Impact of ileostomy reversal on gut microbiome and metabolome in rectal cancer: a review of mechanisms and clinical consequences

Prophylactic ileostomy is a critical measure for preventing anastomotic leakage after low rectal cancer surgery; however, the incidence of diarrhea following stoma reversal remains high, posing a major clinical challenge. Recent studies have revealed that the underlying pathophysiology involves not only anal sphincter dysfunction but also a comprehensive imbalance in the gut microbiota–metabolite–immune axis. This review systematically elucidates the dynamic evolution of the gut microbiome after stoma reversal and its interplay with host metabolism. It further delves into multidimensional pathophysiological mechanisms, including gut dysbiosis, reduced production of short-chain fatty acids, dysregulated bile acid metabolism, and impaired intestinal barrier integrity. In light of recent advances, this article analyzes the clinical characteristics and subtypes of postoperative diarrhea, summarizes precision diagnostic strategies based on multi-omics technologies, and provides an objective assessment of emerging therapies such as probiotics, fecal microbiota transplantation, metabolic interventions, and nutritional support. Finally, the necessity of establishing an integrated multidisciplinary management model is discussed, with the aim of offering new perspectives and a theoretical foundation for improving the quality of life in rectal cancer patients after surgery.

Highlights

Systematically elucidates the core mechanism of postoperative diarrhea after ileostomy reversal lies in the asynchrony between "anatomical continuity restoration" and "functional microbiota recovery".

In-depth analysis of the cascading effects among structural gut microbiota imbalance, short-chain fatty acid and bile acid metabolic disorders, and multi-level intestinal barrier damage.

Proposes a precision diagnostic classification strategy based on multi-omics (microbiome, metabolome), shifting clinical diagnosis from symptom description to mechanistic classification.

Comprehensive review of the paradigm shift from traditional symptomatic treatment to emerging etiology-targeted interventions, including precision probiotics, microbiota transplantation, metabolite supplementation, and personalized nutrition.

Advocates for establishing a multidisciplinary integrated management model, providing a systematic theoretical framework and practical pathway for improving postoperative quality of life in rectal cancer patients.

Colorectal cancer (CRC) is a major global public health issue and the second most common malignancy in China, with its incidence showing a continuous upward trend. In 2022, there were approximately 517,100 new cases in China, accounting for 26.9% of global new cases [1]. Unlike Western countries where colon cancer predominates, CRC in China exhibits distinct characteristics of “rectal cancer predominance and a high proportion of low-lying lesions,” with low-lying rectal cancer comprising 60%–70% of cases [2]. This anatomical feature leads to a significantly increased risk of anastomotic leakage (AL) following surgery in patients with low-lying rectal cancer. Therefore, protective ileostomy (PI) has become a standard protective strategy after anterior resection for mid-to-low rectal cancer. It effectively diverts fecal flow, reduces AL-related mortality by approximately 60%, and significantly shortens hospital stays for patients with abdominal infections [3, 4].

However, “creating a stoma is easy, but closing it is difficult.” Although ileostomy closure aims to restore intestinal continuity, about 30%–50% of patients experience postoperative diarrhea, with 15%–20% developing chronic diarrhea (duration > 4 weeks) [5–7]. Such diarrhea not only leads to direct complications such as water-electrolyte imbalances, malnutrition, and incontinence-associated dermatitis but also prolongs hospitalization, increases medical costs, and worsens patient prognosis [8–11]. Previously, this type of diarrhea was often attributed to low anterior resection syndrome (LARS). However, with the widespread adoption of laparoscopic and robotic surgeries, the incidence of LARS has declined, while postoperative diarrhea has not shown corresponding improvement, suggesting the existence of deeper, yet insufficiently understood, pathophysiological mechanisms.

In recent years, the rapid development of systems biology approaches such as microbiomics and metabolomics has prompted researchers to re-examine this clinical issue from the new perspective of the “microbiota-gut-organ axis” [12, 13]. The gut microbiota, as the largest microecosystem in the human body, maintains a sophisticated co-metabolic and co-evolutionary relationship with the host [14]. PI fundamentally alters the microenvironment of the distal colon, creating a “physiological diversion.” Although closure surgery restores anatomical continuity of the intestine, the reconstruction of the microecosystem may be significantly delayed or abnormal. This asynchrony between the “restoration of anatomical connectivity” and the “restoration of functional microecology” may represent the core mechanism underlying postoperative diarrhea.

This review examines the dynamic trajectories of gut microbiota structure and plasma metabolic profiles during the perioperative period of ileostomy closure in rectal cancer patients, aiming to reveal the intrinsic connections among microbiota, metabolites, and clinical phenotypes, and to provide a theoretical basis for clinical intervention.

