Letter to the Editor: Gut microbiota–bile acid crosstalk - Prevotellaceae NK3B31 and 7-ketolithocholic acid drive metabolic benefits of distal bowel resection with preservation of terminal ileum

Abstract

This letter commends on the study published in World Journal of Gastroenterology by Xu et al, which elucidated the mechanism by which distal bowel resection with terminal ileum preservation (DBRPI) improves hepatic gluconeogenesis via the Prevotellaceae NK3B31_group/7-ketolithocholic acid (7-KLCA)/farnesoid X receptor (FXR) axis. Using multiomics and functional assays, Xu et al identified this microbial–bile acid (BA) axis as central to the metabolic benefits of DBRPI, linking microbial enrichment (e.g., Prevotellaceae NK3B31_group) to increased 7-KLCA levels and FXR activation, thereby suppressing gluconeogenic gene expression. We highlight the novelty of this work in its focus on taxon-specific microbial and BA dynamics, which advances the understanding of postoperative glucose regulation. Additionally, we note its translational potential—targeting this axis via probiotics or 7-KLCA analogs—and raise several open questions, including causal validation of the microbial taxon, serum 7-KLCA dynamics, and glucagon-like-peptide-1/FXR interplay. Overall, this study bridges gut microbiota and BA crosstalk, offering actionable insights for the treatment of metabolic disease.

Key Words: Distal bowel resection with terminal ileum preservation; Gut microbiota; Bile acid metabolism; Prevotellaceae NK3B31_group; 7-ketolithocholic acid; Glucose homeostasis

Core Tip: Xu et al revealed that the Prevotellaceae NK3B31_group/7-ketolithocholic acid (7-KLCA)/farnesoid X receptor (FXR) axis drives suppression of hepatic gluconeogenesis in distal bowel resection with terminal ileum preservation, a metabolic surgery model. Multiomics analyses linked microbial enrichment to elevated 7-KLCA levels and FXR activation, leading to downregulation of gluconeogenic genes. This work advances the understanding of gut microbiota–bile acid crosstalk, highlighting species-specific roles of bile acids. Its translational potential lies in targeting this axis—via probiotics or 7-KLCA analogs—for the treatment of metabolic disease.

TO THE EDITOR

We read with interest the recent study published in World Journal of Gastroenterology by Xu et al[1]. This study investigated the potential mechanisms underlying improved glucose metabolism after metabolic surgery using a simplified surgical model—distal bowel resection with terminal ileum preservation (DBRPI)—designed to investigate the role of the posterior intestine. By integrating metabolic phenotyping, bile acid (BA)-targeted metabolomics, 16S rRNA sequencing, and molecular biology, the authors compellingly demonstrated the central role of the Prevotellaceae NK3B31_group/7-ketolithocholic acid (7-KLCA)/farnesoid X receptor (FXR) axis in DBRPI-mediated glycemic regulation. This study significantly advances our understanding of how metabolic surgery modulates glucose homeostasis through gut microbiota–BA crosstalk, and we highly commend the authors for their rigorous research design and innovative findings.

CORE CONTRIBUTIONS AND INNOVATIONS

This research addressed a critical gap in metabolic surgery by elucidating the specific contributions of gut microbiota and BA signaling to postoperative glucose regulation. While prior studies have proposed the posterior intestine hypothesis—accelerated nutrient delivery to the distal gut stimulating glucagon-like peptide 1; glucagon-like peptide-1 (GLP-1) secretion—and highlighted the role of BAs in activating the FXR/fibroblast growth factor 19 pathway, Xu et al[1] are the first to focus on specific BA species (e.g., 7-KLCA) and specific gut microbial taxa (Prevotellaceae_NK3B31_group) as mediators of metabolic benefits. They found that DBRPI selectively enriched Prevotellaceae_NK3B31_group, a Gram-negative anaerobe associated with the production of short-chain fatty acids, and elevated levels of 7-KLCA, a secondary BA with lipid-lowering effects but previously unclear glucose-modulating properties. The correlation between Prevotellaceae_NK3B31_group abundance and reduced expression of key hepatic gluconeogenic genes (G6PC and PCK1), together with the positive association between 7-KLCA and FXR activation, strongly suggests this microbial taxon may influence glucose homeostasis by regulating BA metabolism, forming a putative causal axis.

