Microbiota-bile acid crosstalk and hepatic gluconeogenesis after intestinal resection: Revisiting the gut-liver axis for metabolic recovery

Abstract

Intestinal resection induces profound metabolic adaptations through coordinated interactions between the gut microbiota, bile acid signaling, and host endocrine pathways. In a recent study published in World Journal of Gastroenterology, Xu et al identified a Prevotellaceae_NK3B31_group-derived secondary bile acid, 7-ketolithocholic acid, as a potent activator of ileal farnesoid X receptor, linking microbial metabolism to fibroblast growth factor 19 and glucagon-like peptide-1 signaling and suppression of hepatic gluconeogenesis. This editorial highlights the significance of this microbiota-bile acid-hepatic axis within a broader immunometabolic framework. We further discuss the integration of bile acid signaling with inflammatory regulation, gut barrier integrity, and circadian metabolic control. While these findings provide important mechanistic insights, causality remains to be established, and the contribution of specific microbial taxa requires further validation. From a translational perspective, this work supports the development of microbiota-targeted interventions and pharmacologic modulation of bile acid receptors to enhance postoperative metabolic recovery. Understanding the multidomain adaptation triggered by intestinal reconstruction may enable precision strategies to improve metabolic resilience after surgery.

Key Words: Gut-liver axis; Bile acid signaling; Farnesoid X receptor; Glucagon-like peptide-1; Intestinal resection; Microbiota metabolism; Hepatic gluconeogenesis; Metabolic recovery; Immunometabolic adaptation; Precision surgery

Core Tip: Intestinal resection reshapes systemic metabolism through coordinated microbiota-bile acid-hepatic signaling. Xu et al identified a 7-ketolithocholic acid-mediated farnesoid X receptor pathway linking microbial metabolism to suppression of hepatic gluconeogenesis. This editorial integrates these findings with broader immunometabolic and circadian mechanisms, emphasizing the role of bile acid signaling in postoperative metabolic adaptation. These insights highlight potential strategies for microbiota-targeted and receptor-based interventions to enhance metabolic recovery after surgery.

This editorial refers to “Distal small bowel resection with preservation of the terminal ileum suppresses hepatic gluconeogenesis via the Prevotellaceae_NK3B31_group-mediated 7-KLCA-FXR axis” by Xu et al, 2025; https://dx.doi.org/10.3748/wjg.v31.i43.112483.

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INTRODUCTION

The intestine and liver operate as an integrated metabolic organ system, connected through the portal circulation and the enterohepatic circulation of bile acids. This gut-liver axis forms a bidirectional communication network that orchestrates nutrient sensing, bile acid metabolism, glucose and lipid homeostasis, and immune surveillance[1]. Perturbations in this finely balanced system have been implicated in the pathogenesis of major metabolic and inflammatory diseases, including nonalcoholic fatty liver disease, type 2 diabetes, and postoperative catabolic stress. Beyond its physiological importance, the gut-liver axis represents a dynamic interface between the host and its microbiota. The liver continuously receives microbial metabolites, toxins, and antigens from the intestine, while hepatic bile and secreted factors reciprocally shape the gut microbial ecology. This mutualistic relationship ensures metabolic equilibrium but also renders the system vulnerable to disruption following intestinal resection or surgical reconstruction.

Against this backdrop, Xu et al[2] published a study in World Journal of Gastroenterology offered compelling mechanistic insights showing that distal small-bowel resection with preservation of the terminal ileum reprograms host glucose metabolism through a microbiota-bile acid-hepatic signaling cascade. Their identification of the Prevotellaceae_NK3B31_group-7-ketolithocholic acid (7-KLCA)- farnesoid X receptor (FXR)-glucagon-like peptide-1 (GLP-1) axis reveals a sophisticated microbial-endocrine dialogue linking intestinal architecture to hepatic energy regulation. This work reframes intestinal surgery not merely as a structural or digestive intervention but as a powerful model for understanding metabolic adaptation, immunometabolic resilience, and microbial-endocrine reprogramming. Clinically, these insights contextualize gastrointestinal reconstruction as an experimental model to interrogate and therapeutically harness the gut-liver axis, consistent with our previous clinical trials demonstrating that integrated psychological and nutritional modulation enhances postoperative recovery and immunometabolic adaptation in colorectal cancer patients[3,4]. To extend these mechanistic findings, this editorial synthesizes emerging evidence within a broader immunometabolic context and proposes a unified conceptual framework for postoperative metabolic reprogramming. By articulating the multidomain biological processes implicated in recovery, the editorial aims to clarify the translational significance of the original study and to guide future mechanistic and clinical investigations.

