Chyme Reinfusion Restores the Regulatory Bile Salt–FGF19 Axis in Patients With Intestinal Failure

Koelfat, K.V.; Picot, D.; Chang, Xinwei; Desille-Dugast, Mireille; Eijk, Hans M. van; Kuijk, Sander M J van; Leníček, Martin; Layec, S.; Carsin, M.; Dussaulx, L.; Seynhaeve, E.; Trivin, F.; Lacaze, L.; Thibault, Ronan; Schaap, Frank G.; Damink, Steven W. M. Olde

doi:10.1002/hep.32017

Cited by 10 publications

(6 citation statements)

References 39 publications

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“…MBSCs were assayed in a second study, involving patients with acute intestinal failure and verified occurrence of MBSCs in their small intestinal lumen. 18 , 21 Despite examining those patients with the highest MBSC levels in their chyme, none of the individual MBSCs could be detected in corresponding systemic venous blood (Table 2 ).…”

Section: Resultsmentioning

confidence: 99%

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Microbially conjugated bile salts found in human bile activate the bile salt receptors TGR5 and FXR

Ay,

Leníček,

Haider

et al. 2024

Hepatology Communications

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Background: Bile salts of hepatic and microbial origin mediate interorgan cross talk in the gut-liver axis. Here, we assessed whether the newly discovered class of microbial bile salt conjugates (MBSCs) activate the main host bile salt receptors (Takeda G protein-coupled receptor 5 [TGR5] and farnesoid X receptor [FXR]) and enter the human systemic and enterohepatic circulation. Methods: N-amidates of (chenodeoxy) cholic acid and leucine, tyrosine, and phenylalanine were synthesized. Receptor activation was studied in cell-free and cell-based assays. MBSCs were quantified in mesenteric and portal blood and bile of patients undergoing pancreatic surgery. Results: MBSCs were activating ligands of TGR5 as evidenced by recruitment of Gsα protein, activation of a cAMP-driven reporter, and diminution of lipopolysaccharide-induced cytokine release from macrophages. Intestine-enriched and liver-enriched FXR isoforms were both activated by MBSCs, provided that a bile salt importer was present. The affinity of MBSCs for TGR5 and FXR was not superior to host-derived bile salt conjugates. Individual MBSCs were generally not detected (ie, < 2.5 nmol/L) in human mesenteric or portal blood, but Leu-variant and Phe-variant were readily measurable in bile, where MBSCs comprised up to 213 ppm of biliary bile salts. Conclusions: MBSCs activate the cell surface receptor TGR5 and the transcription factor FXR and are substrates for intestinal (apical sodium-dependent bile acid transporter) and hepatic (Na+ taurocholate co-transporting protein) transporters. Their entry into the human circulation is, however, nonsubstantial. Given low systemic levels and a surplus of other equipotent bile salt species, the studied MBSCs are unlikely to have an impact on enterohepatic TGR5/FXR signaling in humans. The origin and function of biliary MBSCs remain to be determined.

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Section: Resultsmentioning

confidence: 99%

“…Furthermore, plasma samples (systemic blood) were analyzed from a previously reported cohort of patients with acute intestinal failure undergoing chyme reinfusion. 21 All research was conducted in accordance with both the Declarations of Helsinki and Istanbul.…”

Section: Methodsmentioning

confidence: 99%

Microbially conjugated bile salts found in human bile activate the bile salt receptors TGR5 and FXR

Ay,

Leníček,

Haider

et al. 2024

Hepatology Communications

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“…These samples were collected in the framework of the FOCUS study (Ethical Commission University Hospital Aachen approval: EK 172/17), following written informed consent of the patient. Furthermore, plasma samples (systemic blood) were analyzed from a previously reported cohort of patients with acute intestinal failure undergoing chyme reinfusion (21). All research was conducted in accordance with both the Declarations of Helsinki and Istanbul.…”

Section: Methodsmentioning

confidence: 99%

Microbially-conjugated Bile Salts Found in Human Bile Activate the Bile Salt Receptors TGR5 and FXR

