Bile Acids Are Substrates for Amine N-Acyl Transferase Activity by Bile Salt Hydrolase
Open accessPreprint — published as 10.1038/s41586-023-06990-w · Paper page
Abstract
Bacteria in the gastrointestinal tract (GI) produce a variety of amino acid bile acid amidates that impact host-mediated metabolic processes; however, the bacterial gene(s) responsible for their production remain unknown. Herein, we report that bile salt hydrolase (BSH) possesses dual functions, including a new role in bile acid metabolism by functioning as an amine N-acyl transferase that conjugates amines to form bacterial bile acid amidates (BBAAs). To characterize this new amine N-acyl transferase role for BSH, we used pharmacological inhibition of BSH, heterologous expression of bsh in Escherichia coli, and generated a bsh knockout and knockin in Bacteroides fragilis to demonstrate that BSH is necessary and sufficient for BBAA production. Lastly, we report that BBAAs activate host ligand-activated transcription factors including the farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, and the aryl hydrocarbon receptor. These new findings expand our understanding and appreciation for the important roles that bacteria play in shaping the bile acid metabolic network.
AI snapshot
Written from the paper’s full text.
TL;DR
The paper reports that bacterial bile salt hydrolase (BSH) has a previously unknown amine N-acyltransferase activity that conjugates amines to bile acids, forming bacterial bile acid amidates (BBAAs), in addition to its canonical deconjugation role. It links BSH/bsh to BBAA production in bacterial isolates, gnotobiotic mice, and human infants, and shows BBAAs can activate host nuclear receptors in cell and organoid models.
Key findings
- BSH is necessary and sufficient for BBAA formation: the pan-BSH inhibitor GR-7 reduced BBAA production; purified BlBSH synthesized BBAAs from CA or TCA; E. coli expressing BlBSH produced BBAAs; B. fragilis Δbsh eliminated BBAA production from CA/TCA and complementation rescued it.
- bsh presence was significantly associated with BBAA production across combined isolate datasets (P = 9.4 × 10−6, phylogenetic linear regression); in B. longum, bsh was upregulated by CA/DCA (RNA-seq log2FC = 2.14, adjusted P = 6.52 × 10−85; RT-qPCR 2.7-fold, P = 0.0026).
- In germ-free mice monocolonized with B. fragilis WT vs Δbsh, Δbsh-colonized mice had depleted BBAA levels (P = 3.1 × 10−4) and altered primary bile acids; free caecal taurine was higher in WT-colonized mice (P = 4.27 × 10−4).
- In a human infant cohort (n = 108), BBAA levels increased from 0–4 days to 12 months; Enterococcus abundance positively correlated with BBAAs, and Bifidobacterium with His/Thr conjugates. BBAAs activated host receptors: Glu-conjugated bile acids activated FXR, CAR3, PXR, AHR and PPARα (P < 0.0001); mouse organoids upregulated Cyp3a11, Cyp1a1 and Bsep, and human organoids upregulated CYP1A1 with 100 µM Glu-CDCA (P < 0.01).
Methods
- Combined LC–MS/MS BBAA data from two published bacterial isolate datasets (202 HMP isolates and 69 representative gut bacteria) with genomes; used phylogenetic linear regression to test bsh–BBAA association; performed RNA-seq and RT-qPCR in B. longum NCTC 11818.
- Used purified BlBSH enzyme assays, heterologous expression and site-directed mutagenesis in E. coli, B. fragilis NCTC 9343 Δbsh and complementation, and germ-free C57BL/6J mice monocolonized with WT or Δbsh B. fragilis (n = 7 WT, n = 8 Δbsh) with LC–MS/MS and 1H NMR.
- Human infant IGRAM cohort stool samples (56 male, 52 female) at birth, 1 month, and 12 months; shotgun metagenomics and LC–MS/MS; cell-based reporter assays for FXR, VDR, CAR3, PXR, AHR, PPARα/β/δ/γ and mouse/human enteroid qPCR.
Limitations
- Stated: the conjugation mechanism is unclear; human organoid responses were less pronounced than mouse; further in vitro and in vivo studies are required to show whether BBAAs affect metabolism of substrates, drugs and carcinogens regulated by PXR and AHR; future studies must re-evaluate BBAA contribution to disease outcomes related to BSH activity.
- Evident from the text: receptor activation evidence is largely cell culture/organoid, not in vivo; human infant findings are observational correlations; mouse work uses monocolonization with one B. fragilis strain, so generalizability to complex microbiota is not established.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
26 of 28 cited sources checked · 10 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Some BBAAs activate host bile acid nuclear receptors like FXR and PXR.
“Some BBAAs activate host bile acid nuclear receptors like the farnesoid X receptor (FXR) and pregnane X receptor (PXR)1,3, but an assessment of other receptors has not been completed.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [1] Quinn RA Global chemical effects of the microbiome include new bile-acid conjugations Nature 2020 579 123 129 10.1038/s41586-020-2047-9 32103176 PMC7252668 source
The “Novel Bile Acids and FXR” section reports that phenylalanine- and tyrosine-conjugated bile acids activate human FXR in a cell-based assay. The passages in our copy do not report activation of PXR, so the citation supports the FXR part but not the PXR part. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [3] Gentry, E. C. et al. Reverse metabolomics for the discovery of chemical structures from humans. Nature10.1038/s41586-023-06906-8 (2023). PMC10849969 38052229 source
The 'Validation of the IBD association' section reports that several conjugated bile acids act as PXR agonists and that two increased PXR activation in intestinal organoids. Our copy does not report that BBAAs activate FXR; FXR appears only in the title of a cited reference, not as a finding of this paper. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Interpretationcitation
BSHs may be instrumental in fine tuning different pathways that promote health or disease.