MECHANISTIC INSIGHTS: THE 7-KLCA–FXR–GLP-1 PATHWAY AS A METABOLIC CONDUIT

Bile acids are no longer viewed as passive emulsifiers but as multifunctional endocrine molecules that regulate metabolism and immunity via the nuclear FXR and the membrane receptor Takeda G-protein-coupled receptor 5 (TGR5)[5]. Activation of intestinal FXR triggers transcriptional networks involving small heterodimer partner, fibroblast growth factor 19 (FGF19), and FGF21, which collectively suppress hepatic cytochrome P450 family 7 subfamily A member 1 expression, modulate glucose output, and promote lipid oxidation[6]. Downstream, hepatic AMP-activated protein kinase (AMPK) and small heterodimer partner programs converge to repress gluconeogenic flux while facilitating triglyceride turnover.

Xu et al[2] showed that distal small-bowel resection with preservation of the terminal ileum selectively enriches Prevotellaceae_NK3B31_group species capable of producing 7-KLCA, a potent FXR ligand. This bile acid metabolite activates ileal FXR, stimulating FGF19 and GLP-1 secretion and subsequently inhibiting hepatic gluconeogenic genes (phosphoenolpyruvate carboxylase, glucose-6-phosphatase). This cascade exemplifies a microbial-host feedback loop where bacterial metabolism of primary bile acids into signaling-active secondary forms recalibrates systemic energy flux. Importantly, these associations should be interpreted cautiously, as the study design does not establish causality. The enrichment of Prevotellaceae_NK3B31_group may function as a marker of broader ecological restructuring - rather than a direct mechanistic driver - given that gnotobiotic validation, mediation analysis, and other causal-inference approaches were not performed.

Mechanistically, this pathway parallels observations in bariatric and metabolic surgery, where alterations in the overall bile acid pool - including other secondary bile acids such as deoxycholic acid and lithocholic acid - and increased FXR/TGR5 activation enhance insulin sensitivity and energy expenditure[7-9]. TGR5 signaling in brown adipose tissue and skeletal muscle promotes mitochondrial thermogenesis through cAMP–AMPK pathways, while FXR signaling modulates triglyceride turnover and intestinal permeability. These multilayered bile acid effects reflect the broader metabolic cascade initiated by surgical reconstruction[10]. Moreover, bile acid-FXR signaling regulates tight junctions via transcriptional and post-translational regulation of occludin and zonula occludens-1, reinforcing the intestinal barrier and reducing endotoxemia. This not only limits hepatic inflammation but also prevents metabolic endotoxemia, a key driver of insulin resistance. Therefore, intestinal resection appears to reset the gut-liver equilibrium through a structured ecological and endocrine adaptation.

INTEGRATING IMMUNOMETABOLIC AND MICROBIAL PERSPECTIVES

Beyond metabolism, bile acid receptors serve as crucial immunoregulatory and neuroendocrine sensors. FXR activation in macrophages inhibits nuclear factor kappaB transcriptional activity and promotes anti-inflammatory M2 polarization[10,11]. Likewise, TGR5 activation dampens NLR family pyrin domain-containing 3 inflammasome signaling, thereby curbing hepatic and intestinal cytokine cascades. The resulting reduction in systemic inflammation contributes directly to improved insulin responsiveness and tissue repair. The bile acid-FXR-GLP-1 axis also interfaces with the gut-liver-brain network. GLP-1 released from enteroendocrine L-cells engages vagal afferents and hypothalamic centers to suppress appetite, regulate hepatic glucose production, and enhance peripheral glucose uptake[12]. Thus, microbial-driven bile acid signaling indirectly affects central energy regulation - an insight increasingly recognized as part of the microbiota-brain-metabolic triad.

Such integration may help explain improvements in appetite regulation and energy balance occasionally observed following metabolic or reconstructive gastrointestinal surgery. An often-overlooked dimension of this axis is its synchronization with the circadian clock. Hepatic and intestinal FXR expression follows diurnal rhythms that align with feeding-fasting cycles and microbial bile acid transformation[13]. Surgical alteration of nutrient flow may reset this circadian-metabolic coupling, allowing metabolic recovery to proceed under a new rhythmic equilibrium. This chronobiological angle enriches our understanding of postoperative adaptation as not only a biochemical but also a temporal recalibration of metabolism. Similar interactions between behavioral-sleep modulation and postoperative inflammatory and metabolic recovery have been demonstrated in colorectal cancer surgery, further supporting the multidomain nature of postoperative immunometabolic adaptation[14].