The study clarified how DBRPI reshapes BA synthesis. Specifically, it upregulates CYP27A1 (alternative pathway) and CYP8B1 (which controls the conversion of cholic acid to chenodeoxycholic acid) while downregulating cholesterol 7α-hydroxylase (CYP7A1) (classical pathway). This shift biases the BA pool toward FXR-activating species (e.g., 7-KLCA) and reduces FXR antagonists (a-muricholic acid and glycocholic acid). Such species-specific modulation, rather than changes in the total BA pool, underscores the importance of BA composition over quantity in metabolic regulation—a nuance often overlooked in broader BA profiling studies.

For context, Bae et al[2] observed that 2 weeks of high-fat diet feeding in Yucatan minipigs induced changes in the amount and composition of peripheral blood BA release and increased BA release from peripheral organs, dominated by hyocholic acid and chenodeoxycholic acid. In contrast, intestinal BA species and secretion were markedly decreased, potentially linked to CYP7A1 downregulation and altered CYP8B1 activity induced by a high-fat diet. BAs exert critical metabolic and immunological effects; however, alterations in gut microbial composition remain the primary driver of BA profile changes and diversity.

Studies by Lamichhane et al[3] and Guzior et al[4] show that microbially derived BA amides exhibit significant abundance changes across different physiological states and diseases. Tang et al[5] found that thalidomide treatment was associated with increased levels of the microbial metabolite 7-KLCA in mice with intestinal Crohn’s disease. This metabolite may stabilize FOXP3 expression by targeting the receptor FMR1 autosomal homolog 1 to inhibit autophagy. During 7-KLCA biosynthesis, 7β-hydroxysteroid dehydrogenase (7β-HSDH) catalyzes the reversible reaction between 7K-LCA and ursodeoxycholic acid, thereby determining the biosynthesis level of 7K-LCA[6].

Thus, the impact of DBRPI on gut microbiota and BAs may stem from altered lengths of specific intestinal segments, leading to increased abundance of specific taxa such as Prevotellaceae_NK3B31_group. The abundance of this microbial taxon may, in turn, affect the activity of 7β-HSDH, thereby enhancing the synthesis of 7K-LCA. The role of this genus in BA modification and its biological effects warrants further investigation.

CLINICAL AND TRANSLATIONAL IMPLICATIONS

The findings hold significant translational potential. First, as Prevotellaceae_NK3B31_group emerges as a key microbial driver of metabolic improvement, targeting this taxon via probiotics, prebiotics, or other means could mimic the benefits of DBRPI in nonsurgical patients with obesity or type 2 diabetes. Second, 7-KLCA, as an FXR activator and gluconeogenesis inhibitor, offers a new direction for developing 7-KLCA analogs or customized FXR agonists to improve glycemic control. Third, the technical simplicity of the DBRPI model provides a feasible system for future exploration of gut microbiota–BA crosstalk, potentially accelerating advances in understanding the mechanisms of metabolic surgery.

PERSPECTIVES AND OPEN QUESTIONS

Despite robust correlational evidence, several intriguing questions warrant further investigation: (1) Causality of Prevotellaceae_NK3B31_group: Can direct manipulation of this taxon (e.g., fecal microbiota transplantation) recapitulate the effects of DBRPI on 7-KLCA levels and glucose metabolism? (2) Serum 7-KLCA dynamics: The study focused on fecal 7-KLCA; measuring serum levels would clarify whether microbial effects translate into systemic BA signaling; (3) Interplay between GLP-1 and FXR: DBRPI-induced upregulation of terminal ileal GLP-1 aligns with the posterior intestine hypothesis, but how FXR activation regulates GLP-1 secretion (previously controversial) remains to be elucidated in this model; and (4) Clinical generalizability: Do these findings apply to other metabolic surgery models (e.g., Roux-en-Y gastric bypass) or to human patients?

MECHANISMS LINKING MICROBIAL MODULATION TO SYSTEMIC SIGNALING: THE ROLE OF 7-KLCA

The microbial influence on systemic BA dynamics likely involves crosstalk among the gut microbiota, hepatic BA synthesis, and enterohepatic circulation. Here, we propose a mechanistic framework for how Prevotellaceae_NK3B31_group and 7-KLCA mediate these systemic effects.

