Minor players, major signals: Unveiling the systemic and gut-localized impact of microbial amidated bile acids in hepatopancreatobiliary disease

EDITORIAL Minor players, major signals: Unveiling the systemic and gut-localized impact of microbial amidated bile acids in hepatopancreatobiliary disease In recent years, bile acids (BAs) have emerged as far more than just detergents for lipid absorption. Their dual identity as metabolic regulators and microbial substrates positions them at the nexus of host physiology, immunity, and microbiota-host communication. The work by Temprano et al,[1]published in this issue of HEPATOLOGY, takes a critical step forward in elucidating the largely uncharacterized subset of gut-derived microbial amino acid– conjugated bile acids (MABAs), and their presence—or more accurately, their notable scarcity—in the bile of patients with hepatopancreatobiliary diseases. By employing a robust mass spectrometry platform across a broad BA panel, the authors systematically quantified MABAs' levels in bile from patients with various hepatopancreatobiliary conditions. They uncovered that although more than 50 MABA species were detected in the feces and lumen of the human gut in prior studies, their representation in bile is remarkably limited—often falling below 1 in 10,000 total BAs. This seemingly simple observation leads to profound implications: are MABAs functionally negligible, or are they potent, context-dependent signaling molecules acting in highly localized or transient niches? This question gains particular relevance when juxtaposed with recent findings by Lin et al (2025) in Cell,[2]who identified tryptophan-conjugated cholic acid (Trp-CA) as a microbiota-derived BA capable of improving glucose tolerance in mouse models of dietinduced obesity. Trp-CA, acting through the previously orphaned receptor MRGPRE, regulates glucose metabolism independently of FXR or TGR5, the canonical BA receptors. This receptor, although previously categorized in the itch-sensing GPCR family, appears to mediate metabolic benefits without pruritogenic activity —a tantalizing prospect for therapeutic development. The current HEPATOLOGY study extends this conversation by demonstrating that despite being present in feces and intestinal samples, MABAs are barely detectable in bile, even in pathological conditions associated with altered BA transport, synthesis, and recycling. The data, elegantly presented and validated across independent cohorts and methods, suggest that MABAs may not significantly enter the enterohepatic circulation—or if they do, they are rapidly metabolized or deconjugated. This supports a model of spatial compartmentalization, where MABAs act primarily in the intestinal lumen, perhaps engaging apical receptors like MRGPRE on enterocytes or immune cells, rather than systemically (Figure 1). This gut-localized model fits well with the mode of action proposed for Trp-CA: it is produced by gut microbes, remains within the gut, and signals through an intestinally expressed receptor to impact systemic glucose control. It also highlights an important methodological insight—the choice of sampling compartment is crucial when evaluating these novel molecules. Studies focusing on plasma or bile may miss metabolites with important local but transient effects. Another strength of the current study lies in its meticulous profiling of noncanonical amino acid conjugates, expanding the known diversity of MABAs and establishing their chemical validation in clinical samples. This builds on foundational work demonstrating microbial BA amidation as a widespread phenomenon, especially in dysbiotic states such as T2D and NAFLD (reviewed in Fleishman and Kumar[3]and Wahlström et al[4]). That these novel conjugates are present in patients with cholestasis, gallstone disease, and pancreatic tumors also raises the possibility that their production or clearance is not disease-specific, but reflects more universal constraints of microbial enzyme activity, host reabsorption mechanisms, or BA pool dynamics. However, a few limitations are worth noting. First, the study does not directly assess MABAs' signaling activity or receptor interactions. The absence of functional assays leaves unanswered whether MABAs in bile, despite their low levels, might exert paracrine or autocrine functions at the level of cholangiocytes, hepatocytes, or immune cells in the biliary tree. Second, the source of detected MABAs remains inferred rather Abbreviations: BAs, bile acids; MABAs, gut-derived microbial amino acid–conjugated bile acids; Trp-CA, tryptophan-conjugated cholic acid. ------------------------------------------------------------------------------------------------------- Copyright © 2025 American Association for the Study of Liver Diseases. Received: 14 July 2025 | Accepted: 14 July 2025 DOI: 10.1097/HEP.0000000000001473 Hepatology. 