CLINICAL AND TRANSLATIONAL IMPLICATIONS

The Prevotellaceae_NK3B31_group-7-KLCA-FXR-GLP-1 pathway opens multiple translational avenues: (1) Microbiota-targeted modulation. Rational probiotics, prebiotics, and synbiotics can reshape the bile acid pool to favor FXR and TGR5 activation[13,15]. Supplementation with Prevotella-enriched strains or bile acid-transforming species may mimic the metabolic benefits of surgical remodeling without anatomical modification; (2) Mechanistic basis for metabolic surgery. The FXR-GLP-1 circuit provides a mechanistic explanation for rapid postoperative glycemic improvements after Roux-en-Y gastric bypass or ileal interposition[16]. Profiling bile acid subtypes and microbial signatures predictive of response could refine surgical indications and risk stratification; (3) Pharmacological translation. FXR agonists such as obeticholic acid (OCA) and tropifexor, and TGR5 agonists including 6-ethyl-23(S)-methyl-cholic acid, are under clinical evaluation for metabolic liver disease[6,17]. Postoperative combination of these agents with microbiota-targeted strategies may theoretically enhance metabolic recovery and mitigate hepatic steatosis. However, the clinical use of OCA requires particular caution. OCA is associated with dose-dependent pruritus, adverse lipid changes - including elevations in low-density lipoprotein-cholesterol - and reported hepatic safety concerns in susceptible subgroups. These limitations substantially constrain its tolerability in postoperative settings, where inflammatory and metabolic stress may heighten vulnerability to drug-related adverse effects. Accordingly, any consideration of FXR agonists after intestinal surgery must incorporate rigorous safety monitoring, careful patient selection, and risk-benefit evaluation. These concerns further highlight the need for next-generation FXR agonists with improved safety profiles and more selective modulation of downstream pathways; (4) Precision metabolic rehabilitation. Integration of metagenomics, bile acid metabolomics, transcriptomics, and host genetics may identify biomarkers of impaired FXR-GLP-1 signaling[18]. These multi-omics frameworks can inform personalized nutrition or pharmacotherapy after intestinal surgery, jointly tailored to individual metabolic and microbiome profiles, guided by perioperative omics dashboards; and (5) Systemic crosstalk and long-term health. The gut-liver-adipose axis mediates not only hepatic but also systemic metabolic homeostasis. FXR-GLP-1 signaling affects skeletal muscle glucose uptake, adipose tissue lipolysis, and even cardiovascular inflammation, linking gastrointestinal reconstruction to whole-body metabolic resilience[19,20]. Collectively, these translational insights redefine gastrointestinal surgery as a platform for metabolic modulation rather than mere structural restoration.

A UNIFIED CONCEPTUAL FRAMEWORK FOR POSTOPERATIVE IMMUNOMETABOLIC REPROGRAMMING

To provide a more systematized and integrative perspective, we propose a conceptual framework that synthesizes the multiple layers of metabolic adaptation triggered by intestinal resection. This framework encompasses five mutually reinforcing regulatory domains: (1) Microbial ecological restructuring, characterized by large-scale shifts in community composition, substrate utilization, and metabolite-generating capacity, which collectively reshape host metabolic signaling networks and energy handling[21,22]; (2) Secondary bile acid remodeling, in which microbiota-driven alterations in bile acid composition modulate FXR-dependent signaling and downstream enterohepatic endocrine pathways[23,24]; (3) Short-chain fatty acid (SCFA)-mediated pathways, particularly involving AMPK- and peroxisome proliferator-activated receptor–related signaling, enhancing mitochondrial oxidative metabolism and contributing to systemic metabolic regulation[25,26]; (4) Immune-inflammatory recalibration, mediated in part through bile acid-activated receptors and microbiota-dependent signaling cascades that attenuate intestinal and hepatic inflammatory tone[27,28]; and (5) Circadian-hepatic coupling, whereby microbiota-derived rhythmic signals and host circadian systems interact to restore metabolic timing and promote systemic homeostasis[29,30].

Together, these interconnected pathways indicate that postoperative metabolic remodeling is not driven by a single microbial taxon or bile acid species, but rather emerges from a coordinated, multidomain biological response. This integrative framework provides a conceptual basis for interpreting postoperative metabolic improvement and establishes a mechanistic rationale for targeted therapeutic strategies leveraging the gut-liver axis. This integrative framework is summarized in Figure 1.

