1.

Role of gut microbiota in maintaining host health

Metabolic homeostasis

Barrier protection

Immune regulation

Gut–organ axis communication

Gut microbiota dysbiosis

Definition and features of gut microbiota dysbiosis

Fig. 2.

Causes and consequences of gut microbiota dysbiosis

Gut microbiota in disease development and progression

Fig. 3.

Gut microbiota in gastrointestinal diseases: colorectal cancer as a representative example

Colorectal Cancer (CRC)

Fig. 4.

Genotoxicity

Signal transduction

Immune modulation

Metabolism

Other gastrointestinal diseases

Inflammatory Bowel Disease (IBD)

Irritable Bowel Syndrome (IBS)

Gut microbiota in extra-intestinal diseases: the gut–organ axis

Gut–liver axis

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

Primary Sclerosing Cholangitis (PSC)

Cirrhosis

Gut–brain axis

Autism Spectrum Disorder (ASD)

Parkinson’s Disease (PD)

Major Depressive Disorder (MDD)

Gut–endocrine axis

Type 2 Diabetes Mellitus (T2DM)

Other gut–organ axes

Clinical applications and translational perspectives of the gut microbiota in disease

Fig. 5.

Microbiota-based biomarkers

Fig. 6.

Microbiota-targeted interventions

Table 1.

Dietary modulation

Probiotics, prebiotics, synbiotics, and postbiotics

Fecal Microbiota Transplantation (FMT)

Emerging precision microbiota therapies

Challenges and future perspectives in clinical translation

Conclusion

Acknowledgements

Abbreviations

Authors' contributions

Funding

Data availability

Declarations

Ethics approval and consent to participate

Consent for publication

Competing interests

Footnotes

Contributor Information

References

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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