The Gut Microbiota–Insulin Resistance Axis: Mechanisms, Clinical Implications, and Therapeutic Potential

ABSTRACT

Emerging evidence highlights the pivotal role of the gut microbiota (GM) in regulating host metabolism and contributing to the development of insulin resistance (IR). Gut dysbiosis alters the production of critical metabolites, including short‐chain fatty acids (SCFAs), bile acids, indole derivatives, and trimethylamine N‐oxide (TMAO), which influence intestinal barrier integrity, inflammatory pathways, and glucose homeostasis. Recent clinical and translational studies indicate that SCFAs can improve fasting insulin and HOMA‐IR, although the magnitude of benefit varies substantially across individuals, highlighting ongoing controversy surrounding their metabolic effects. Altered microbial regulation of bile‐acid metabolism has also been implicated in impaired lipid and glucose signaling, reinforcing the relevance of FXR‐ and TGR5‐mediated pathways in IR. Elevated TMAO levels have further been associated with adverse metabolic outcomes, though debate persists regarding its causal role versus its function as a diet‐dependent biomarker. Microbiota‐targeted strategies, including dietary fiber, probiotics, and fecal microbiota transplantation (FMT), show potential to modulate these metabolic pathways, yet clinical results remain inconsistent. This narrative review synthesizes recent mechanistic discoveries and clinical findings on microbiota‐derived metabolites in IR, highlights key controversies, and outlines future priorities for translating microbiome science into effective and personalized interventions for metabolic disease prevention and management.

Dysbiosis‐induced alterations in microbial metabolite production promote intestinal barrier disruption and systemic inflammation, driving insulin resistance and metabolic dysfunction. Microbiota‐targeting therapies represent promising approaches to restore host metabolic health.

1. Introduction

Insulin resistance (IR) is a condition that is characterized by reduced sensitivity of cells to the hormone insulin, which is essential for maintaining glucose homeostasis. In individuals with IR, insulin's ability to facilitate the uptake of glucose into skeletal muscle, the liver, and adipose cells is diminished, leading to compensatory hyperinsulinemia and dysregulated glucose metabolism. Over time, metabolic diseases are exacerbated by this dysfunction such as cardiovascular diseases, non‐alcoholic fatty liver disease (NAFLD), and type 2 diabetes mellitus (T2DM). Insulin resistance (IR) has a complex pathophysiology, influenced by dietary patterns, systemic inflammation, physical inactivity, and genetic predisposition [1, 2]. According to the Global Burden of Disease Study 2021, an estimated 529 million people worldwide were living with diabetes in 2021, over 90% of whom had T2DM, and prevalence is projected to reach 1.27 billion by 2050 [3]. These trends underscore the urgent need to identify modifiable contributors to IR and explore new therapeutic pathways.

Although IR is traditionally associated with genetic susceptibility, obesity, sedentary behavior, chronic inflammation, and ectopic lipid deposition, recent advances in multi‐omics technologies have uncovered a major additional regulator of metabolic health: the gut microbiota. This diverse microbial ecosystem influences host physiology through fermentation of dietary fibers, modulation of immune responses, regulation of gut‐barrier integrity, and production of bioactive metabolites, including short‐chain fatty acids (SCFAs), bile acids, indole derivatives, and trimethylamine N‐oxide (TMAO). Disruption of microbial composition, dysbiosis, alters these metabolic pathways and can promote inflammation, affect insulin signaling, and contribute to metabolic dysfunction [4, 5, 6, 7].

Recent studies illustrate both the potential and complexity of microbiota–IR interactions. For instance, clinical meta‐analyses demonstrate that SCFAs can improve fasting insulin and HOMA‐IR, yet individual responses vary markedly, reflecting unresolved biological heterogeneity [8]. Altered microbial regulation of bile‐acid metabolism has also been linked to changes in FXR and TGR5 signaling, a relationship demonstrated in diabetic animal models where dysbiosis disrupts bile‐acid profiles and down‐regulates these receptors, contributing to metabolic disturbances [9]. In humans, emerging evidence suggests that bile‐acid signaling through FXR and TGR5 plays an important role in glucose and lipid regulation, although the specific contribution of microbiota‐driven alterations remains an active area of investigation [10].

Beyond SCFAs and bile acids, other gut‐derived metabolites such as trimethylamine‐N‐oxide (TMAO) have also been implicated in metabolic regulation. Elevated circulating levels of TMAO have been increasingly associated with adverse metabolic outcomes. Recent prospective data show that higher baseline TMAO levels, as well as upward changes over time, are linked to a greater risk of incident type 2 diabetes, suggesting that TMAO may reflect early metabolic deterioration [11]. However, substantial debate persists regarding whether TMAO acts as a direct causal mediator of insulin resistance or instead serves primarily as a diet‐ and kidney‐dependent biomarker. Evidence indicates that circulating TMAO concentrations are strongly influenced by dietary patterns, particularly the intake of red meat, eggs, and fish, as well as by renal clearance, prompting caution in interpreting its mechanistic role [12]. Together, these findings underscore the clinical relevance of TMAO while highlighting the uncertainty that still surrounds its causal contribution to metabolic disease. Despite growing recognition of the gut microbiota's role in IR, there is a lack of synthesis on how to translate these insights into therapies and how to resolve conflicting findings. This review aims to (1) consolidate the latest mechanistic knowledge, (2) critically evaluate therapeutic interventions targeting the microbiota, and (3) discuss controversies, such as causality vs. correlation and inconsistent results across studies.

2. Gut Microbiota and Metabolite Production

The human gastrointestinal tract is home to a diverse microbial ecosystem, the gut microbiota, which significantly contributes to host physiology through a complex web of metabolic interactions. Far from passive inhabitants, these microbes engage in the bioconversion of dietary and endogenous compounds, producing a vast repertoire of metabolites that influence host metabolism, immunity, and endocrine function. Microbiota‐derived metabolites, such as short‐chain fatty acids (SCFAs), secondary bile acids, trimethylamine N‐oxide (TMAO), and indole derivatives, act locally in the intestinal milieu and systemically through receptor‐mediated and epigenetic pathways. The regulatory capacity of these metabolites extends from modulating intestinal barrier integrity to influencing energy homeostasis, insulin sensitivity, and systemic inflammation [13, 14].