Ay,

Leníček,

Haider

et al. 2023

Preprint

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Background & Aims Bile salts of hepatic and microbial origin mediate inter-organ crosstalk in the gut-liver axis. Here, we assessed whether the newly discovered class of microbial bile salt conjugates (MBSCs), activate the main host bile salt receptors (TGR5 and FXR) and enter the human systemic and enterohepatic circulation. Approach & Results N-amidates of (chenodeoxy)cholic acid and leucine, tyrosine and phenylalanine were synthesized. Receptor activation was studied in cell-free and cell-based assays. MBSCs were quantified in mesenteric and portal blood and bile of patients undergoing pancreatic surgery. MBSCs were activating ligands of TGR5 as evidenced by recruitment of Gs alpha protein, activation of a cAMP-driven reporter, and diminution of LPS-induced cytokine release from macrophages. Intestine- and liver-enriched FXR isoforms were both activated by MBSCs, provided that a bile salt importer was present. Affinity of MBSCs for TGR5 and FXR was not superior to host-derived bile salt conjugates. Individual MBSCs were generally not detected (i.e. <2.5 nmol/L) in human mesenteric or portal blood, but Leu- and Phe-variants were readily measurable in bile, where MBSCs comprised up to 213 ppm of biliary bile salts. Conclusions MBSCs activate the cell surface receptor TGR5 and the transcription factor FXR, and are substrates for intestinal (ASBT) and hepatic (NTCP) transporters. Their entry into the human circulation is, however, non-substantial. Given low systemic levels and surplus of other equipotent bile salt species, the studied MBSCs are unlikely to have an impact on enterohepatic TGR5/FXR signaling in humans. Origin and function of biliary MBSCs remain to be determined.

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“…This is exemplified by Clostridium scindens, which inhibits Microbial BSHs catalyze the deconjugation of bile salts. BSH activity is widespread in gut bacteria, especially in Gram-positive bacteria, that due to their lack of an outer membrane are more sensitive to detergent effects of bile salts [42]. Bacterial deconjugation of bile salts entering the colon is nearly quantitative, with only minor fractions of conjugated species found in feces.…”

Section: Potential Roles Of Mbscs In the Gutmentioning

confidence: 99%

New Kids on the Block: Bile Salt Conjugates of Microbial Origin

Leníček

Claßen

et al. 2022

Metabolites

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Biotransformation of host bile salts by gut microbes results in generation of secondary bile salt species that have biological and physicochemical properties that are distinct from the parent compounds. There is increased awareness that a bile salt–gut microbiome axis modulates various processes in the host, including innate and adaptive immunity, by interaction of microbial bile salt metabolites with host receptors. Omics and targeted approaches have vastly expanded the number and repertoire of secondary bile salt species. A new class of microbial bile salt metabolites was reported in 2020 and comprises bile salts that are conjugated by microbial enzymes. Amino acids other than those employed by host enzymes (glycine and taurine) are used as substrates in the formation of these microbial bile salt conjugates (MBSCs). Leucocholic acid, phenylalanocholic acid and tyrosocholic acid were the first MBSCs identified in mice and humans. The number of distinct MBSCs is now approaching 50, with variation both at the level of bile salt and amino acid employed for conjugation. Evidence is emerging that MBSC generation is a common feature of human gut bacteria, and initial links with disease states have been reported. In this review, we discuss this intriguing new class of secondary bile salts, with yet enigmatic function.

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Chyme Reinfusion Restores the Regulatory Bile Salt–FGF19 Axis in Patients With Intestinal Failure

Cited by 10 publications

References 39 publications

Microbially conjugated bile salts found in human bile activate the bile salt receptors TGR5 and FXR

Microbially conjugated bile salts found in human bile activate the bile salt receptors TGR5 and FXR

Microbially-conjugated Bile Salts Found in Human Bile Activate the Bile Salt Receptors TGR5 and FXR

New Kids on the Block: Bile Salt Conjugates of Microbial Origin

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