“As there are hundreds of different BSHs found in microbiota that synthesize different BBAAs3, BSHs may be instrumental in fine tuning different pathways that promote health or disease.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [3] Gentry, E. C. et al. Reverse metabolomics for the discovery of chemical structures from humans. Nature10.1038/s41586-023-06906-8 (2023). PMC10849969 38052229 source
The Microbial production of bile amides section reports that bacteria produce some conjugated bile acids, and Validation of the IBD association reports immune activity for several conjugates. But the copy does not say that BSHs synthesize different BBAAs or fine-tune health- or disease-related pathways; searches for “BSH” and “bile salt hydrolase” found only a reference-list entry. (LLM, conf=0.73)
Experimental — accuracy not yet measured
- Premisecitation
Bacteria in the gastrointestinal tract produce amino acid bile acid amidates that can affect host-mediated metabolic processes.
“Bacteria in the gastrointestinal tract produce amino acid bile acid amidates that can affect host-mediated metabolic processes1–6; however, the bacterial gene(s) responsible for their production remain unknown.”
Quote in the paperSubstantial claim6 of 6 sources checked- cites [1] Quinn RA Global chemical effects of the microbiome include new bile-acid conjugations Nature 2020 579 123 129 10.1038/s41586-020-2047-9 32103176 PMC7252668 source
- cites [2] Lucas LN Dominant bacterial phyla from the human gut show widespread ability to transform and conjugate bile acids mSystems 2021 6 e00805 e00821 10.1128/mSystems.00805-21 PMC12338150 34463573 source
- cites [3] Gentry, E. C. et al. Reverse metabolomics for the discovery of chemical structures from humans. Nature10.1038/s41586-023-06906-8 (2023). PMC10849969 38052229 source
- cites [4] Hoffmann MA High-confidence structural annotation of metabolites absent from spectral libraries Nat. Biotechnol. 2022 40 411 421 10.1038/s41587-021-01045-9 34650271 PMC8926923 source
In Results, ‘Searching for novel bile acid conjugates’ (page unavailable), the paper describes amino-acid bile acid conjugates produced by microbes and suggests microbial involvement in producing additional conjugates. It says bile acids act as signaling molecules, but does not establish that the amino-acid conjugates affect host-mediated metabolic processes. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [5] Funabashi M A metabolic pathway for bile acid dehydroxylation by the gut microbiome Nature 2020 582 566 570 10.1038/s41586-020-2396-4 32555455 PMC7319900 source
The Abstract says gut bacteria produce the secondary bile acids DCA and LCA, which modulate host metabolism. It does not say they produce amino acid bile acid amidates or that those amidates affect host metabolic processes; the paper addresses a different class of bile acid products. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [6] Aatsinki, A.-K. et al. Dynamics of gut metabolome and microbiome maturation during early life. Preprint at medRxiv10.1101/2023.05.29.23290441 (2023). source
The Introduction (page unavailable) says microbial transformation of bile acids can regulate human physiology, and the Discussion (page unavailable) links bile acids to metabolic processes. Neither passage says gut bacteria produce amino acid bile acid amidates specifically; the Discussion instead describes bacterial deconjugation of glycine from bile acids. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Interpretationcitation
The greater diversity of BBAAs produced by purified BlBSH in vitro compared to BlBSH-expressing E. coli is probably a result of different amino acid profiles in E. coli, where alanine is about 100-fold more concentrated than serine.
“However, the greater diversity of BBAAs produced by purified BlBSH in vitro (Fig. 2b) compared to BlBSH-expressing E. coli (Fig. 2c) is probably a result of the different amino acid profiles in E. coli (alanine is present at about a 100-fold greater concentration than serine)23.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [23] Bennett BD Absolute metabolite concentrations and implied enzyme active site occupancy in Escherichia coli Nat. Chem. Biol. 2009 5 593 599 10.1038/nchembio.186 19561621 PMC2754216 source
The Results and Discussion describe measurements of E. coli metabolite concentrations, but the passages found for “alanine,” “serine,” and their concentration ratio give no values for either amino acid. Our copy therefore does not verify the approximately 100-fold comparison for which this paper is cited. (LLM, conf=0.73)
Experimental — accuracy not yet measured
- Findingown data
Most BBAA activators of human FXR were conjugates of CDCA (5 of 8, P < 0.0001).
“Most of the BBAA activators of the human bile acid receptor FXR were conjugates of CDCA (5 of 8, P < 0.0001), probably reflecting the potency of CDCA as an FXR agonist26.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [26] Li T Chiang JYL Nuclear receptors in bile acid metabolism Drug Metab. Rev. 2013 45 145 155 10.3109/03602532.2012.740048 23330546 PMC3676171 source
- Findingown data
In cell culture models, BBAAs activate host ligand-activated transcription factors including the pregnane X receptor and the aryl hydrocarbon receptor.
“Lastly, we report that in cell culture models, BBAAs activate host ligand-activated transcription factors including the pregnane X receptor and the aryl hydrocarbon receptor.”
Quote in the paperSubstantial claim - Findingown data
In a human infant cohort, BBAA production is positively correlated with colonization of bsh-expressing bacteria.
“We further show in a human infant cohort that BBAA production is positively correlated with the colonization of bsh-expressing bacteria.”