Figure 1 A unified microbiota-bile acid - farnesoid X receptor framework orchestrates postoperative immunometabolic reprogramming. This schematic illustrates a unified, three-stage framework of postoperative immunometabolic reprogramming following intestinal resection, structured as perturbation, mechanistic reprogramming, and system-level outcomes. A: Intestinal resection induces a primary perturbation characterized by altered nutrient flow and microbial ecological disruption (dysbiosis). These changes initiate downstream alterations in gut-derived metabolites, including bile acids and short-chain fatty acids, thereby reshaping the intestinal metabolic environment; B: Microbiota-driven metabolic reprogramming is mediated through two principal axes. First, microbial modulation of bile acid composition promotes the conversion of primary to secondary bile acids, leading to activation of farnesoid X receptor signaling across the intestine-liver axis. Farnesoid X receptor activation regulates enterohepatic feedback, including suppression of hepatic bile acid synthesis (e.g., CYP7A1 inhibition), and coordinates metabolic homeostasis. Second, microbial fermentation generates short-chain fatty acids, which activate metabolic signaling pathways such as AMP-activated protein kinase, contributing to enhanced mitochondrial oxidative metabolism. These signaling pathways converge to drive immune recalibration and mitochondrial metabolic adaptation, representing an integrated host response to microbiota-derived metabolic cues; C: The integrated effects of these pathways result in system-level outcomes, including reduced inflammatory tone, improved metabolic regulation, enhanced energy homeostasis, and restoration of physiological balance. These coordinated adaptations support recovery of systemic metabolic stability following surgical perturbation. Together, this framework highlights that postoperative metabolic remodeling emerges from a coordinated microbiota-metabolite-host signaling network, rather than from isolated pathways, providing a conceptual basis for targeted therapeutic modulation of the gut-liver axis. FXR: Farnesoid X receptor; SCFA: Short-chain fatty acid; AMPK: AMP-activated protein kinase.

FUTURE PERSPECTIVES

While Xu et al[2] have illuminated key mechanistic relationships, several critical challenges remain. Establishing causal links between specific microbial configurations and metabolic phenotypes will require germ-free or gnotobiotic models, combined with mechanistic tracking of microbial metabolite flux and bile acid transformation pathways[21,23]. Translational validation in humans should incorporate longitudinal profiling of bile acid composition, microbiome dynamics, and circulating endocrine mediators such as FGF19 and GLP-1 following surgery.

The temporal dynamics of postoperative metabolic reprogramming also warrant further investigation. Current evidence suggests an early adaptive phase characterized by rapid restructuring of microbial communities and bile acid pools, accompanied by shifts in host metabolic signaling[22,24]. Whether this adaptive microbiota-bile acid feedback loop stabilizes into a persistent metabolic state or gradually attenuates over time remains unclear[29]. This uncertainty highlights the importance of longitudinal multi-omics studies and suggests that the timing of therapeutic intervention may be critical.

In addition, the interaction between bile acids and SCFAs represents an important secondary regulatory layer[25,26]. SCFAs modulate host energy metabolism and mitochondrial function, and may synergize with bile acid-dependent signaling pathways to shape postoperative metabolic recovery. However, intestinal resection is also associated with potential adverse consequences, including dysbiosis, bile acid malabsorption, small-bowel bacterial overgrowth, micronutrient deficiency, and inflammatory complications[27,30]. Ultimately, precision modulation of the gut-liver ecosystem - through microbiota-targeted interventions, bile acid-based therapeutics, and circadian-aligned nutritional strategies - may enable a more individualized and systems-level approach to postoperative metabolic rehabilitation.

CONCLUSION

The study by Xu et al[2] elegantly demonstrates that intestinal reconstruction can reprogram systemic metabolism through a defined microbiota-bile acid-hepatic signaling network. By elucidating the Prevotellaceae_NK3B31_group-7-KLCA-FXR-GLP-1 axis, this work deepens our understanding of how microbial metabolites serve as endocrine mediators linking intestinal structure to metabolic function. As surgical science embraces systems biology, the gut-liver axis emerges as a targetable network for metabolic restoration. The convergence of microbial ecology, bile acid chemistry, and endocrine physiology heralds a transformative paradigm - one in which gastrointestinal surgery becomes not merely curative, but regenerative, fostering a durable metabolic renaissance in the post-surgical state, and invites rigorous clinical testing to translate mechanistic insight into durable metabolic benefit.

ACKNOWLEDGEMENTS

We are also grateful to our colleagues at the Department of General Surgery and the Department of Neurology, The First Affiliated Hospital of Soochow University, for their support in scientific discussion and manuscript preparation.