Search strategy

A systematic search was conducted in PubMed, Embase, Web of Science, Scopus, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Data, and China Biology Medicine disc (CBM) databases to retrieve relevant literature published prior to November 2025. The search strategy employed subject terms including “ileostomy reversal” and “gut microbiota.” The inclusion criteria comprised: (1) retrospective studies that examined the association between ileostomy reversal and gut microbiota; and (2) interventional studies assessing the dynamic changes in gut microecology following ileostomy reversal and their interactions with host metabolism. Studies were excluded if they were: (1) secondary literature (e.g., reviews, case reports, editorials, commentaries, and conference abstracts); (2) non-human studies; or (3) studies with incomplete or inadequate statistical reporting. The detailed search strategy is presented in Fig. 1.

Fig. 1.

Flow chart of literature search strategies

I. Pathogenesis of postoperative diarrhea

Postoperative gut microbiota reconstitution: surgical consequence or continuation of cancer-associated dysbiosis? Distinguishing between these two drivers is essential to understanding microbial dynamics after ileostomy reversal. CRC itself is characterized by significant microbial alterations—termed ‘tumor-associated dysbiosis’ [15]—marked by pathogen enrichment, butyrate-producer depletion, and reduced diversity. In contrast, diverting ileostomy imposes a profound environmental shift on the distal colon: complete deprivation of luminal fermentable substrates (dietary fiber). This triggers acute collapse of short-chain fatty acid (SCFA)-producers and disrupts mucus homeostasis—a drastic ecological shift driven directly by surgery [16]. Using a longitudinal design with intra-individual comparisons, Xu et al. [17] demonstrated that surgical intervention—stoma creation and reversal—is an independent and dominant driver of gut microbiota fluctuation. Therefore, understanding post-reversal diarrhea requires situating it within the context of underlying cancer-associated dysbiosis, with emphasis on the superimposed and amplifying effects of ileostomy.

Structural remodeling and ecological dysbiosis of the gut microbiota

The healthy adult intestine harbors approximately 10¹⁴ microorganisms—a complex ecosystem dominated by Firmicutes and Bacteroidetes that maintain dynamic equilibrium. Patients with CRC universally harbor baseline dysbiosis, characterized by reduced α-diversity, altered community structure, and enrichment of potentially pathogenic bacteria [15]. Creation of a diverting ileostomy profoundly exacerbates this dysbiosis. During the stoma period, substrate depletion (e.g., dietary fiber) in the excluded colon triggers massive decline of obligate anaerobes, particularly SCFA-producing genera (Faecalibacterium, Roseburia, Eubacterium) [16, 18, 19]. Concomitantly, the mucus layer becomes a primary carbon source, driving proliferation of mucin-degraders like Akkermansia muciniphila. While A. muciniphila is generally beneficial, its overgrowth in the postoperative inflammatory milieu can compromise mucus integrity, exacerbating barrier dysfunction [20]. After stoma reversal, microbial reconstitution often deviates: recovery of beneficial bacteria is delayed, while opportunistic pathogens (e.g., Escherichia coli, Klebsiella spp., Enterococcus spp.) rapidly colonize vacated niches [17]. This “failed colonization” perpetuates microbial imbalance and predisposes patients to subsequent metabolic disturbances.

This bacterial remodeling, however, represents only one facet of a more complex picture. The gut mycobiota—a long-neglected ecosystem dimension—remains a critical blind spot in understanding post-reversal diarrhea. Ileostomy-induced environmental shifts (pH, oxygen, nutrients) also reshape mycobiota composition [21]. For instance, bacterial-derived SCFAs suppress opportunistic fungi like Candida albicans [22]. When SCFA-producers are depleted post-ileostomy, this cross-kingdom resistance collapses, enabling fungal overgrowth. After reversal, multi-kingdom dysbiosis exacerbates inflammation and barrier dysfunction. For example, β-glucan from fungal cell walls, fermented by bacterial enzymes, produces metabolites that paradoxically promote expansion of co-existing pathogens (e.g., Klebsiella, Enterobacter, Acinetobacter) [23]. Future research must therefore adopt a multi-kingdom perspective, integrating the mycobiota to fully elucidate the mechanisms driving postoperative diarrhea.

Functional disruption of key metabolic pathways

Structural changes in the gut microbiota directly impact its metabolic functions, with dysregulation of SCFA and bile acid (BA) metabolism being particularly prominent.