Recent advances in sequencing, metabolomics, and host‐microbe signaling have enabled a more nuanced understanding of how microbial metabolism integrates with host biological systems. These insights have profound implications for therapeutic strategies aimed at restoring metabolic balance, particularly in the context of obesity, insulin resistance, type 2 diabetes, and inflammatory disorders. The expanding scientific interest in the relationship between the gut microbiota and metabolic regulation is reflected in recent bibliometric analyses. In a study analyzing over 1200 publications from 2000 to 2024, Abildinova et al. reported a more than threefold increase in related research output over the past decade [15]. Their co‐authorship mapping revealed extensive international collaboration, particularly among institutions in China, the United States, and Western Europe. Thematic clustering and keyword co‐occurrence analyses identified major research hubs focused on “short‐chain fatty acids,” “insulin resistance,” “bile acid metabolism,” and “gut inflammation.” These findings underscore a global recognition of the gut microbiota's pivotal role in endocrine and metabolic disease pathogenesis and emphasize the urgent need to translate mechanistic insights into therapeutic innovations [15].

2.1. Gut Microbiota Composition and Functional Capacity

The gut microbiota is composed of trillions of microorganisms, predominantly bacteria, that collectively encode more than three million genes, over 150 times the number found in the human genome. These organisms are not randomly distributed but are instead organized into a relatively conserved structure dominated by four phyla: Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria [14, 16]. The relative abundance and activity of these microbial communities are shaped by several factors, including host genetics, age, geographic location, medication use, and most notably, diet [17].

Functionally, the gut microbiota exhibits remarkable metabolic plasticity, compensating for the host's enzymatic limitations. It participates in the fermentation of non‐digestible carbohydrates, protein catabolism, and the biotransformation of bile acids, polyphenols, and amino acids. These microbial processes yield bioactive compounds that enter systemic circulation and interact with host organs from the liver to the brain [18, 19, 20]. The spatial organization of these microbes further modulates their metabolic outputs. For instance, saccharolytic fermentation is predominant in the colon, where strict anaerobes convert dietary fibers into SCFAs, while proteolytic fermentation and bile acid deconjugation are more pronounced in the distal small intestine.

2.2. Short‐Chain Fatty Acids (SCFAs)

Short‐chain fatty acids, notably acetate, propionate, and butyrate, are principal microbial metabolites produced by the anaerobic fermentation of indigestible dietary polysaccharides such as resistant starch and inulin. These metabolites are present in millimolar concentrations in the colon and vary in abundance and composition depending on diet and microbiota composition. Acetate is the most abundant SCFA, followed by propionate and butyrate, each serving distinct biological roles and originating from different bacterial pathways [19, 21].

SCFAs exert pleiotropic effects by activating G protein‐coupled receptors such as FFAR2 and FFAR3 on enteroendocrine and immune cells. Through these pathways, SCFAs modulate insulin sensitivity, satiety signaling, and inflammatory responses [22, 23]. Additionally, butyrate acts as a histone deacetylase (HDAC) inhibitor, promoting anti‐inflammatory gene expression and reinforcing gut barrier integrity [24]. These actions can improve metabolic health and counteract diet‐induced obesity and insulin resistance, although their effects may vary according to host and microbial factors [25].

Beyond these mechanistic insights, recent human studies have examined whether SCFA modulation translates into measurable metabolic improvements. Recent human evidence supports the potential metabolic benefits of SCFAs but also reveals notable variability in clinical responses. A 2024 systematic review and meta‐analysis by Pham et al. found that strategies designed to elevate systemic SCFA levels, through direct supplementation or fiber interventions, were associated with modest improvements in fasting insulin and HOMA‐IR in adults, though effect sizes varied substantially across studies [8]. These findings suggest that SCFAs can enhance insulin sensitivity under certain conditions, but their impact is influenced by baseline microbiota composition, metabolic status, and the type and dose of intervention.

Importantly, emerging literature indicates that SCFAs are not uniformly beneficial. Sasidharan Pillai et al. highlighted that both reduced and elevated SCFA concentrations have been linked to adverse metabolic outcomes, including associations between higher circulating SCFAs and obesity or insulin resistance in some cohorts, while other studies report the opposite: improved glycemic control and weight regulation with increased SCFAs [26]. Similarly, Liu et al. noted that although SCFAs can ameliorate IR through anti‐inflammatory and gut‐barrier mechanisms, clinical findings remain inconsistent and context dependent, emphasizing that SCFA effects may follow a nonlinear, host‐specific pattern [27]. Together, these findings underscore that SCFAs represent key but potentially dual‐edged mediators in the gut microbiota–insulin resistance axis, with their metabolic outcomes influenced by dose, microbial ecology, and host metabolic state.

As summarized in Table 1, acetate, propionate, and butyrate differ not only in their microbial origins but also in their receptor engagement and downstream metabolic effects, highlighting the functional heterogeneity of SCFAs in insulin resistance.

TABLE 1.

Overview of SCFAs.

SCFA	Producers	Receptors	Functions	Studies showing metabolic effects
Acetate	Bifidobacterium	FFAR2, FFAR3	Lipid metabolism, appetite control [28]	Takeuchi et al. showing acetate‐producing pathways linked to insulin sensitivity and improved metabolic profiles in humans [29]
Propionate	Bacteroides	FFAR2, FFAR3	Gluconeogenesis, satiety [30]	Sanna et al. showed propionate‐producing pathways causally linked to lower T2D risk [31]
Butyrate	Faecalibacterium	FFAR3, HDAC	Barrier function, anti‐inflammation [20]	Münte et al. confirmed butyrate's anti‐inflammatory + insulin‐sensitizing pathways [7]. van Deuren et al. verified evidence summarizing beneficial vs. inconsistent effects in obesity and IR models [32]

2.3. Bile Acids

Bile acids (BAs) represent a key pathway through which the gut microbiota influences host metabolic homeostasis. Primary BAs synthesized from cholesterol in the liver are transformed into secondary BAs, such as deoxycholic acid (DCA) and lithocholic acid (LCA), by microbial bile‐salt hydrolases and 7α‐dehydroxylating enzymes. Foundational work and updated pathway mappings identify several gut taxa, including Clostridium, Eubacterium, and related genera, as major contributors to these transformations, with Bacteroides species also involved in bile‐salt deconjugation [28, 33].