Quote in the paperSubstantial claim - Findingown data
bsh expression is upregulated in B. longum NCTC 11818 treated with 100 μM unconjugated CA and DCA.
“Global transcriptional profiling identified 1,929 genes, of which 89 were differentially expressed (adjusted P ≤ 0.05 and log2FC ≤ −1.5 or ≥ 1.5), including bsh, which was significantly upregulated (log2FC = 2.14, adjusted P = 6.52 × 10−85) (Extended Data Fig. 2 and Supplementary Table 1).”
- Also stated in: another passage · plain
“We also validated the RNA sequencing results with quantitative reverse transcription polymerase chain reaction (RT-qPCR), confirming that bsh messenger RNA was increased 2.7-fold (P = 0.0026) (Fig. 1e).”
Quote in the paperSubstantial claim - Also stated in: another passage · plain
- Findingown data
Germ-free mice colonized with wild-type or Δbsh B. fragilis equally colonized the mouse gastrointestinal tract seven days after gavage.
“Both strains equally colonized the mouse gastrointestinal tract seven days after gavage (Fig. 2f), and there was no change in body weight between the groups (Extended Data Fig. 5).”
Quote in the paperSubstantial claim - Findingown data
In human organoids, CYP1A1 expression was upregulated with 100 μM Glu-CDCA treatment (P < 0.01).
“Responses in human organoids were less pronounced, but CYP1A1 expression was also upregulated with 100 µM Glu-CDCA treatment (P < 0.01, Extended Data Figs. 8b and 9b).”
Quote in the paperSubstantial claim - Findingown data
Bile acids conjugated with glutamate activated human FXR, CAR3, PXR, AHR and PPARα (P < 0.0001).
“Bile acids conjugated with glutamate activated human FXR, CAR3, PXR, AHR and PPARα (P < 0.0001).”
Quote in the paperSubstantial claim - Findingown data
The bsh gene is significantly associated with BBAA production across human-associated bacterial isolates (P = 9.4 × 10−6, phylogenetic linear regression).
“We found that the bile salt hydrolase (bsh) gene was significantly associated (P = 9.4 × 10−6, phylogenetic linear regression) with BBAA production (Fig. 1d and Extended Data Fig. 1).”
Quote in the paperSubstantial claim - Findingown data
In samples collected at 0-4 days, levels of several BBAAs (Ala-CA, Glu-CDCA, Tyr-CA, His-CA, Ile/leu-CA, Trp-CA, Ser-CA and Tyr-CDCA) were positively correlated with hours elapsed after birth.
“Further stratifying the samples collected at 0–4 days, the levels of several BBAAs (Ala-CA, Glu-CDCA, Tyr-CA, His-CA, Ile/leu-CA, Trp-CA, Ser-CA and Tyr-CDCA) were positively correlated with the hours elapsed after birth (Extended Data Fig. 6).”
Quote in the paperNot a substantial claim - Findingown data
GR-7 does not inhibit B. longum growth, as colony-forming units were equal with or without GR-7.
“The attenuated BBAA synthesis was not due to bacterial growth inhibition because colony-forming units (CFUs) were equal with or without GR-7 (Extended Data Fig. 3).”
Quote in the paperSubstantial claim - Findingown data
In mouse organoids, Glu-CA and Glu-CDCA upregulated Cyp3a11, Cyp1a1 and Bsep expression.
“In mouse organoids, Glu-CA and Glu-CDCA upregulated Cyp3a11, Cyp1a1 and Bsep expression, indicating that PXR and AHR were transcriptionally activated (Extended Data Figs. 8a and 9a).”
Quote in the paperSubstantial claim - Findingown data
BBAA levels increased from 0-4 days to 12 months after birth.
“The levels of BBAAs also increased from 0–4 days to 12 months after birth (Fig. 3d).”
Quote in the paperSubstantial claim - Findingown data
Pharmacological inhibition of BSH with GR-7 significantly decreases BBAA production in B. longum treated with equimolar 100 μM CA and DCA, particularly phenylalanine- and alanine-conjugates.
“Addition of 100 μM GR-7 resulted in a significant decrease in the production of BBAAs, particularly phenylalanine- and alanine-conjugates, as compared to vehicle-treated controls (Fig. 2a).”
Quote in the paperSubstantial claim - Findingown data
Microbial diversity measured by the Shannon Index increases from birth through 12 months in infant stool.
“Metagenomic sequencing showed an increase in microbial diversity, measured by the Shannon Index, from birth through 12 months (Fig. 3a).”
Quote in the paperNot a substantial claim - Findingown data
None of the mutations inhibited expression of the BlBSH protein.
“None of the mutations inhibited expression of the BlBSH protein (Extended Data Fig. 4).”
Quote in the paperSubstantial claim - Findingown data
In 12-month-old infants, Enterococcus abundance was positively correlated with host-conjugated bile acids and BBAAs including Ala, Ile/Leu, Phe, Ser and Tyr.
“In 12-month-old infants, Enterococcus abundance was positively correlated with host-conjugated bile acids and BBAAs including Ala, Ile/Leu, Phe, Ser and Tyr (Fig. 3e).”
Quote in the paperSubstantial claim - Findingown data
There was no change in body weight between wild-type- and Δbsh-colonized mice.
“Both strains equally colonized the mouse gastrointestinal tract seven days after gavage (Fig. 2f), and there was no change in body weight between the groups (Extended Data Fig. 5).”
Quote in the paperNot a substantial claim - Findingown data
Bacteroides abundance was not correlated with BBAA production.