Impairment of SCFA metabolism

SCFAs are the primary metabolites produced by gut microbiota through the fermentation of dietary fiber. Acetate, propionate, and butyrate collectively account for over 90% of total SCFAs, typically in a ratio of approximately 1:1:3 [24, 25]. SCFAs exert their effects via G protein-coupled receptors 41 (GPR41), GPR43, and GPR109a, serving as key regulators of glucose, lipid, and energy metabolism [26, 27]. For instance, SCFAs can enhance the secretion of glucagon-like peptide‑1 from intestinal L cells through GPR41 and GPR43 [28], thereby inhibiting hepatic lipogenesis and gluconeogenesis, while promoting fatty acid oxidation by upregulating hepatic peroxisome proliferator-activated receptor α and AMP-activated protein kinase [29]. SCFAs play multiple roles in maintaining intestinal homeostasis. Butyrate serves as the primary energy source for colonic epithelial cells, meeting 60%–70% of their energy demands. It also regulates gene expression by inhibiting histone deacetylases, thereby promoting epithelial cell differentiation and the synthesis of tight junction proteins [30, 31]. Furthermore, SCFAs modulate the proliferation, differentiation, phenotype, and cytokine expression of various immune cells, including monocytes, T cells, B cells, and innate lymphoid cells. For example, butyrate regulates metabolic reprogramming in macrophages by increasing oxidative phosphorylation and inhibiting aerobic glycolysis. It also promotes their polarization toward the anti-inflammatory M2 phenotype and IL‑10 secretion via GPR109a [32]. Studies by Kespohl et al. [33] and Chen et al. [34] further demonstrate that SCFAs can guide naïve T-cell differentiation toward Th1 rather than Th17 by upregulating T‑bet and downregulating RORγt, thereby reducing IL‑17 production.During stoma diversion, the lack of fermentable substrates in the intestine leads to a significant reduction in SCFA levels. Ohigashi et al. [16] reported that the total fecal organic acid concentration in CRC patients postoperatively was lower than preoperatively (77.9 ± 40.1 vs. 50.1 ± 37.0 µmol/g, p < 0.001), with SCFAs notably decreased. This state of “metabolite starvation” results in insufficient energy supply to the colonic epithelium, disruption of tight junctions (e.g., downregulation of tight junction proteins and zonula occludens‑1), and reduced mucus secretion, ultimately leading to severe impairment of intestinal barrier function [35].

Dysregulation of BA metabolism

BA metabolism represents another key pathway significantly impacted. The bile acid pool is composed of both primary bile acids (PBAs) and secondary bile acids (SBAs). Approximately 95% of PBAs synthesized in the liver are reabsorbed in the terminal ileum, entering the enterohepatic circulation. The remaining portion enters the colon, where it undergoes metabolic transformation by the gut microbiota. In the colon, PBAs conjugated with taurine or glucuronic acid are deconjugated by bile salt hydrolases (enzymes widely distributed across various microbial taxa including Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, and Archaea) [36]. Subsequently, the unconjugated PBAs can be further converted into SBAs via 7α-dehydroxylation, a reaction catalyzed by 7α-hydroxylase encoded by bile acid-inducible operons present in certain bacteria of the Clostridium cluster XIVa [37]. Conversely, bile acids themselves can directly shape microbiota structure through their detergent-like properties and their susceptibility to microbial metabolism, and indirectly influence microbial composition by modulating host antimicrobial peptide expression and immune responses [38]. Following ileostomy closure, patients’ fecal microbiota often exhibits an expansion of Proteobacteria (e.g., Escherichia coli from the Enterobacteriaceae family) and a decrease in the abundance of Firmicutes (e.g., members of the order Clostridiales). This shift leads to the accumulation of PBAs and increased levels of sulfated bile acids, while SBAs are correspondingly reduced. Excess PBAs can increase intestinal permeability, downregulate the expression of tight junction proteins, and stimulate massive secretion of water and electrolytes, constituting a key mechanism for secretory diarrhea [39]. Simultaneously, alterations in the composition of the bile acid pool can disrupt the Farnesoid X Receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) signaling pathways, further perturbing intestinal metabolic homeostasis [40]. These changes can also lead to a significant reduction in the number of colonic FOXP3 + regulatory T (Treg) cells, compromising immune homeostasis and increasing susceptibility to inflammatory colitis [41].