Secondary BAs function as ligands for the nuclear receptor farnesoid X receptor (FXR) and the G‐protein–coupled receptor TGR5. Activation of FXR modulates bile‐acid synthesis, hepatic lipid and glucose metabolism, and fibroblast growth factor 15/19 (FGF15/19) signaling, whereas TGR5 signaling promotes glucagon‐like peptide‐1 (GLP‐1) secretion and increases energy expenditure, collectively enhancing insulin sensitivity [10, 30]. Recent clinical and experimental evidence summarized by Hou et al. indicates that individuals with type 2 diabetes frequently exhibit altered circulating BA profiles and BA‐receptor signaling, and that changes in BA composition are associated with impaired insulin sensitivity and β‐cell function [10].

Complementary mechanistic and translational data reviewed by Li et al. further show that dysregulated BA‐FXR signaling contributes to glucose dysregulation, inflammation, and lipid accumulation in metabolic diseases, including MAFLD and T2D, while modulation of BA–FXR pathways, for example through BA sequestration or FXR‐targeted agents, can improve metabolic outcomes [30]. Together, these findings support bile acids and their receptors FXR and TGR5 as important mediators linking gut microbial composition to insulin resistance and as emerging therapeutic targets in metabolic disease.

Table 2 summarizes how microbial transformation of primary bile acids generates secondary bile acids that act as signaling molecules influencing glucose and lipid metabolism via FXR‐ and TGR5‐mediated pathways.

TABLE 2.

Microbial bile acid derivatives and host receptors.

Metabolite	Microbes	Receptor	Effects
Deoxycholic acid	Clostridium scindens	FXR, TGR5	Bile acid regulation, lipolysis [11, 34, 35]
Lithocholic acid	Bacteroides	TGR5	GLP‐1 secretion, energy metabolism [34, 35, 36]

2.4. Trimethylamine N‐Oxide

Trimethylamine N‐oxide (TMAO) is a gut microbiota‐derived metabolite formed through the microbial breakdown of dietary choline, L‐carnitine, and phosphatidylcholine into trimethylamine (TMA), which is subsequently oxidized by hepatic flavin monooxygenase 3 (FMO3). TMAO has emerged as a robust biomarker and mechanistic contributor to cardiometabolic disorders. In a clinical study of patients with type 2 diabetes, elevated plasma TMAO levels were independently associated with increased risk of cardiovascular mortality, even after controlling for glycemic indices and renal function, indicating its potential as a non‐redundant prognostic factor [29].

More recently, evidence has implicated TMAO in promoting renal fibrosis and inflammatory signaling. Kapetanaki et al. demonstrated that TMAO enhances TNF‐α–induced fibrotic mediator release in renal fibroblasts, suggesting a direct pathogenic role in chronic kidney disease (CKD) [31].

Interest in TMAO as a therapeutic target has grown in parallel with these observations. Recent reviews highlight its involvement in diabetes‐related complications, cardiovascular disease, and chronic kidney disease via gut–renal metabolic interactions [32, 34, 35]. Preclinical strategies aimed at lowering TMAO production, such as microbial TMA‐formation inhibitors and targeted dietary modulation, demonstrate reductions in circulating TMAO and improvements in cardiometabolic parameters. Notably, novel approaches explored in cardiac research suggest that modulating TMAO may complement existing therapies for heart failure [36].

However, debate persists regarding TMAO's causal status. Circulating TMAO levels are strongly shaped by dietary intake, as well as renal clearance, raising the possibility that TMAO reflects broader dietary and metabolic patterns rather than acting as a direct mediator of insulin resistance. Current evidence remains mixed, and further mechanistic and interventional studies are needed to resolve whether TMAO functions primarily as an effector molecule or as a correlated biomarker [32, 34].

Collectively, these findings position TMAO as a metabolically relevant and clinically informative gut‐derived molecule, whose dual role as a potential therapeutic target and an indicator of underlying dietary–renal physiology underscores the need for continued high‐quality research to determine its precise contribution to insulin resistance and cardiometabolic disease.

2.5. Indole Derivatives

Tryptophan (Trp) metabolism by both host and microbial pathways gives rise to a broad spectrum of immunologically active metabolites. Mounting evidence points to the significance of the kynurenine pathway as a parallel axis of host–microbiome signaling. This pathway, initiated by the host enzymes indoleamine 2,3‐dioxygenase (IDO) and tryptophan 2,3‐dioxygenase (TDO), results in the production of metabolites such as kynurenine, kynurenic acid, and quinolinic acid. These bioactive compounds regulate immune tolerance, neuroinflammation, oxidative stress, and mitochondrial function through interaction with receptors such as the aryl hydrocarbon receptor (AhR), GPR35, and NMDA receptors [37]. Dysregulation of this pathway, particularly increased kynurenine production during inflammation, has been linked to obesity, metabolic syndrome, and other cardiometabolic disorders [38].

Gut microbes complement these host processes by generating indole derivatives, such as indole, indole‐3‐propionic acid (IPA), indole‐3‐aldehyde, and indole‐3‐acetic acid, from dietary Trp. These metabolites act as endogenous AhR ligands that support epithelial barrier integrity and mucosal immune balance [16]. Disruptions in microbial Trp metabolism and indole production are observed in inflammatory bowel disease, where dysbiosis contributes to impaired mucosal homeostasis [39].

Recent studies highlight the metabolic relevance of these pathways. Gut microbiota–mediated remodeling of Trp metabolism has been shown to link intestinal immune dysregulation with metabolic syndrome, and abnormal Trp pathway activity is increasingly recognized as a contributor to metabolic inflammation and insulin resistance [38, 40]. Among microbial Trp metabolites, IPA is of particular interest: Zeng et al. demonstrated that IPA alleviates diabetic kidney disease by protecting mitochondrial function and stabilizing SIRT1, while its antioxidant and anti‐inflammatory properties have been further characterized in neuroprotective contexts [41, 42].