“Bacteroides abundance was not correlated with BBAA production.”
Quote in the paperNot a substantial claim - Findingown data
Beta-diversity differs between one-month- and 12-month-old infants (PERMANOVA P = 0.001).
“Principal coordinates analysis of Bray–Curtis dissimilarity supports the differences in beta-diversity between one-month- and 12-month-old infants (Fig. 3b, permutational multivariate analysis of variance (PERMANOVA) P = 0.001).”
Quote in the paperNot a substantial claim - Findingown data
AHR is activated by both bacterially conjugated and conventional bile acids in vitro.
“We previously showed that Glu-conjugated bile acids were activators of human PXR in vitro14, and herein, we observed activation of AHR by both bacterially conjugated and conventional bile acids in vitro.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] Joyce SA Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut Proc. Natl Acad. Sci. USA 2014 111 7421 7426 10.1073/pnas.1323599111 24799697 PMC4034235 source
- Findingown data
Free taurine was significantly higher in caecal contents of wild-type-colonized mice compared to Δbsh-colonized mice.
“Similarly, free taurine was also significantly higher in caecal contents of wild-type-colonized mice compared to Δbsh-colonized mice (Fig. 2h).”
Quote in the paperSubstantial claim - Interpretationown data
BSH acts as an amine N-acyltransferase that conjugates amines to bile acids to form bacterial bile acid amidates (BBAAs).
“Herein, we report that bile salt hydrolase (BSH) possesses dual functions in bile acid metabolism. Specifically, we identified a previously unknown role for BSH as an amine N-acyltransferase that conjugates amines to bile acids, thus forming bacterial bile acid amidates (BBAAs).”
- Also stated in: another passage · boosted
“We demonstrate herein that bacterial BSHs re-amidate bile acids to produce BBAAs in addition to their known role in hydrolysing conjugated bile acids (Fig. 1c).”
Quote in the paperSubstantial claim - Also stated in: another passage · boosted
- Premisecitation
BSH hydrolyses the amide linkage of conjugated bile acids.
“Bile salt hydrolase (BSH), an enzyme commonly found in bacteria inhabiting the small intestine and colon, hydrolyses the amide linkage of conjugated bile acids11 (Fig. 1b).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Grill J Schneider F Crociani J Ballongue J Purification and characterization of conjugated bile salt hydrolase from Bifidobacterium longum BB536 Appl. Environ. Microbiol. 1995 61 2577 2582 10.1128/aem.61.7.2577-2582.1995 16535071 PMC1388489 source
- Interpretationown data
BBAAs may facilitate communication between the microbiota and host through activation of human ligand-activated transcription factors.
“These BBAAs may facilitate communication between the microbiota and host through the activation of the human ligand-activated transcription factors.”
Quote in the paperSubstantial claim - Interpretationown data
These data support that BSHs from Bifidobacterium species are amine N-acyltransferases that produce BBAAs in humans.
“These data support our findings that BSHs from Bifidobacterium species are amine N-acyltransferases that produce BBAAs in humans.”
Quote in the paperSubstantial claim - Interpretationown data
In mouse organoids, Glu-CA and Glu-CDCA treatment indicates that PXR and AHR were transcriptionally activated.
“In mouse organoids, Glu-CA and Glu-CDCA upregulated Cyp3a11, Cyp1a1 and Bsep expression, indicating that PXR and AHR were transcriptionally activated (Extended Data Figs. 8a and 9a).”
Quote in the paperSubstantial claim - Interpretationown data
BSH has a previously undescribed role as an amine N-acyltransferase that produces BBAAs in mice and humans.
“We identified a previously undescribed role for BSH as an amine N-acyltransferase that produces BBAAs in mice and humans.”
Quote in the paperSubstantial claim - Interpretationown data
In the infant cohort, the shift from host-conjugated to unconjugated primary bile acids with age is due to colonization of bsh-positive bacteria.
“As the microbiota evolved with age, we observed a shift from host-conjugated to unconjugated primary bile acids due to the colonization of bsh-positive bacteria (Fig. 3d).”
Quote in the paperSubstantial claim - Interpretationown data
In the mouse gastrointestinal tract, colonization with BSH-positive bacteria is required for bile acid hydrolysis and re-amidation.
“Therefore, in the mouse gastrointestinal tract, colonization with BSH-positive bacteria is required for bile acid hydrolysis and re-amidation.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 13
- May combine two claims. 12
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationBBAAs are abundant in the gastrointestinal tract and have been associated with human inflammatory bowel disease.
“Furthermore, bacterial bile acid amidates (BBAAs) are abundant in the gastrointestinal tract18 and have been associated with human inflammatory bowel disease3.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [18] Shalon D Profiling the human intestinal environment under physiological conditions Nature 2023 617 581 591 10.1038/s41586-023-05989-7 37165188 PMC10191855 source
- cites [3] Gentry, E. C. et al. Reverse metabolomics for the discovery of chemical structures from humans. Nature10.1038/s41586-023-06906-8 (2023). PMC10849969 38052229 source
May combine two claims.
PremisecitationCys1 of BlBSH is predicted to be the primary catalytic residue, although other active site residues such as Thr2, Trp21, Thr171, Asn172 and Arg225 may also be important for BSH activity or substrate specificity.