Impairment of intestinal barrier integrity and function

The intact intestinal barrier is comprised of the mechanical barrier (intestinal epithelial cells and their tight junctions), the chemical barrier (mucus layer), the immune barrier (immune cells and their secreted factors), and the biological barrier (gut microbiota and their metabolites) [42]. Under physiological conditions, these barrier components function synergistically and regulate each other, collectively maintaining intestinal homeostasis and systemic metabolic-immune balance. Dysbiosis and metabolic disturbances can jointly disrupt this multi-layered defense system. Regarding the mechanical barrier, reduced levels of SCFAs impair energy metabolism in intestinal epithelial cells, leading to the downregulation of tight junction proteins such as zonula occludens (ZO)-1, -2, -3, and occludin. Consequently, epithelial permeability increases. The chemical barrier is primarily composed of Mucin-2 (MUC2) secreted by goblet cells and antimicrobial peptides (AMPs) produced by Paneth cells. The colonic mucus layer is densely structured and continuous, with MUC2 anchored to the epithelial surface, effectively blocking pathogen infiltration. Studies indicate that FXR activation can inhibit goblet cell apoptosis [43], while deoxycholic acid can significantly upregulate Muc2 mRNA expression in goblet cells, promoting MUC2 secretion and thereby enhancing chemical barrier function [44]. Following stoma closure, microbiota dysbiosis triggers goblet cell apoptosis, resulting in thinning and compositional changes of the mucus layer, which diminishes its defensive capacity. The immune barrier primarily consists of immune cells distributed within the intraepithelial lymphocyte compartment, lamina propria, and Peyer’s patches, such as monocytes, T lymphocytes, B cells, and innate lymphoid cells (ILCs). Functionally, they can be categorized into two major groups: immunosuppressive (anti-inflammatory) populations, including M2 macrophages, regulatory T (Treg) cells, ILC3s, and B cells; and immunostimulatory (pro-inflammatory) populations, including M1 macrophages, Th1, and Th17 cells [45]. Macrophages are central regulators of intestinal immunity. Upon stimulation by IFN-γ, TNF-α, or lipopolysaccharide, they can polarize into the M1 phenotype, secreting IL-1β, IL-6, IL-12, TNF-α, and various chemokines (e.g., CCL2–5, CXCL9–11), thereby exerting pro-inflammatory effects [46]. Conversely, M2 macrophages primarily mediate immunosuppression via IL-10 secretion [47]. ILC3s play a crucial bridging role in the interaction between macrophages and Treg cells: regulated by macrophage-derived IL-1β, ILC3s can produce granulocyte-macrophage colony-stimulating factor, which in turn activates dendritic cells and macrophages to secrete IL-10, promoting Treg cell differentiation [48]. Microbiota disruption can upset this immune equilibrium, manifesting as decreased proportions of Treg cells, M2 macrophages, ILC3s, and B cells, alongside increased proportions of pro-inflammatory cells such as M1 macrophages, Th1, and Th17 cells. This leads to abnormal IgA secretion, dysfunction of mucosa-associated lymphoid tissue, and a disruption of the pro-inflammatory/anti-inflammatory balance. These multi-faceted barrier dysfunctions ultimately create a state of “leaky gut,” facilitating the translocation of bacteria and endotoxins into the portal circulation. This activates systemic low-grade inflammation, which further deteriorates the intestinal microenvironment, forming a vicious cycle.

Synergistic amplification effect of high-risk factors

Multiple patient-related and iatrogenic factors can synergistically amplify the aforementioned pathological processes:

Patient factors

Age ≥ 65 years increases postoperative diarrhea risk, driven by diminished gut microbiota stability—characterized by an altered Firmicutes/Bacteroidetes ratio and reduced diversity—as well as impaired mucosal repair capacity and immune senescence [49]. Diabetes-related microvascular dysfunction, autonomic neuropathy, and chronic inflammation each compromise intestinal barrier integrity, increasing diarrhea risk by 15% (95% CI: 7.8–22) [50]. Active inflammatory bowel disease (IBD) confers a substantially higher risk [51, 52]. First, active inflammation directly disrupts the intestinal barrier, increasing permeability, impairing tight junctions, and suppressing epithelial regeneration. Second, IBD-associated dysbiosis—reduced diversity, enrichment of pro-inflammatory taxa, and altered SCFA metabolism—not only weakens barrier function but also amplifies local inflammatory responses. Perioperative factors—particularly antibiotic exposure and surgery-induced anatomical alterations (e.g., ileocecal valve resection, reduced absorptive surface)—further exacerbate this dysbiosis and barrier dysfunction.

Iatrogenic factors

Neoadjuvant chemotherapy—particularly irinotecan-based regimens—directly injures intestinal epithelial cells and disrupts the gut microbiota. This is evidenced by reduced abundances of beneficial taxa (e.g., Bifidobacterium, Lactobacillus) and the induction of intestinal mucositis [53, 54]. Neoadjuvant radiotherapy inflicts persistent mucosal and microbial damage via DNA damage and oxidative stress, reducing α-diversity and inducing dysbiosis [55]. Prolonged broad-spectrum antibiotics (> 7 days) exacerbate microbiota disruption and mucosal injury, with damage severity correlating with treatment duration. This increases the risk of postoperative diarrhea several-fold, particularly antibiotic-associated diarrhea and C. difficile infection [56, 57]. Duration of diverting ileostomy represents an independent risk factor for postoperative diarrhea: retention exceeding 6 months is associated with a 1.5-fold increased risk [58]. This elevated risk is primarily attributable to distal colonic mucosal atrophy, neuromuscular dysfunction, and persistently altered colonization resistance. The duration of ileostomy not only determines the severity of dysbiosis but also influences its nature and reversibility, exhibiting a clear temporal gradient effect.