Together, the kynurenine and indole pathways illustrate how host and microbial Trp metabolism jointly modulate inflammation, barrier integrity, and mitochondrial homeostasis. Excessive kynurenine pathway activation may promote metabolic dysfunction, whereas microbial indoles, especially IPA, appear to support metabolic resilience and may play a protective role against insulin resistance.

2.6. Inflammation and Insulin Resistance

Low‐grade systemic inflammation is a hallmark of metabolic disease and is tightly linked to microbial dysbiosis. Loss of SCFA‐producing taxa increased intestinal permeability and endotoxin translocation all contributed to metabolic endotoxemia, triggering pro‐inflammatory cytokine production and impairing insulin signaling [43]. Semo et al. demonstrated that specific gut microbial pathways related to carbohydrate metabolism exacerbate hepatic inflammation and insulin resistance, highlighting the role of microbial functional capacity in host glycemic control [44].

Microbiota‐targeted therapies provide clinical support for the inflammation–insulin resistance link. In a 2023 meta‐analysis of randomized trials, Qiu et al. found that fecal microbiota transplantation modestly improved insulin resistance and inflammatory markers in metabolic syndrome, indicating that restoring microbial balance may dampen systemic inflammation [45]. Recent reviews further emphasize the role of gut microbes in metabolic inflammation and obesity, describing how dysbiosis‐driven immune activation contributes to impaired metabolic homeostasis [26].

However, the long‐standing Firmicutes/Bacteroidetes (F/B) ratio, once widely viewed as a marker of metabolic dysbiosis, shows inconsistent associations with obesity and type 2 diabetes in contemporary research. Studies report both positive and null correlations between F/B ratio and metabolic profiles, highlighting that this metric oversimplifies the complexity of microbial ecology [46, 47]. Dietary influences further complicate the picture: Thomas et al. illustrate how diet‐induced microbial shifts can promote chronic low‐grade inflammation independent of F/B ratio changes [48].

Overall, metabolic inflammation reflects a multifactorial disruption involving gut‐barrier dysfunction, endotoxemia, diet–microbiota interactions, and altered microbial metabolism, collectively contributing to the development and progression of insulin resistance.

Table 3 and Figure 1 jointly synthesize the major classes of gut microbiota–derived metabolites and illustrate how their convergent interactions shape inflammation, insulin signaling, and overall metabolic homeostasis.

TABLE 3.

Summary of metabolites and host effects.

Metabolite class	Example metabolites	Microbial pathway	Host effects
SCFAs	Acetate, propionate	Fiber fermentation	Metabolic regulation, immune modulation [9, 20]
Bile acids	DCA, LCA	Deconjugation/dehydroxylation	Lipid/glucose metabolism [34, 36]
TMAO	Trimethylamine	Choline metabolism	Inflammation, insulin resistance [42, 49]
Indoles	IPA, IAA	Tryptophan metabolism	Barrier integrity, anti‐inflammatory signaling [45, 47]
Monosaccharides	Glucose, fructose	Carb fermentation	Hepatic inflammation [50]

FIGURE 1.

Overview of gut microbiota‐derived metabolites and their impact on insulin sensitivity.

3. Metabolites and Host Metabolism

3.1. Gut Microbiota‐Derived Metabolites Interaction With Host Metabolism

The gut microbiota and its various metabolites are essential in host metabolism and overall health. Studies focused on the complex interactions between metabolites derived from gut microbiota and host physiology, focusing on the diversity of these metabolites. Gut microbiota can synthesize various metabolites, including short‐chain fatty acids (SCFAs), bile acids, amino acid derivatives, vitamins, and other compounds [50, 51]. These metabolites can function as signaling molecules, regulating host processes such as immune function, energy metabolism, and neurological function [52, 53].

Studies have shown that changes in food can cause gut microbiota to shift their metabolic capacity, which impacts host metabolism. For example, colonocytes use butyrate, a SCFA generated by gut bacteria, as their main energy source. It also affects energy homeostasis systemically, impacting metabolic processes in the brain, liver, and adipose tissue [49, 54, 55]. According to Mrdjen et al. [56] and Agus et al. [57], the gut microbiota is the primary mediator of the creation of metabolites such as indole derivatives from tryptophan metabolism. These metabolites can impact neurotransmitter levels, mood, and behavior. This demonstrates how the gut microbiota functions as a virtual endocrine organ by generating bioactive substances that affect host physiology [57].

Alterations in the gut microbiome and its metabolic profile have been associated with various disease states, including inflammatory bowel diseases, metabolic disorders, and neurodegenerative diseases [52, 58, 59, 60]. Gut microbiota‐derived metabolites can influence disease pathogenesis by modulating inflammation, oxidative stress, and direct signaling pathways [60]. Dietary factors may significantly impact the gut microbiome and its metabolic output, highlighting the importance of the interplay between diet, gut microbiota, and host metabolism [61]. Strategies targeting the gut microbiome, such as dietary interventions, probiotics, or fecal microbiota transplantation, have shown promise in modulating host metabolism and health [52].

3.2. Metabolites Affecting Insulin Sensitivity, Glucose Metabolism, and Lipid Metabolism

Studies have identified various metabolites and their mechanisms of action, highlighting the crucial role metabolites play in controlling lipid metabolism, glucose metabolism, and insulin sensitivity. Research demonstrates that as insulin resistance develops, toxic fatty molecules build up in organs, affecting insulin signaling pathways. In addition, lipotoxic metabolites build up because of inadequate fatty acid oxidation, which impairs insulin sensitivity [62]. The production of ceramide, a potent signaling molecule that contributes to insulin resistance during the breakdown of sphingomyelin, further underscores the importance of lipid metabolites in glucose metabolism [63]. Beyond classical host lipid pathways, recent work suggests that the gut microbiota can influence ceramide metabolism and thereby modulate these lipotoxic cascades. For example, in high‐fat‐diet mice treated with a long‐acting GLP‐1 receptor agonist, Lin et al. showed that drug‐induced shifts in gut microbiota composition, particularly an increased abundance of Lactobacillus reuteri , were accompanied by reduced circulating ceramide levels via upregulation of alkaline ceramidase 2, supporting a microbiota–ceramide regulatory axis [64]. Xiong et al. similarly reviewed microbial sphingolipids and gut‐microbiota‐driven lipid metabolism, highlighting how bacterial lipids interact with host sphingolipid pathways and metabolic signaling [65]. In diabetes, Yan et al. and Guo et al. emphasized that gut‐derived metabolites such as short‐chain fatty acids, bile acids, trimethylamine‐N‐oxide, and branched‐chain amino acids are intertwined with host lipid metabolism, positioning the gut microbiota as an upstream regulator of insulin signaling and inflammation [66, 67]. Jin et al. further showed that gut‐microbiota‐derived metabolites orchestrate metabolic reprogramming in diabetic cardiomyopathy, including lipid handling and mitochondrial function, reinforcing the broader notion that microbiota‐driven changes in lipid intermediates, such as ceramides and related sphingolipids identified in metabolic studies, may feed into insulin resistance and cardiometabolic complications [68].