“the terminal cysteine Cys1 of BlBSH is predicted to be the primary catalytic residue, although other active site residues (for example, Thr2, Trp21, Thr171, Asn172 and Arg225) may also be important for BSH activity or substrate specificity24.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [24] Kumar RS Structural and functional analysis of a conjugated bile salt hydrolase from Bifidobacterium longum reveals an evolutionary relationship with penicillin V acylase J. Biol. Chem. 2006 281 32516 32525 10.1074/jbc.M604172200 16905539 source
Classified as probably not a substantial claim.
PremisecitationThe bacterial enzymes responsible for producing amino acid bile acid amidates are unknown.
“The enzymes responsible for these conjugation reactions are unknown.”
Quote in the paperSubstantial claim6 of 6 sources checked- cites [1] Quinn RA Global chemical effects of the microbiome include new bile-acid conjugations Nature 2020 579 123 129 10.1038/s41586-020-2047-9 32103176 PMC7252668 source
- cites [2] Lucas LN Dominant bacterial phyla from the human gut show widespread ability to transform and conjugate bile acids mSystems 2021 6 e00805 e00821 10.1128/mSystems.00805-21 PMC12338150 34463573 source
- cites [3] Gentry, E. C. et al. Reverse metabolomics for the discovery of chemical structures from humans. Nature10.1038/s41586-023-06906-8 (2023). PMC10849969 38052229 source
The “Microbial production of bile amides” section (page unavailable) identifies bacteria that produce amino-acid-conjugated bile acids, but does not say whether the enzymes responsible are known. Searches for “enzymes,” “unknown enzymatic mechanism,” and genes encoding conjugation enzymes found no passage addressing enzyme identity. (LLM, conf=0.72)
Experimental — accuracy not yet measured - cites [4] Hoffmann MA High-confidence structural annotation of metabolites absent from spectral libraries Nat. Biotechnol. 2022 40 411 421 10.1038/s41587-021-01045-9 34650271 PMC8926923 source
The Results section, “Searching for novel bile acid conjugates” (page unavailable), describes amino acid–bile acid conjugates and suggests microbial involvement in their production. It does not address whether the enzymes responsible for the conjugation reactions are known; searches for the enzyme claim and related terms found no such statement. (LLM, conf=0.75)
Experimental — accuracy not yet measured - cites [6] Aatsinki, A.-K. et al. Dynamics of gut metabolome and microbiome maturation during early life. Preprint at medRxiv10.1101/2023.05.29.23290441 (2023). source
The Discussion (page unavailable) describes bile salt hydrolase enzymes that deconjugate bile acids, not enzymes that produce amino acid bile acid amidates. Searches for the claimed unknown conjugation enzymes and for amino acid bile acid amidates found no passage in our copy addressing whether those enzymes are known. (LLM, conf=0.75)
Experimental — accuracy not yet measured - cites [17] Wang M Mass spectrometry searches using MASST Nat. Biotechnol. 2020 38 23 26 10.1038/s41587-019-0375-9 31894142 PMC7236533 source
The paper’s main text describes MASST as a tool for searching mass-spectrometry data; it does not address which enzymes produce amino acid bile acid amidates. Searches for the conjugation reactions, bile acids, and their bacterial enzymes found no relevant passage in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationRecent studies demonstrated that bacteria have bile acid amine N-acyltransferase activity, with dozens of bacterially conjugated amino acid amidates identified.
“Recent studies demonstrated that bacteria, in addition to the host, have bile acid amine N-acyltransferase activity, with dozens of bacterially conjugated amino acid amidates identified1–4,6,17.”
Quote in the paperSubstantial claim6 of 6 sources checked- cites [1] Quinn RA Global chemical effects of the microbiome include new bile-acid conjugations Nature 2020 579 123 129 10.1038/s41586-020-2047-9 32103176 PMC7252668 source
In “Microbes produce the novel bile acids” (page unavailable), the paper reports that C. bolteae synthesized amino-acid-conjugated bile acids, supporting bacterial conjugation activity. In “Discovery of new conjugated bile acids” (page unavailable), it identifies three such amidates—phenylalanine, tyrosine, and leucine conjugates—not dozens. The cited paper therefore supports the bacterial activity but not the stated number of identified amidates. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [2] Lucas LN Dominant bacterial phyla from the human gut show widespread ability to transform and conjugate bile acids mSystems 2021 6 e00805 e00821 10.1128/mSystems.00805-21 PMC12338150 34463573 source
- cites [3] Gentry, E. C. et al. Reverse metabolomics for the discovery of chemical structures from humans. Nature10.1038/s41586-023-06906-8 (2023). PMC10849969 38052229 source
The ‘Microbial production of bile amides’ section (page not provided) reports that bacterial cultures produced cholic- and deoxycholic-acid amidates for 15 amino acids, supporting bacterial production of dozens of amino-acid bile amidates. It does not identify or measure bacterial bile acid amine N-acyltransferase activity specifically; it establishes conjugation from the products detected in culture. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites [4] Hoffmann MA High-confidence structural annotation of metabolites absent from spectral libraries Nat. Biotechnol. 2022 40 411 421 10.1038/s41587-021-01045-9 34650271 PMC8926923 source
The Results section (‘Searching for novel bile acid conjugates’; page not provided) reports amino-acid-conjugated bile acids, including 12 leading novel annotations, and a matching spectrum in a bacterial culture. It says microbial involvement in producing the 12 is suggested, not demonstrated; it does not establish bacterial bile acid amine N-acyltransferase activity or the identification of dozens of bacterially conjugated amidates. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [6] Aatsinki, A.-K. et al. Dynamics of gut metabolome and microbiome maturation during early life. Preprint at medRxiv10.1101/2023.05.29.23290441 (2023). source
The Discussion describes bacterial bile acid metabolism, particularly bile salt hydrolase activity and deconjugation, but does not address bacterial bile acid amine N-acyltransferase activity. A search for bacterial conjugation and amino acid amidates found no passage reporting the identification of dozens of such compounds. The supplied passages have no page numbers. (LLM, conf=0.74)
Experimental — accuracy not yet measured - cites [17] Wang M Mass spectrometry searches using MASST Nat. Biotechnol. 2020 38 23 26 10.1038/s41587-019-0375-9 31894142 PMC7236533 source
The main text describes MASST searches of public mass-spectrometry data, not bacterial bile-acid conjugation. Searches for bile acids, amine N-acyltransferase activity, and amino-acid amidates found no passage addressing the claimed activity or the identification of dozens of amidates. (LLM, conf=0.75)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataBifidobacterium abundance was negatively correlated with host-conjugated bile acids in one-month-old infants and positively correlated with bile acid conjugates of His and Thr.