In the early phase following stoma creation (< 3 months), alterations in the distal colonic microbiota are characterized by acute deprivation of metabolic substrates (dietary fiber), leading to reduced abundance and functional inhibition of SCFA-producing bacteria (e.g., Faecalibacterium, Roseburia); however, the overall microbial community structure retains potential reversibility during this period [59, 60]. During the intermediate phase (3–6 months), sustained intestinal disuse triggers structural shifts in the microbiota. Disruption of the luminal hypoxic microenvironment enables facultative anaerobes (e.g., Enterobacteriaceae) to gain competitive advantage through aerobic respiration or utilization of alternative electron acceptors (nitrate, sulfur oxides), progressively displacing obligate anaerobes and leading to further declines in microbial diversity [61, 62]. Beyond 6 months of ileostomy, prolonged absence of luminal nutrients (particularly butyrate) induces disuse atrophy of the distal colonic mucosa, characterized by goblet cell depletion and thinning of the mucus layer, which consequently reduces total bacterial load and impairs colonization resistance of keystone functional taxa [63]. Following stoma reversal, even after restoration of intestinal continuity, the atrophied mucosa and altered microbial ecosystem cannot readily re-establish a normal microenvironment in the short term. This mechanistic sequence explains the substantially elevated risk of postoperative diarrhea observed in patients with long-term ileostomy.

Heterogeneity and complexity of clinical manifestations

Postoperative diarrhea following ileostomy closure exhibits high heterogeneity in its clinical presentation. Based on its core pathophysiological mechanisms, it can be classified into the following four types:

1. Secretory Diarrhea: Characterized primarily by large volumes of watery stools, with diarrhea volume showing no significant reduction after fasting. Daily stool output often exceeds 1 L. Its occurrence is frequently associated with bile acid malabsorption or bacterial toxin stimulation. Patients often present with significant electrolyte disturbances and dehydration symptoms [64].

2. Osmotic Diarrhea: Mainly caused by carbohydrate malabsorption and insufficient SCFA production. Symptoms may alleviate after fasting, accompanied by an increased fecal osmotic gap. Patients often exhibit manifestations of abnormal carbohydrate fermentation, such as abdominal distension and hyperactive bowel sounds.

3. Motility-associated Diarrhea: Closely related to dysfunction of the enteric nervous system and LARS. Common manifestations include fecal urgency, incontinence, and increased frequency with relatively small individual stool volumes. It often coexists with other types of diarrhea.

4. Inflammatory Diarrhea: Often associated with Clostridioides difficile infection or exacerbation of underlying inflammatory bowel disease. Clinical signs may include fever, abdominal pain, and bloody stools. Fecal calprotectin levels are typically significantly elevated.

Evolution and integration of modern diagnostic strategies

Traditional diagnostic methods, which primarily rely on medical history, physical examination, and routine laboratory tests, are often insufficient for elucidating the underlying mechanisms of diarrhea. Modern diagnostic strategies should integrate multi-omics technologies to drive a transition from symptomatic description to mechanistic subtyping:

Microbiomics analysis

16 S rRNA gene sequencing can be used for rapid assessment of overall microbiota structure and diversity changes; metagenomic sequencing can further dissect functional gene composition and predict metabolic potential [65]. Key indicators to focus on include: microbiota alpha-diversity indices (e.g., Shannon, Chao1), the relative abundance of key functional bacterial groups (e.g., butyrate producers), enterotype distribution, and potential overgrowth of opportunistic pathogens.

Metabolomics analysis

Utilize liquid chromatography-mass spectrometry to profile metabolites in fecal and plasma samples, with a focus on changes in key pathways such as SCFAs, bile acid profiles, and tryptophan metabolites. Metabolomics data not only reflect the functional state of the gut microbiota but also provide direct evidence for related pathophysiological mechanisms [66].

Barrier function and inflammatory markers

Serum zonulin and lipopolysaccharide-binding protein can be used to assess intestinal barrier permeability [67]; fecal calprotectin is a sensitive indicator of intestinal inflammation [68]; serum cytokine profiles (e.g., IL-6, IL-8, TNF-α) help evaluate the systemic inflammatory state.

Integrated bioinformatics analysis

Employ multivariate statistical analysis and machine learning algorithms to integrate microbiome, metabolomic, and clinical data to construct predictive models [69]. This enables precise subtyping of postoperative diarrhea (e.g., “dysbiotic type,” “bile acid type,” “inflammatory type,” and “mixed type”), providing a basis for individualized treatment.