Insulin sensitivity and other metabolites interact in a complicated and multidimensional way. For instance, elevated levels of branched‐chain amino acids (BCAAs) correlate with metabolic disorders and contribute to the development of insulin resistance [69]. Recent evidence also indicates that the gut microbiota plays a significant role in shaping circulating BCAA levels. Human multi‐omics data from obese adults show that dysbiosis alters microbial pathways related to BCAA biosynthesis and degradation, and these shifts are associated with obesity‐related metabolic disturbances [70]. Mechanistic and conceptual reviews further highlight that both host tissues and gut microbes participate in BCAA metabolism, and that microbiota‐driven alterations in BCAA handling may contribute to metabolic dysfunction and increased diabetes risk [71, 72].

Additional metabolites are also relevant. For instance, α‐hydroxybutyrate serves as an early indicator of glucose intolerance and insulin resistance, indicating that oxidative stress and lipid oxidation may be involved in their metabolic pathways [73]. Short‐chain fatty acids and other metabolites produced by the gut microbiota play a particularly important role in improving insulin sensitivity and glucose homeostasis [74]. Recent evidence suggests that toxic lipid intermediates such as ceramides and diacylglycerols (DAGs) may sit at the intersection of these amino acid, oxidative, and microbial pathways. Yan et al. discuss how microbiota‐derived metabolites and host lipids interact to shape insulin signaling and inflammation in diabetes, while Guo et al. frame lipid intermediates and other diabetogenic metabolites as downstream mediators along multiple “gut–X” axes (gut–liver, gut–muscle, gut–cardiac) [66, 67].

Studies have demonstrated a connection between insulin sensitivity and changes in lipid profiles in the setting of lipid metabolism. Insulin resistance, for example, can result from the buildup of specific lipid metabolites, such as sphingolipids and diacylglycerols, which can prevent insulin from acting on the liver and muscle tissues [75].

Although most of this work has historically focused on host lipid metabolism, emerging data indicate that DAG and related lipid species can be shaped by gut microbiota and diet. Chen et al. reported that diacylglycerol derived from camellia oil improved hyperuricemia and modulated gut microbiota composition in mice, suggesting a bidirectional relationship in which dietary DAGs reshape microbial communities and systemic metabolic outcomes [76]. Fu et al. showed that beetroot supplementation modulated gut microbiota‐derived diacylglycerol biosynthesis to enhance anti‐tumor immunity, providing direct evidence that DAG species can originate from microbiota‐dependent pathways and are dynamically regulated by diet [77]. Together with broader reviews of gut‐microbiota‐driven lipid metabolism, these findings support the concept that the accumulation of ceramides and DAGs implicated in insulin resistance can be influenced not only by host lipid handling but also by microbiota composition and function [65, 66, 67].

Collectively, these studies underscore that insulin resistance arises from an integrated network of host and microbial processes, in which gut‐microbiota‐derived metabolites, particularly ceramides, DAGs, BCAAs, and short‐chain fatty acids, shape lipid signaling, metabolic inflammation, and systemic glucose regulation.

3.3. Metabolite Signaling Pathways and Their Impact on Insulin Signaling

Metabolite signaling pathways impact bodily metabolic processes and are essential for controlling insulin signaling. One of the main signaling cascades that insulin activates is the phosphatidylinositol 3‐kinase (PI3K)/Akt pathway, which helps target tissues like muscle and adipose tissue absorb and metabolize glucose [78, 79]. According to recent research, metabolites such as fatty acids and amino acids have a significant role in regulating insulin signaling via several pathways, such as changing the lipid content of membranes and controlling gene expression [78, 80]. Recent findings further show that gut‐microbiota‐derived metabolites, particularly SCFAs, can directly activate PI3K/Akt signaling in metabolic tissues. For example, Liu et al. demonstrated that SCFAs produced by remodeled gut microbiota stimulate the FGF21–PI3K/Akt–GLUT4 axis in adipose tissue, thereby improving insulin sensitivity [81].

Insulin and metabolites interact in a complicated fashion through a network of signaling channels impacted by the nutritional status of the body. By altering the PI3K/Akt pathway in adipocytes, for example, ω‐3 fatty acids improve insulin sensitivity, increase glucose absorption, and lessen insulin resistance brought on by high‐fat diets [78]. Similarly, conjugated linoleic acid (CLA) supplementation reshaped gut microbiota toward SCFA‐producing taxa, and improvements in PI3K/Akt and AMPK activation in liver and adipose tissue occurred alongside increased SCFA‐producing bacteria and higher fecal SCFA levels, indicating a microbiota‐associated enhancement of insulin signaling pathways [82]. This implies that through metabolite‐mediated pathways, dietary factors can have a substantial effect on insulin signaling. Additionally, the dynamic character of the adipocyte phosphoproteome suggests that insulin controls mRNA stability and turnover in addition to activating the Akt pathway, all of which are essential for preserving metabolic balance and cellular growth [83].