“Bifidobacterium abundance was negatively correlated with host-conjugated bile acids in one-month-old infants and positively correlated with bile acid conjugates of His and Thr (Fig. 3e).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPurified BlBSH produces BBAAs from 100 μM CA or TCA with a 250 μM equimolar mixture of amino acids, but not all amino acids are conjugated, demonstrating substrate selectivity.
“Next, we purified BlBSH and assayed for BBAA production from 100 μM CA or TCA and a 250 μM equimolar mixture of amino acids. Both CA and TCA treatment yielded BBAAs, but not all amino acids were conjugated, demonstrating substrate selectivity by BSH.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe Bacteroides population expanded from one to 12 months, whereas the relative abundance of Bifidobacterium was reduced.
“The Bacteroides population expanded from one to 12 months, whereas the relative abundance of Bifidobacterium was reduced (Fig. 3c).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn Δbsh-colonized mice, the bile acid pool showed reduced release of unconjugated primary bile acids and significantly depleted BBAA levels.
“The bile acid pool of Δbsh-colonized mice reflected a perturbation in bile acid hydrolysis, as the release of unconjugated primary bile acids was reduced and the production of BBAAs attenuated (Fig. 2g,i).”
- Also stated in: another passage · boosted
“Importantly, we demonstrate that colonization with wild-type B. fragilis is key to the production of BBAAs, as BBAA levels are significantly depleted in Δbsh-colonized mice (Fig. 2i).”
Quote in the paperSubstantial claim- Also stated in: another passage · boosted
May combine two claims.
Findingown dataHeterologous expression of BlBSH in E. coli confers amine N-acyltransferase activity, producing BBAAs from 1 mM CA or TCA, whereas untransformed E. coli does not produce BBAAs.
“Heterologous expression of the enzyme in E. coli, which lacks endogenous bsh, confers amine N-acyltransferase activity. Incubation of the E. coli-BlBSH with 1 mM CA or 1 mM TCA produced BBAAs, whereas the untransformed E. coli did not produce BBAAs (Fig. 2c).”
Quote in the paperSubstantial claim- Rests on an assumption: E. coli lacks endogenous bsh.
May combine two claims.
Findingown dataDeletion of bsh in B. fragilis eliminates BBAA production from both CA and TCA, whereas complementation rescues BBAA production.
“Deletion of bsh eliminated the production of BBAAs from both CA and TCA, whereas complementation rescued BBAA production (Fig. 2d).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSite-directed mutagenesis of nine residues proximal to the active site of BlBSH showed that C1A, R17A, N172A and R225A are essential for N-acyltransferase activity, and N-acyltransferase activity closely mirrored deconjugation activity with each mutation.
“We performed site-directed mutagenesis on nine residues proximal to the active site of BlBSH to identify which are necessary for N-acyltransferase activity in BSH (Fig. 2e). The N-acyltransferase activity of BSH closely mirrored the deconjugation activity with each mutation, with C1A, R17A, N172A and R225A all being essential for its function.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Findingnone givenThe new construct pER363 contains a deletion of a 765 bp DNA fragment from the bsh gene.
“The new construct, pER363, contains a deletion of 765 bp DNA fragment from the bsh gene.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningVariation in sample diversity between 0 and 4 days is probably due to rapid maturation of the gut microbiota.
“Variation in sample diversity between 0 and 4 days is probably due to the rapid maturation of the gut microbiota.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataBSH prefers amino acids with smaller side chains, as indicated by large proportions of alanine and serine conjugates produced by B. fragilis, BlBSH-expressing E. coli, and purified BlBSH.
“The large proportion of alanine and serine conjugates produced by B. fragilis (Fig. 2d), BlBSH-expressing E. coli (Fig. 2c) and purified BlBSH (Fig. 2b) indicate that the enzyme prefers amino acids with smaller side chains.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenThe B. fragilis NCTC 9343 Δbsh mutant isolates (BER-279) were tested for loss of erythromycin resistance and by respiratory test.
“The B. fragilis NCTC 9343 Δbsh mutant isolates (BER-279) were also tested for loss of erythromycin resistance and respiratory test.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenIn each shotgun metagenomics plate, two positive controls containing a mix of Vibrio campbellii and PhiX lambda phage were added.
“In each plate, two positive controls containing a mix of Vibrio campbellii and PhiX lambda phage were added.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenPeak areas for each conjugated bile acid from IGRAM stool samples were normalized to peak areas from deuterated internal standards of GCA-d4, GUDCA-d4 or GDCA-d4, matching the bile acid.