Prevotellaceae_NK3B31_group may modulate BA metabolism via bile salt hydrolase activity, deconjugating primary BAs (e.g., cholic acid) to release free BAs, which are subsequently converted into secondary BAs such as 7-KLCA. This process alters BA pool composition, favoring FXR activation[7]. As a lipid-lowering BA, 7-KLCA is reabsorbed in the ileum via the apical sodium-dependent BA transporter and transported to the liver, where it binds FXR, suppressing CYP7A1, the rate-limiting enzyme in BA synthesis, to reduce hepatic BA output and systemic BA levels[8].

7-KLCA may indirectly enhance GLP-1 secretion by inhibiting intestinal FXR, which normally suppresses proglucagon expression in L cells. Reduced FXR activity derepresses Gcg (GLP-1 precursor), increasing GLP-1 release into the circulation. In addition, the lipid-lowering properties of 7-KLCA may reduce hepatic inflammation—via inhibition of nuclear factor kappa B—thereby improving insulin sensitivity. This observation aligns with findings that obesity-associated changes in BA composition contribute to increased systemic inflammation[9].

GLP-1–FXR CROSSTALK: MECHANISTIC INSIGHTS

The interplay between GLP-1 and FXR has emerged as a critical regulatory axis in metabolic health. Recent advances indicate that FXR activation suppresses Gcg expression in intestinal L cells by binding to its promoter region. Conversely, FXR antagonists (e.g., 7-KLCA) relieve this suppression, enhancing GLP-1 secretion. In addition, FXR regulates intestinal stem cell (ISC) proliferation via Olfm4 and Lgr5; inhibition of FXR promotes ISC expansion, increasing L-cell numbers and GLP-1 production[9].

GENERALIZABILITY TO OTHER METABOLIC SURGERY MODELS AND HUMAN PATIENTS

The findings from DBRPI not only align with broader mechanisms of metabolic surgery but also highlight unique pathways. Both DBRPI and Roux-en-Y gastric bypass (RYGB) enhance GLP-1 secretion by accelerating nutrient delivery to the distal gut. However, the selective preservation of the ileum in DBRPI may better preserve FXR activation compared to RYGB, which substantially alters intestinal transit time and BA exposure. In addition, RYGB induces pronounced shifts in the gut microbiota (e.g., a bloom in Proteobacteria), whereas DBRPI selectively enriches Prevotellaceae, suggesting distinct microbial mediators underlying their metabolic benefits[10].

While enrichment of Prevotellaceae correlates with metabolic improvement in rodent models, human studies have shown variable outcomes owing to differences in diet, genetics, and antibiotic exposure. For example, Prevotella abundance in humans is linked to plant-based diets, complicating direct therapeutic targeting. Moreover, the human BA pool is larger and more complex than that in murine models. Clinical trials (e.g., studies of ursodeoxycholic acid in osteoarthritis) suggest that BA modulation is feasible but requires precise dosing to avoid off-target effects, such as pruritus associated with excessive FXR activation.

Instead of single-taxa interventions, transplantation of Prevotellaceae-enriched microbial consortia may better replicate the effects of DBRPI. Preclinical studies in germ-free mice have shown promise. In addition, developing 7-KLCA analogs with improved bioavailability (e.g., oral formulations resistant to intestinal degradation) could help mimic the benefits of DBRPI in nonsurgical populations.

CONCLUSION

Xu et al[1] constructed a robust mechanistic framework linking DBRPI, gut microbiota remodeling, BA metabolism, and FXR activation to explain improved glucose homeostasis. This work not only deepens our understanding of the posterior intestine mechanism in metabolic surgery but also provides a basis for developing future therapeutic targets, including specific microbial taxa and BA species. We look forward to follow-up studies addressing these open questions and translating these insights into clinical practice.

ACKNOWLEDGEMENTS

We are deeply grateful to Professor Cai-Wen Duan for his guidance on this letter. As authoritative experts in oncology and metabolomics, their insightful suggestions have significantly enhanced the academic rigor and professional depth of this manuscript.