Furthermore, studies showed that time‐dependent insulin secretion patterns preferentially control metabolic processes such as gluconeogenesis, glycolysis, and glycogenesis. Such patterns are essential for the accurate regulation of glucose metabolism since various insulin temporal profiles can result in varied metabolic consequences [79]. Gut‐derived metabolites are increasingly recognized as contributors to these regulatory dynamics. Wang et al. showed that SCFAs, bile acid derivatives, and microbial indole metabolites signal through GPCRs such as GPR43, TGR5, and FXR to activate downstream PI3K, Akt, and mTOR nodes, thereby influencing metabolic and inflammatory signaling relevant to insulin action [84]. The existence of several metabolites that can function as signaling molecules and affect the activity of important proteins involved in insulin signaling further complicates the control of these pathways.

Metabolites like amino acids can improve insulin signaling by activating mTOR, a vital regulator of cell growth and metabolism [85, 86]. Metabolite sensing is a basic process that allows cells to recognize variations in their metabolic environment and modify their signaling pathways correspondingly. Network‐level analyses further support this integration: Yao et al. identified AKT1 as a core diabetes‐related target of gut‐microbiota‐derived metabolites and highlighted PI3K/Akt as one of the principal pathways through which these metabolites exert their metabolic effects [87]. By integrating signals from various metabolites and coordinating metabolic responses, this sensing ability enables cells to impact insulin signaling and metabolic health in general [85]. Metabolites can alter insulin action and metabolic processes, as evidenced by the activation of AMPK and mTOR signaling pathways in response to changes in nutrition availability, and microbiota‐associated increases in SCFAs have been linked to AMPK activation in metabolic tissues in experimental models [82, 85].

Moreover, metabolites can directly affect insulin signaling and regulate genes related to fat and glucose metabolism. Studies showed that the interaction of vitamin A and insulin signaling pathways controls hepatic glucose and fat metabolism, illustrating the significance of communication between various signaling pathways [80]. Gut‐derived metabolites such as SCFAs, bile acids, and indoles also contribute to these processes by binding to GPCRs and nuclear receptors that converge on PI3K/Akt, mTOR, and NF‐κB signaling pathways [84]. Consequently, the synergistic impact that this cross‐talk may have on metabolic regulation affects the function of metabolites in regulating insulin activity.

Additionally, the discovery of certain metabolites that bind to G‐protein‐coupled receptors (GPCRs) provides a better understanding of how metabolites might affect insulin signaling and play a role in the development of insulin resistance and obesity, highlighting how GPCR‐mediated signaling pathways may be useful therapeutic targets [88]. SCFAs binding to GPR43 and bile acid metabolites binding to TGR5 have been shown to engage downstream PI3K/Akt and mTOR pathways controlling energy balance and insulin sensitivity [84]. The combination of transcriptomics and metabolomics allows the understanding of the intricate relationships between metabolites and insulin signaling pathways. This may allow for the discovery of biomarkers for metabolic diseases and a better understanding of the regulatory processes underlying insulin action by studying the changes in metabolite profiles and gene expression in response to insulin [89]. Additionally, using an integrated approach may open the doors to new pharmaceutical interventions that target insulin sensitivity and delay the development of insulin resistance.

Figure 2 summarizes the mechanistic pathways linking gut dysbiosis to insulin resistance, highlighting the roles of microbial metabolites, inflammatory signaling, and impaired insulin receptor pathways.

FIGURE 2.

Mechanistic model of how gut dysbiosis contributes to insulin resistance.

Dysbiosis increases LPS production, activating TLR4–JNK/IKK signaling and inhibiting IRS‐1, which shifts metabolism toward insulin resistance. This state is reinforced by elevated BCAAs and impaired gut barrier integrity, while SCFAs produced in eubiotic conditions promote insulin sensitivity by reducing inflammation and strengthening the barrier. Several therapeutic strategies act on these nodes, including dietary fiber to increase SCFAs, reduced saturated fat to lower LPS, omega‐3 fatty acids and exercise to dampen inflammatory signaling, and probiotics or microbiota‐targeted therapies to restore beneficial taxa.

4. Role of Gut Microbiota‐Derived Metabolites in Insulin Resistance

Low‐grade inflammation has been linked to insulin resistance and a variety of metabolic disorders [90]. According to the findings of the Human Microbiome Project, the human gut is predominantly inhabited by gram‐positive Firmicutes, with additional significant populations of Actinobacteria and gram‐negative Bacteroidetes present [90]. More recent human studies have expanded this understanding. A 2025 systematic review in adults with obesity reported reproducible shifts in specific genera, including higher abundances of Blautia, Collinsella, and Megamonas and lower levels of Bifidobacterium and Faecalibacterium, alongside reduced microbial diversity and functional alterations in metabolic pathways [91]. Obesity has long been associated with reduced Bacteroidetes and increased Firmicutes, although more recent evidence indicates that these phylum‐level shifts are not universally consistent across populations [90].

Other studies suggest that the decrease in bacteroidetes can be associated with an increase in actinobacteria rather than firmicutes [90]. Although an elevated Firmicutes‐to‐Bacteroidetes ratio has been proposed to enhance the breakdown of indigestible polysaccharides into SCFAs, subsequently converted to triglycerides in the liver, large‐scale reviews demonstrate that this ratio does not consistently correlate with obesity [90]. In children and adolescents, a 2025 systematic review of 70 studies reported substantial heterogeneity and no consistent association between the F/B ratio and obesity‐related phenotypes [92]. Similarly, a 2024 adult cohort from Croatia observed no association between the ratio and body mass, suggesting that phylum‐level markers may not reliably capture microbiome alterations relevant to metabolic disease [47].

The interaction between LPS from gram‐negative bacteria and Toll‐like receptors contributes to insulin resistance and obesity [93]. Obesity and high‐fat diets increase intestinal epithelial permeability, enabling the translocation of LPS into the bloodstream and promoting metabolic endotoxemia [93]. Human trials reinforce this mechanism: in a 2025 randomized crossover study, adults, particularly those with obesity, exhibited significant increases in circulating endotoxin and zonulin after only 5 days of a high‐fat diet, demonstrating rapid diet‐induced permeability changes [94]. Because LPS is transported through chylomicrons, fat‐rich diets may further amplify insulin resistance [93]. Additional clinical evidence supports the inflammatory relevance of endotoxemia: reduced circulating LBP concentrations were associated with greater hepatic fat accumulation, adipose inflammation, and more advanced MAFLD in adults with obesity [95].