“Peak areas for each conjugated bile acid were normalized to peak areas from deuterated internal standards of GCA-d4, GUDCA-d4 or GDCA-d4, matching the bile acid.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenPCR amplification using BSH-mutcheck-FOR and BSH-mutcheck-REV primers was used to identify chromosomal double-crossed over genetic recombination.
“PCR amplification using BSH-mutcheck-FOR and BSH-mutcheck-REV primers was used to identify chromosomal double-crossed over genetic recombination.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductown dataQuantification of bile acids was performed against a standard curve of authentic standards at eight concentrations ranging from 7.81 nM to 1 μM.
“Quantification was performed against a standard curve of authentic standards at eight concentrations ranging from 7.81 nM to 1 µM.”
- Also stated in: another passage · plain
“Quantification was performed against a standard curve of authentic standards at eight concentrations ranging from 7.81 nM to 1 µM.”
Quote in the paperSubstantial claim- Also stated in: another passage · plain
Classified as probably not a substantial claim.
Study design and conductnone givenSterility of mice was ensured by qPCR and aerobic/anaerobic culture with rich media.
“Sterility of mice was ensured by qPCR and aerobic/anaerobic culture with rich media.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductnone givenPeak areas for each conjugated bile acid from bacterial cultures were normalized to peak areas from deuterated internal standards of GCA-d4 or GDCA-d4, matching the bile acid.
“Peak areas for each conjugated bile acid were normalized to peak areas from deuterated internal standards of GCA-d4 or GDCA-d4, matching the bile acid.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAfter automatic processing, the phase, baseline and internal standard were checked and modified manually for each NMR spectrum for quality assurance.
“After automatic processing, the phase, baseline and internal standard were checked and modified manually for each spectrum for quality assurance.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataSuccessful mutations were confirmed by QIAprep Spin Miniprep kit preparation of plasmid DNA followed by Sanger sequencing from the T7 promoter region.
“Individual colonies were selected, and successful mutations were confirmed by QIAprep Spin Miniprep kit (Qiagen) preparation of plasmid DNA followed by Sanger sequencing from the T7 promoter region.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
E. coli lacks endogenous bsh.
“Heterologous expression of the enzyme in E. coli, which lacks endogenous bsh, confers amine N-acyltransferase activity.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
BSHs are involved in MCBA production.
“Additionally, these data suggest that BSHs are involved in MCBA production; indeed, other studies are already investigating the possibility of BSH-catalysed reconjugation46,47.”
From Bile salt hydrolases shape the bile acid landscape and restrict Clostridioides difficile growth in the murine gut (2023) · cites this paper as [46]
BSH enzymes can catalyse reconjugation to generate MCBAs capable of activating host ligand-activated receptors.
“Furthermore, BSH activity is complicated by the emerging data indicating that these enzymes can catalyse reconjugation to generate MCBAs capable of activating host ligand-activated receptors31,33,46,47.”
From Bile salt hydrolases shape the bile acid landscape and restrict Clostridioides difficile growth in the murine gut (2023) · cites this paper as [46]
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Self-citation
Flagged first, then by citations
3 of the 49 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
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Gut symbionts alleviate MASH through a secondary bile acid biosynthetic pathway
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“…acts as a substrate for BSH from the bacterial species Lactobacillus spp., Enterocloster bolteae (formerly Clostridium bolteae ), Bifidobacterium longum and Bacteroides fragilis to furnish amino acid-conjugated bile acids, as highlighted by representative examples from the literature 42,158 (Fig.”
InfluentialSelf-citationThe underappreciated diversity of bile acid modifications
Mohanty, I., Mannochio-Russo, H., Schweer, J. V., Abiead, Y. E., Bittremieux, W., Xing, S., Schmid, R., Zuffa, S., Vasquez, F. J. D. A., Muti, V. B., et al. (2024) · Cell · doi:10.1016/j.cell.2024.02.019 · Cited by 202 · see citing works
“35,38 The BSHs, from Bacteroides fragilis , Clostridium perfringens , and Lactobacillus species, known to catalyze the hydrolysis of taurocholate and glycocholate, have now also been shown to possess amino-transferase activities.”
InfluentialSelf-citationFoley, M. H., Walker, M. E., Stewart, A. K., O’Flaherty, S., Gentry, E. C., Patel, S., Beaty, V. V., Allen, G., Pan, M., Simpson, J. B., et al. (2023) · Nature Microbiology · doi:10.1038/s41564-023-01337-7 · Cited by 181 · see citing works
Self-citationAnother renaissance for bile acid gastrointestinal microbiology
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“Two new studies demonstrate that BSH enzymes are capable of generating MCBAs with patterns emerging between BSH amino acid sequences and amino acid conjugation specificity 112,113 .”
How bile acids and the microbiota interact to shape host immunity
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Self-citationThe central role of the gut microbiota in the pathophysiology and management of type 2 diabetes
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The functions of gut microbiota-mediated bile acid metabolism in intestinal immunity
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“Not only can it deconjugate amines from BAs, but it also acts as a bacterial N-acyltransferase, catalyzing the formation of amine-conjugate d BAs with unconjugated BAs as the substrate [25].”
Immunology of bile acids regulated receptors
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“Studieshaverevealedthatinthetranscriptomeof Bi fi dobacterium longum ,thecombinedimpactofDCAandCAonbacterialribosomesisless pronounced compared to that observed in Bacteroides ovatus 56 .”