Despite their mechanistic insights, multi-omics technologies are not yet cost-effective for routine use. Routine metagenomic or untargeted metabolomic profiling in all patients is neither economically viable nor clinically justified. The priority is to distill a core set of robust biomarkers from large-scale prospective cohorts—biomarkers that can function as first-line clinical screening tools. For instance, a combinatorial assay of fecal butyrate, serum bile acid profiles, and fecal calprotectin could provide a low-cost tool for initial subtyping into microbial, bile acid, or inflammatory phenotypes. Technically, even accessible methods like 16 S rRNA sequencing suffer from inter-laboratory heterogeneity, precluding unified clinical interpretation standards [65]. More comprehensive approaches—metagenomics and metabolomics—remain confined to research due to high costs, long turnaround times, and specialized expertise requirements. Thus, the path to precision diagnosis lies not in deploying complex research tools at the bedside, but in translating fundamental discoveries into rapid, low-cost, and standardized diagnostic kits.

Microecological modulation strategies: rebuilding a healthy gut ecosystem

Precision probiotic intervention

Probiotics—administered as single or multi-strain formulations—modulate the gut microbiota and intestinal barrier, playing a well-established role in the prevention and management of postoperative diarrhea [70]. Strain selection (e.g., Lactobacillus, Bifidobacterium) should be guided by the patient’s specific microbiota deficiencies to ensure targeted replenishment. In the context of CRC, lactobacilli can synergistically enhance the abundance of beneficial taxa such as Bifidobacterium and Faecalibacterium. They also modulate the tumor microenvironment by suppressing pro-inflammatory cytokines (IL-1β, IL-6, IL-17a) while upregulating anti-inflammatory mediators (IL-12, IFN-γ, IL-10) [71]. Furthermore, engineered Lactobacillus strains have been shown to attenuate intestinal inflammation by upregulating M2 macrophages and Th17 cells, thereby reducing oxidative stress at sites of mucosal injury [72]. These limitations underscore the need for personalized probiotic regimens, designed on the basis of individual microbiota profiles, to achieve true precision modulation. However, these benefits are tempered by significant limitations in current evidence and practice. First, probiotic effects are highly strain-specific; benefits from one Lactobacillus strain cannot be extrapolated to others. Second, significant heterogeneity across RCTs—in strains, doses, populations, and endpoints—has led meta-analyses to conclude that evidence quality is low, particularly for surgical infection prevention [73]. Third, colonization resistance poses a fundamental barrier: exogenous probiotics typically fail to engraft in occupied niches, resulting in transient passage without sustained functional effects [74]. Therefore, probiotic use must transition from empirical supplementation to a precision-based strategy, guided by host characteristics and niche ecology.

Innovative applications of microbiota transplantation

Fecal microbiota transplantation (FMT) is a cornerstone of intestinal ecosystem reconstitution, established as first-line therapy for recurrent Clostridioides difficile infection with cure rates of 85%–90% [75]. Emerging evidence supports its efficacy in patients with severe antibiotic-induced dysbiosis or chronic diarrhea refractory to conventional treatments [76, 77]. Beyond FMT, targeted probiotic prophylaxis has shown promise. In a study of 400 patients undergoing radical resection for colorectal cancer (including 257 with enterostomy), Yang et al. reported that perioperative administration of Clostridioides butyricum reduced diarrhea incidence from 5.0% to 1.5% and intra-abdominal infection from 16.0% to 8.5%, while accelerating recovery of intestinal function—effects attributed to increased circulating T cells and enhanced systemic immunity [78]. FMT can be delivered via colonoscopy, nasoenteric tube, or oral capsules. Encapsulated frozen formulations are gaining traction due to their convenience and potential for standardization. Despite its efficacy, widespread adoption of FMT is constrained by substantial challenges. Foremost among these is safety. While short-term efficacy is high, long-term safety data remain limited. Case reports have documented transmission of multidrug-resistant organisms [79], and epidemiological associations with obesity, IBD, and autoimmune conditions have raised concerns [79]. A critical bottleneck is the lack of global regulatory consensus on whether FMT should be classified as a drug or a medical technology, a distinction that directly dictates the uniformity of preparation protocols, quality control, and clinical implementation. Addressing these challenges will require: (1) defining reproducible “super-donor” characteristics, (2) standardizing fecal preparation protocols, and (3) establishing evidence-based donor-recipient matching networks.

Synergistic effects of prebiotics

Supplementation with specific prebiotics (e.g., pectin, resistant starch, and galactooligosaccharides) can provide a selective growth advantage for residual beneficial bacteria, promoting their colonization and metabolic activity, and exerting synergistic effects with probiotics [80, 81].