TLR4 recognizes LPS as well as saturated fatty acids, triggering downstream inflammatory signaling in metabolic tissues. Activation of the TLR4 pathway stimulates key serine kinases, including JNK and IKKβ, through MyD88‐ and TRIF‐dependent cascades, promoting inflammatory gene expression and impairing insulin signaling [96, 97]. This mechanistic link is supported by in vivo evidence: mice harboring a loss‐of‐function mutation in TLR4 are protected from high‐fat‐diet–induced obesity, inflammation, and insulin resistance [98]. In adipose and metabolic tissues, TLR4 activation increases pro‐inflammatory cytokines such as TNF‐α and IL‐6, further amplifying insulin resistance [90]. Moreover, TLR4 engagement induces iNOS expression, elevating nitric oxide levels; in skeletal muscle cells, increased NO promotes IRS‐1 degradation and disrupts downstream insulin signaling [99]. Together, these inflammatory and nitrosative processes illustrate how TLR4‐driven signaling contributes directly to impaired insulin receptor pathway function and systemic insulin resistance. Complementing these mechanistic data, human genetic evidence supports physiological relevance: the TLR4 Thr399Ile polymorphism has been associated with increased risk of type 2 diabetes [100].

TLR2, which is responsible for recognizing both pathogen‐associated molecular patterns (PAMPs) and danger‐associated molecular patterns (DAMPs), also plays a role in metabolic inflammation [90]. When activated by fatty acids or microbial products, it can cause an inflammatory cascade that produces cytokines like TNF‐α and IL‐6, which can impair insulin signaling [90]. Also, TLR2 activation in adipocytes and muscle cells activates pro‐inflammatory pathways such as NF‐κB and MAPK, which contribute to insulin resistance [90]. Unlike TLR4 deletion, which protects against insulin resistance, TLR2 and TLR5 knockout mouse models develop obesity, suggesting that alterations in gut microbiota composition can override genotype‐based protection and promote insulin resistance [90, 93]. These findings collectively highlight that gut‐derived inflammatory signaling pathways, particularly those involving LPS–TLR interactions, play a central role in connecting microbial dysbiosis to impaired insulin sensitivity.

5. Dietary Factors and Lifestyle

5.1. Dietary Interventions

The composition of the gut microbiota and its metabolite production have been redundantly shown to be greatly influenced by the individuals' diet and lifestyle choices; this subsequently has greater implications on their overall health and wellbeing. Dietary choices can rapidly change gut microbial composition and gene expression. A study comparing following a fast‐food diet versus Mediterranean diets found that within only 4 days, each diet distinctly changed the human gut microbiome and associated tryptophan metabolites [101]. Similar studies revealed that plant‐based diets have been shown to quickly modify gut microbial composition and gene expression, leading to significant changes in metabolite products [102].

Emerging evidence from recent human studies further highlights the metabolic effects of specific dietary components. Dietary fibers that promote the production of short‐chain fatty acids, such as acetate, propionate, and butyrate, support the growth of bacteria including Bifidobacterium and Akkermansia muciniphila . These SCFAs improve insulin sensitivity by reducing inflammation, strengthening gut barrier function, and regulating glucose metabolism through G‐protein–coupled receptors [43, 103]. A 2025 randomized controlled trial demonstrated that intrinsic chicory root fibers increased fecal butyrate and upregulated butyrate‐producing pathways while simultaneously improving whole‐body and peripheral insulin sensitivity in adults with obesity [104]. Likewise, a 2024 placebo‐controlled pilot RCT in adults with pre‐diabetes found that a diverse prebiotic fiber supplement improved insulin sensitivity, reduced inflammatory biomarkers, and modulated gut microbial composition and SCFA‐related pathways [105].

Furthermore, plant‐based foods, rich in polyphenols and prebiotics such as those found in fruits, vegetables, and whole grains, are metabolized by gut bacteria into bioactive compounds that can alleviate oxidative stress and inflammation, thus improving insulin sensitivity [4, 106].

High‐fiber and plant‐rich dietary patterns have also been evaluated at the meta‐analytic level. A 2023 systematic review and meta‐analysis of dietary interventions in type 2 diabetes reported that high‐fiber, Mediterranean‐style, and personalized diets frequently increased SCFA‐producing bacteria and improved metabolic parameters such as fasting glucose, LDL‐cholesterol, or HOMA‐IR, depending on the dietary subtype [107]. Similarly, a 2024 systematic review examining prebiotics and Mediterranean or plant‐based diets found consistent improvements in gut microbiota composition, particularly increases in Bifidobacterium and favorable shifts in the Firmicutes/Bacteroidetes profile, although glycemic improvements (FBG, HbA1c) were modest and variable across trials [108].

Fat quality also plays a central role. Omega‐3 fatty acids, while not directly altering gut microbiota in the trials reviewed, have been repeatedly shown to improve systemic metabolic outcomes. A 2023 meta‐analysis of randomized controlled trials in women with gestational diabetes demonstrated that omega‐3 supplementation significantly reduced fasting glucose, fasting insulin, HOMA‐IR, triglycerides, and CRP while increasing HDL cholesterol [109]. These findings reinforce the insulin‐sensitizing and anti‐inflammatory potential of omega‐3 fatty acids in human metabolic disorders.

Conversely, high‐fat diets, mostly those rich in saturated fats, negatively affect gut microbiota composition by leading to an increase in lipopolysaccharide (LPS)‐producing bacteria which subsequently results in endotoxemia and promoting chronic inflammation, which exacerbates insulin resistance [110, 111]. Lipopolysaccharides and branched‐chain amino acids contribute to insulin resistance by inducing inflammation and disrupting metabolic pathways metabolites [110, 112].

Collectively, these studies highlight dietary interventions, especially increased fermentable fiber intake, diverse prebiotic supplementation, plant‐rich or Mediterranean dietary patterns, and reduced saturated fat consumption as effective strategies to modulate gut microbiota, enhance SCFA production, and improve insulin sensitivity.