ResultNovel approaches in IBD therapy: targeting the gut microbiota-bile acid axis
Pan, Y., Zhang, H., Li, M., He, T., Guo, S., Zhu, L., Tan, J., & Wang, B. (2024) · Gut Microbes · doi:10.1080/19490976.2024.2356284 · Cited by 78 · see citing works
“105 The intrinsic acyltransferase activity of BSH/T greatly diversifies BA chemistry.”
BackgroundMicrobiota-derived bile acids antagonize the host androgen receptor and drive anti-tumor immunity
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Lindner, S., Miltiadous, O., Ramos, R. J. J. F., Paredes, J., Kousa, A. I., Dai, A., Fei, T., Lauder, E., Frame, J., Waters, N. R., et al. (2024) · Nature Microbiology · doi:10.1038/s41564-024-01617-w · Cited by 68 · see citing works
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“67, 68 In addition to amine-conjugated BAs, microbial acylated BAs such as 3-acetylated CA and 3-succinylated CA were also discovered by a click chemistry-based mass spectrometry approach.”
MethodNew insights into microbial bile salt hydrolases: from physiological roles to potential applications
Dong, Z., Yang, S., Tang, C., Li, D., Kan, Y., & Yao, L. (2025) · Frontiers in Microbiology · doi:10.3389/fmicb.2025.1513541 · Cited by 64 · see citing works
“In vivo studies have demonstrated that the production of MCBAs positively correlated with the colonization of BSH-active bacteria (Rimal et al., 2024).”
Dysregulated bile acid homeostasis: unveiling its role in metabolic diseases
Wang, Y., Xu, H., Zhou, X., Chen, W., & Zhou, H. (2024) · Medical Review · doi:10.1515/mr-2024-0020 · Cited by 61 · see citing works
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Balance between bile acid conjugation and hydrolysis activity can alter outcomes of gut inflammation
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Gut microbial bile and amino acid metabolism associate with peanut oral immunotherapy failure
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“29,30 The recent finding of microbially derived phenylalanine-and tyrosine-conjugated CAs demonstrated that they are even more potent agonists of FXR than CDCA, which was previously acknowledged as the most potent ligand.”
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- Authors
- Patterson, A., Rimal, B., Collins, S., Granda, M., Koo, I., Solanka, S., Hoque, N., Gentry, E., Yan, T., Bisanz, J., Krausz, K., Desai, D., Amin, S., Rocha, E., Coleman, J., Shah, Y., Gonzalez, F., Heuvel, J. V., Dorrestein, P., & Weinert, E.
- Affiliations
- Pennsylvania State University (US)
- University of Michigan
- University of California San Diego (US)
- National Institutes of Health (US)
- East Carolina University (US)
- University of Michigan (US)
- Penn State University
- Corresponding author
- Patterson, Andrew
- ORCID
- Venue
- Nature
- Published
- 2022-10-10
- Volume
- 626
- Issue
- 8000
- Pages
- 859-863
- ISSN
- 0028-0836 (ISSN-L)
- PMC
- PMC10881385
- OpenAlex
- W4391616565
- Cited by
- 245
- References
- 49
- Citations by year
- 2026: 85 · 2025: 91 · 2024: 60 · 2023: 9
- FWCI
- 27.76
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- U.S. Department of Agriculture (1009993, U01DK119702)
- American Heart Association (19POST34380588)
- Pennsylvania Department of Health (UL1TR001878)
- Children's Hospital of Philadelphia (UL1TR001878)
- University of Pennsylvania (P30 DK050306)
- University of Michigan (DK034933, P30CA046592, P50CA130810)
- Pennsylvania State University
- Crohn's and Colitis Foundation (675191, 623914)
- American Beverage Foundation for a Healthy America
- National Institutes of Health (1s10od021750-01a1, 1009993, 1u24dk133658-01, PEN047702, P30CA046592, R01 DK095201, P50 CA130810, T32GM102057, UL1TR001878, P30 DK050306, R01 CA148828, R01CA245546, R35-GM138369, U01DK119702, T32DK120509, DK034933)
- University of Michigan Comprehensive Cancer Center (P30 CA046592)
- National Cancer Institute (P30CA046592., P50CA130810, R01CA245546, R01CA148828, UL1-TR001878, P30DK050306)
- National Institute of General Medical Sciences (R 35 GM151045, T32GM102057, R01 GM125842, R35GM138369)
- National Institute of Allergy and Infectious Diseases (R00 AI147165)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 034933, P30/DK034933, T32 DK120509, R01DK107565, UL1TR001878, U24DK133658, U01 DK119702, P-30-DK050306, R01DK095201, R01 DK136117)
- National Institute of Environmental Health Sciences (R35ES035027)
- National Center for Research Resources (UL1TR001878)
- National Center for Advancing Translational Sciences (UL1-TR-001878)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Keywords
- bile salt hydrolase, bile acid metabolism, Bacteroides fragilis, gut microbiota, infant gut colonization, pregnane X receptor, aryl hydrocarbon receptor, ligand-activated transcription factors, Escherichia coli
- MeSH terms
- Gastrointestinal Microbiome, Pregnane X Receptor, Acyltransferases, Amidohydrolases, Amines, Bacteria, Bacteroides fragilis, Bile Acids and Salts, Catalysis, Escherichia coli, Humans, Infant, Ligands, Transcription Factors, Cohort Studies, Receptors, Aryl Hydrocarbon, Cell Culture Techniques, Biocatalysis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-11.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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