Metabolic intervention therapies: compensating for microbiota functional deficits

SCFA supplementation

SCFAs, as important members of the postbiotic family, exert broad therapeutic effects, including reducing disease activity, suppressing tumorigenesis (e.g., Ki67 inhibition), preserving colon length, and downregulating pro-inflammatory cytokines (e.g., IL-6, TNF-α, IL-17) [82]. However, a fundamental pharmacokinetic barrier thwarts the clinical translation of butyrate: after oral administration, it is rapidly absorbed in the upper gut, with negligible amounts reaching the colon [83]. Several strategies aim to circumvent this limitation. One approach uses butyrate precursors, such as tributyrin. Using an in vitro model, Duysburgh et al. demonstrated that 40–49% of tributyrin resists small intestinal hydrolysis and reaches the colon, where it increases butyrate levels and modulates microbiota composition [84]. Another approach bypasses the upper gut entirely via local delivery. Luceri et al. confirmed that butyrate enemas prevent disuse atrophy and restore structural integrity in the diverted colorectum [85]. For severe SCFA deficiency, direct colonic delivery via suppositories or enemas can restore epithelial nutrition and barrier function. However, poor patient acceptability and adherence limit their clinical utility. This underscores the need for colon-targeted, sustained-release oral formulations to overcome the pharmacokinetic barrier. An alternative, and potentially more physiologic, paradigm is emerging: endogenous enhancement. Rather than exogenous supplementation, prebiotics (e.g., resistant starch, pectin) can stimulate residual butyrate-producing bacteria in the colon, offering a strategy that leverages the native microbiota.

Modulation of BA metabolism

For diarrhea attributable to BA malabsorption, BA-binding agents such as colestyramine and colestipol constitute first-line pharmacotherapy [86]. In clinical practice, disease severity can be assessed using the 7-day SeHCAT retention rate to inform decisions regarding concomitant low-fat dietary intervention. Treatment should be initiated at the lowest effective dose, with gradual titration, alongside regular monitoring of fat-soluble vitamin levels and coagulation function to mitigate long-term safety risks [87].

Individualization of nutritional support therapy

Developing personalized nutritional plans based on the patient’s microbiota and metabolic profiles is crucial. For individuals with severe dysbiosis, a low-FODMAP diet can be adopted initially to alleviate symptoms, followed by the gradual introduction of fermentable dietary fibers to progressively promote the growth of beneficial bacteria. If patients suffer from severe malnutrition, adequate protein and micronutrient support should be provided, with enteral nutrition intervention considered when necessary [88].

The paradox of common medications: essential therapeutics vs. drivers of dysbiosis

Antibiotics epitomize this therapeutic paradox in postoperative diarrhea: they are indispensable for certain infections yet potent disruptors of the gut ecosystem. For pathogen-specific infections, antibiotics are indispensable. Vancomycin and fidaxomicin are the standard of care for Clostridioides difficile infection—a leading cause of postoperative diarrhea [87]. Similarly, non-absorbable antibiotics like rifaximin effectively treat diarrhea secondary to small intestinal bacterial overgrowth [89]. Conversely, inappropriate use of broad-spectrum antibiotics—particularly prolonged perioperative prophylaxis—profoundly disrupts the gut microbiota and compromises colonization resistance. This disruption not only precipitates antibiotic-associated diarrhea but also constitutes the primary risk factor for C. difficile infection [90].

Beyond antibiotics, proton pump inhibitors (PPIs) are major iatrogenic modifiers of the gut ecosystem. By suppressing gastric acid secretion and raising intragastric pH, PPIs compromise the gastric acid barrier, thereby facilitating the downward migration of oral and upper gastrointestinal microbiota. This process promotes dysbiosis, characterized by fecal enrichment of oral commensals (e.g., Streptococcus spp.) and expansion of opportunistic pathogens like Enterococcus [91]. Epidemiological data confirm that long-term PPI use correlates strongly with increased risk of C. difficile and other enteric infections [92, 93]. Therefore, the etiological workup of postoperative diarrhea should include a thorough medication history review. For patients on PPIs without a clear therapeutic indication, discontinuation or a switch to an alternative acid suppressant is recommended.

Establishment of a multidisciplinary integrated management model

The complexity of postoperative diarrhea necessitates a multidisciplinary approach to management. A dedicated team comprising specialists from colorectal surgery, clinical nutrition, gastroenterology, rehabilitation medicine, and psychology can deliver comprehensive, individualized care throughout the patient journey. Encompassing preoperative risk assessment and intervention, intraoperative microecological protection, early postoperative nutritional support and functional rehabilitation, as well as long-term follow-up and lifestyle guidance, this collaborative framework addresses the multifaceted nature of the condition. Notably, psychological intervention warrants integration into routine management: cognitive behavioral therapy and supportive counseling can alleviate anxiety and depression, thereby enhancing treatment adherence and quality of life.