5.2. Lifestyle Factors

Lifestyle behaviors, including physical activity, overall dietary patterns, and other environmental exposures, also influence gut microbiome composition and metabolic health. Regular physical exercise has been shown to positively affect skeletal muscle function, immune regulation, and gut microbial profiles across age groups [113]. Recent human evidence reinforces these findings. A 2025 systematic review and meta‐analysis in individuals with obesity and type 2 diabetes demonstrated that structured exercise interventions (aerobic, resistance, or combined training) modestly increased microbial diversity, enriched short‐chain–fatty‐acid–producing taxa, and were often accompanied by improvements in glycemic control and cardiometabolic markers [114].

Similarly, in a 6‐week resistance training trial among young adults with overweight and obesity, Cullen et al. reported favorable shifts in gut microbiome composition alongside improvements in cardiometabolic health, indicating that resistance exercise alone can modulate both microbial communities and metabolic risk profiles [115]. In postmenopausal women with type 2 diabetes, a randomized controlled trial of home‐based exercise training led to significant improvements in metabolic parameters and cognitive outcomes, accompanied by increases in several bacterial taxa linked to beneficial metabolic effects [116]. However, not all training protocols elicit substantial microbiota changes: a 10‐week resistance training trial in younger and older adults reported minimal alterations in gut microbiota, short‐chain fatty acids, and fecal metabolomic profiles despite measurable gains in muscular strength, underscoring inter‐individual variability and the influence of exercise type, duration, and baseline physiological state [117]. Overall, lifestyle patterns more broadly determine microbial diversity, abundance of beneficial taxa, and production of key metabolites that influence host physiology [118, 119].

Environmental factors additionally modulate microbiota composition. For example, co‐housing studies demonstrate microbial transfer between animals and corresponding changes in metabolic phenotypes [90]. Diet remains the dominant determinant of microbial composition, as the gut microbiota relies heavily on dietary substrates for metabolite production [120].

Evidence from long‐term integrated lifestyle interventions further supports this interaction: in a 1‐year randomized clinical trial in adults with metabolic syndrome, an energy‐reduced Mediterranean diet combined with physical activity promotion resulted in greater weight loss and broader cardiometabolic improvements compared with an ad libitum Mediterranean diet. These benefits were accompanied by increased microbial diversity, reductions in potentially adverse taxa, such as the Eubacterium hallii group and Dorea, and shifts in fecal metabolite subnetworks, including bile acids, sphingolipids, and fatty acids that correlated with improved metabolic outcomes [121].

Collectively, lifestyle interventions involving exercise and sustained dietary improvements, particularly those that increase fiber intake and reduce saturated fat, offer a promising non‐pharmacological approach for improving gut microbiota composition and mitigating insulin resistance.

6. Conclusion

Insulin resistance is a complicated disorder that is intricately linked to both local and systemic metabolic processes. Of these, the gut microbiota and its byproducts have been found to have a major role in controlling insulin sensitivity and metabolic health in [122]. Gut microbiota affects the equilibrium between metabolic homeostasis and dysfunction by modifying important pathways through the synthesis of bioactive substances such as BCAAs and SCFAs [17]. By strengthening the intestinal barrier, lowering inflammation, and affecting energy metabolism, SCFAs like butyrate and acetate improve insulin sensitivity [123]. On the other hand, persistent low‐grade inflammation and metabolic stress are linked to higher levels of BCAAs and other toxic microbial metabolites, such as LPS, which worsen insulin resistance [124].

Although substantial progress has been made, several important gaps remain. The microbial taxa and metabolite signatures most strongly linked to causal changes in insulin signaling are still being refined, and the balance between direct microbial metabolite actions and indirect immune‐ or endocrine‐mediated effects remains incompletely clarified [125]. Interactions between host factors, including diet, genetics, medication exposure, and lifestyle, and the microbiome continue to constrain our ability to predict individual responses to therapy. Advancing the field will require integrative multi‐omics analyses, mechanistic studies, and longitudinal human cohorts capable of linking microbial function with metabolic outcomes [126].

Future research should prioritize randomized controlled trials testing microbiome‐directed dietary strategies, targeted probiotic and synbiotic formulations, SCFA‐ and bile‐acid–based therapeutics, and optimized fecal microbiota transplantation protocols in metabolic disease. Precision‐nutrition trials stratified by baseline microbiome composition, as well as studies evaluating pharmacological modulation of microbial metabolites, represent key translational avenues.

Emerging therapeutic strategies targeting the gut microbiota provide a promising path forward. Dietary modulation, probiotics, prebiotics, synbiotics, fecal microbiota transplantation, and metabolite‐based therapeutics have all demonstrated potential for restoring microbial balance and improving insulin sensitivity [127]. Continued exploration of these microbial‐derived metabolites, as well as synthetic or pharmacological analogs, may yield next‐generation interventions capable of modulating insulin signaling with greater specificity [128]. The development of personalized, microbiome‐informed therapeutic strategies will be essential, as interindividual variation in microbial composition and metabolic output strongly shapes treatment outcomes [129].

In summary, the gut microbiota has evolved from a peripheral component of metabolism to a central determinant of insulin resistance and metabolic disease. Harnessing its therapeutic potential, through diet, targeted microbial interventions, and metabolite‐based strategies, holds considerable promise. Realizing this potential will require deeper mechanistic insight and rigorous clinical validation, but it offers one of the most compelling future directions for combating the global burden of insulin resistance and type 2 diabetes.

Author Contributions

M. Al Qassab, N. Chaarani, A. Hamou, R. Harb, A. Jradi, and M. Zeineddine contributed equally to the conception, literature review, data synthesis, and drafting of the manuscript. F. Harb and A. Kanaan served as corresponding authors and supervised the overall work. H.E. Ghadieh, Z. Abi Khattar, and S. Azar critically proofread the manuscript and provided valuable intellectual input. S. Azar also supported the work in his role as Dean of the Faculty. All authors read and approved the final version of the manuscript.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Al Qassab M., Chaarani N., Hamou A., et al., “The Gut Microbiota–Insulin Resistance Axis: Mechanisms, Clinical Implications, and Therapeutic Potential,” FASEB BioAdvances 8, no. 1 (2026): e70080, 10.1096/fba.2025-00218.

Data Availability Statement

Stored in repository.