2025;00:000–000. www.hepjournal.com | 1 © 2025 American Association for the Study of Liver Diseases. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article prohibited. than demonstrated; paired fecal or mucosal samples would enhance our understanding of microbial contribution and spatial origin. Moreover, from a translational perspective, these findings should encourage rethinking BA-based therapies. Conventional BA analogs like obeticholic acid activate the FXR systemically and cause dose-limiting pruritus. In contrast, gut-restricted molecules like TrpCA, which act through non-pruritic, tissue-localized receptors such as MRGPRE, may offer safer metabolic benefits—as also suggested by the lack of itch-related effects in MRGPRE signaling. Finally, the concept of MABAs as “minority metabolites with major impact”introduces a new paradigm in gut–liver signaling. Much like classical hormones or neuromodulators, these compounds may require only nanomolar concentrations to elicit powerful effects if the receptors they target are highly sensitive and spatially restricted. In conclusion, the work by Temprano et al[1]in HEPATOLOGY represents a critical step in characterizing the metabolic fate of microbially amidated BAs in disease states. It complements emerging literature suggesting that these unusual conjugates are not merely metabolic curiosities, but key players in host– microbe dialog, with potential implications for glucose metabolism, intestinal homeostasis, and therapeutic innovation. Further exploration of their signaling targets—such as MRGPRE—and their microbiomederived origins will undoubtedly shape the next generation of interventions in metabolic and hepatobiliary disease. TGR5 ? enterohepatic circulation ? BAs MABAs ? FXR TGR5 + FXR MRGPRE FIGURE 1 Proposed model of MABAs in the gut–liver axis. BAs synthesized in the liver undergo enterohepatic circulation and can act through canonical receptors such as FXR and TGR5. In the intestinal lumen, microbial enzymes conjugate BAs with specific amino acids, producing MABAs. These MABAs were found to be scarcely present in bile, suggesting minimal reabsorption or rapid deconjugation or metabolism. Instead, MABAs may exert localized effects potentially via specific receptors such as MRGPRE. Dashed arrows and question marks indicate unsolved aspects regarding their absorption, stability, and systemic effects. Issues need to be explored to understand their role and influence in health and disease. Created in BioRender. Gonzalez Recio, I. (2025) https://BioRender.com/koilbx2. Abbreviations: BA, bile acids; MABAs, microbial amino acid–conjugated bile acids. 2 | HEPATOLOGY © 2025 American Association for the Study of Liver Diseases. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article prohibited. FUNDING INFORMATION Giselle Adriana Abruzzese is supported by a HORIZON-MSCA-2023-PF grant 101154878. CONFLICTS OF INTEREST The authors have no conflicts to report. Giselle Adriana Abruzzese 1 Maria Luz Martínez-Chantar 1,2 1 Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain 2 Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain Correspondence María Luz Martínez-Chantar, Liver Disease Laboratory, CIC bioGUNE, Ed. 801A Parque Tecnológico de Bizkaia, 48160 Derio, Bizkaia, Spain. Email: [email protected] ORCID Giselle Adriana Abruzzese https://orcid.org/0000– 0003–3498–7010 Maria Luz Martínez-Chantar https://orcid.org/0000– 0002–6446–9911 REFERENCES 1. Temprano AG, Romero MR, Ghallab A, Llera L, Macias RIR, van Eijk HM, et al. Gut-to-Bile transfer of microbially amidated minor bile acids in patients with hepatopancreatobiliary disorders. Hepatology. 2025. doi:10.1097/HEP.0000000000001441. Epub ahead of print. 2. Lin J, Nie Q, Cheng J, Zhong Y-N, Zhang T, Zhang X, et al. A microbial amino-acid-conjugated bile acid, tryptophancholic acid, improves glucose homeostasis via the orphan receptor MRGPRE. Cell. 2025;S0092-8674: 00560–4. 3. Fleishman JS, Kumar S. Bile acid metabolism and signaling in health and disease: Molecular mechanisms and therapeutic targets. Sig Transduct Target Ther. 2024;9:97. 4. Wahlström A, Sayin SI, Marschall H-U, Bäckhed F. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 2016;24:41–50. EDITORIAL | 3 © 2025 American Association for the Study of Liver Diseases. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article prohibited.