IV. A phenotype-driven framework for managing postoperative diarrhea

Synthesizing the foregoing mechanistic and diagnostic insights, we present a framework that stratifies postoperative diarrhea into distinct phenotypes to guide targeted intervention (Fig. 2).

Fig. 2.

Phenotype-driven management algorithm. This algorithm integrates diagnostic markers (fecal SCFAs, bile acids, calprotectin) to stratify patients into four interventional pathways: microbial metabolic failure, bile acid malabsorption, mucosal inflammation, or a mixed phenotype. First-line and subsequent therapeutic options are indicated for each

Foundational Support (Applicable to All Patients):

Foundational support, applicable to all patients, includes fluid and electrolyte repletion, nutritional assessment and optimization, perianal skin care, and comprehensive patient education.

Phenotype-Specific Interventions:

Type I: Microbial metabolic failure (dysbiosis-associated diarrhea)

Features: Defined by microbial metabolic failure, this phenotype is characterized by reduced α-diversity, significant depletion of SCFA-producing taxa (e.g., Faecalibacterium), and decreased fecal SCFA concentrations.

First-Line Strategy: Microecological Reconstruction. Initiate with precision prebiotics rich in soluble fiber (e.g., pectin, resistant starch) to promote the recovery of endogenous beneficial bacteria. For inadequate response, consider targeted probiotic supplementation based on specific microbial deficiencies (e.g., Clostridium butyricum). FMT is reserved for refractory cases.

Type II: Bile acid malabsorption

Features: Elevated proportion of fecal PBA (cholic acid, chenodeoxycholic acid), reduced proportion of SBA (deoxycholic acid, lithocholic acid), or elevated serum C4 (7α-hydroxy-4-cholesten-3-one) levels, reflecting compensatory hepatic bile acid synthesis.

First-Line Strategy: BA Sequestrants. Start with low-dose colestyramine and titrate according to bowel habits and tolerability. Periodic monitoring of fat-soluble vitamin levels is recommended.

Type III: Mucosal inflammation

Features: Markedly elevated fecal calprotectin, potentially accompanied by fever, abdominal pain, or bloody stools.

Core Management: Exclude Infection: First, test for Clostridioides difficile toxins. Treat confirmed cases with vancomycin or fidaxomicin. Initiate Anti-inflammatory Therapy: If infection is ruled out, assess for underlying IBD activity and, in consultation with a gastroenterologist, initiate appropriate anti-inflammatory therapy.

Type IV: Mixed phenotype

Features: Concurrent features of two or more of the above phenotypes.

Strategy: Comprehensive, Stepwise Intervention. Prioritize therapeutic targets based on the patient’s most distressing symptoms. Employ combination therapy (e.g., bile acid sequestrants plus prebiotics) with close follow-up and dynamic treatment adjustment.

This stratified framework shifts the management of postoperative diarrhea from an empirical, symptom-focused approach to a mechanism-based, precision medicine paradigm. Prospective studies are now required to validate the efficacy and cost-effectiveness of each phenotype-specific pathway, with the goal of establishing evidence-based guidelines that improve long-term quality of life for rectal cancer survivors.

Ⅴ. Conclusion

Postoperative diarrhea following ileostomy closure is a complex clinical issue arising from the interplay of multiple factors and mechanisms. Its core pathophysiological foundation lies in the systemic imbalance of the gut microbiota-metabolite-immune axis. The traditional single-modality symptomatic treatment model is increasingly inadequate for addressing this challenge, necessitating a paradigm shift towards novel precision prevention and treatment strategies based on multi-omics analysis. By delving into the structural and functional evolution of the gut microbiota, developing targeted microecological and metabolic interventions, and establishing a multidisciplinary, integrated, and comprehensive management pathway, we have the potential to fundamentally improve postoperative recovery and long-term prognosis for rectal cancer patients. This progression will propel colorectal surgery into a new era characterized by precision and individualization.

Authors’ contributions

(I) Study design and revision: Rongbiao Ying; (II) Administrative support: Rongbiao Ying; (III) Manuscript drafting: Haipeng Jin, Wenqiang Zhou; (IV) Data collection and assembly: Haipeng Jin, Wenqiang Zhou; (V) Final approval of manuscript: All authors.

Funding

This work was supported by the Social Development Science and Technology Project of Wenling City, Zhejiang Province (2024S00023).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Approval of the research protocol by an Institutional Reviewer Board: N/A.

- Informed Consent: N/A.

- Registry and the Registration No. of the study/trial: N/A.

- Animal Studies: N/A.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.