Bile acid fitness determinants of a
            <i>Bacteroides fragilis</i>
            isolate from a human pouchitis patient

Fiebig, Aretha; Schnizlein, Matthew K.; Pena-Rivera, Selymar; Trigodet, Florian; Dubey, Abhishek Anil; Hennessy, Miette K.; Basu, Anindita; Pott, Sebastian; Dalal, Sushila; Rubin, David; Sogin, Mitchell L.; Eren, A. Murat; Chang, Eugene B.; Crosson, Sean

doi:10.1128/mbio.02830-23

Cited by 2 publications

(2 citation statements)

References 95 publications

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“…S9), which is consistent with a model whereby DCA stimulates B. fragilis P207 to convert glutamate into GABA. However, DCA was recently reported to strongly induce expression of glutamate dehydrogenase (gene locus PTOS_003163 ) in B. fragilis P207 ( 27 ), suggesting that the metabolite flux involving glutamate is likely modulated in multiple ways by DCA. Cultivation of B. fragilis P207 did not greatly affect the levels of amino acids in BHIS overall, though glycine, GABA, glutamine, histidine, methionine, proline and tyrosine increased significantly (q < 0.01) after B. fragilis was cultivated in the medium.…”

Section: Resultsmentioning

confidence: 99%

Microbially catalyzed conjugation of GABA and tyramine to bile acids

Mullowney,

Fiebig,

Schnizlein

et al. 2024

J Bacteriol

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Bile acids (BAs) are cholesterol-derived molecules that aid in digestion and nutrient absorption, regulate host metabolic processes, and influence physiology of the gut microbiota. Both the host and its microbiome contribute to enzymatic modifications that shape the chemical diversity of BAs in the gut. Several bacterial species have been reported to conjugate standard amino acids to BAs, but it was not known if bacteria conjugate BAs to other amine classes. Here, we show that Bacteroides fragilis strain P207, isolated from a bacterial bloom in the J-pouch of a patient with ulcerative colitis pouchitis, conjugates standard amino acids and the neuroactive amines γ-aminobutyric acid (GABA) and tyramine to deoxycholic acid. We extended this analysis to other human gut isolates and identified species that are competent to conjugate GABA and tyramine to primary and secondary BAs, and further identified diverse BA-GABA and BA-tyramine amides in human stool. A longitudinal metabolomic analysis of J-pouch contents of the patient from whom B. fragilis P207 was isolated revealed highly reduced levels of secondary bile acids and a shifting BA amide profile before, during, and after onset of pouchitis, including temporal changes in several BA-GABA amides. Treatment of pouchitis with ciprofloxacin was associated with a marked reduction of nearly all BA amides in the J-pouch. Our study expands the known repertoire of conjugated bile acids produced by bacteria to include BA conjugates to GABA and tyramine and demonstrates that these molecules are present in the human gut. IMPORTANCE BAs are modified in multiple ways by host enzymes and the microbiota to produce a chemically diverse set of molecules that assist in the digestive process and impact many physiological functions. This study reports the discovery of bacterial species that conjugate the neuroactive amines, GABA and tyramine, to primary and secondary BAs. We further present evidence that BA-GABA and BA-tyramine conjugates are present in the human gut, and document a shifting BA-GABA profile in a human pouchitis patient before, during, and after inflammation and antibiotic treatment. GABA and tyramine are common metabolic products of the gut microbiota and potent neuroactive molecules. GABA- and tyramine-conjugated BAs may influence receptor-mediated regulatory mechanisms of humans and their gut microbes, and absorption of these molecules and their entry into enterohepatic circulation may impact host physiology at distal tissue sites. This study defines new conjugated bile acids in the human gut.

show abstract

Section: Resultsmentioning

confidence: 99%

Microbially catalyzed conjugation of GABA and tyramine to bile acids

Mullowney,

Fiebig,

Schnizlein

et al. 2024

J Bacteriol

Self Cite

View full text Add to dashboard Cite

show abstract

“…DCA treatment did not impact glutamine levels, but it did lead to a modest reduction in glutamate concentrations (q < 0.01; Figure S9), which is consistent with a model whereby DCA stimulates B. fragilis P207 to convert glutamate into GABA. However, DCA was recently reported to strongly induce expression of glutamate dehydrogenase (gene locus PTOS_003163 ) in B. fragilis P207 (27), suggesting that the metabolite flux involving glutamate is likely modulated in multiple ways by DCA. Cultivation of B. fragilis P207 did not greatly affect the levels of amino acids in BHIS overall, though glycine, GABA, glutamine, histidine, methionine, proline and tyrosine increased significantly (q < 0.01) after B. fragilis was cultivated in the medium.…”

Section: Resultsmentioning

confidence: 99%

Microbially-catalyzed conjugation of GABA and tyramine to bile acids

Mullowney,

Fiebig,

Schnizlein

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Bile acids (BAs) are cholesterol-derived molecules in the human gut that aid in digestion and nutrient absorption, regulate host metabolic processes, and influence gut microbiome composition. Both the host and its microbiome contribute to enzymatic modifications that shape the chemical diversity of BAs in the gut. Several bacterial species have been reported to conjugate standard amino acids to BAs, but it was not known if bacteria conjugate other classes of amines to BAs. We show thatBacteroides fragilisstrain P207, isolated from a bacterial bloom in the J-pouch of a patient with ulcerative colitis (UC) pouchitis, conjugates standard amino acids and the neuroactive amines γ-aminobutyric acid (GABA) and tyramine to deoxycholic acid. We extended our analysis to other human gut isolates and identified bacterial species that conjugate GABA and tyramine to primary and secondary BAs, and further identified diverse BA-GABA and -tyramine amides in human stool. A time-series metabolomic analysis of UC J-pouch contents revealed a lack of secondary bile acids and a shifting BA conjugate profile before, during and after onset of pouchitis, including temporal changes in several BA-GABA amides. Treatment of pouchitis with ciprofloxacin was associated with a marked reduction of nearly all BA amides in the J-pouch. Our study expands the known repertoire of conjugated bile acids produced by bacteria to include BA conjugates to the neuroactive amines GABA and tyramine, and demonstrates that these molecules are present in the human gut.ImportanceBile acids (BAs) are modified in multiple ways by host enzymes and the microbiota to produce a chemically diverse set of molecules that assist in the digestive process and impact many physiological functions. This study reports the discovery of bacterial species that conjugate the neuroactive molecules, GABA and tyramine, to primary and secondary BAs. We further present evidence that BA-GABA and BA-tyramine conjugates are present in the human gut, and document a shifting BA-GABA profile in a human pouchitis patient before, during and after inflammation and antibiotic treatment. GABA and tyramine are potent neuroactive molecules and common metabolic products of the gut microbiota. GABA- and tyramine-conjugated BAs may influence receptor-mediated regulatory mechanisms within the gastrointestinal tract and absorption of these molecules and their entry into the enterohepatic circulation may impact host physiology at distal tissue sites. This discovery defines new conjugated bile acids in the human gut.

show abstract

Bile acid fitness determinants of a Bacteroides fragilis isolate from a human pouchitis patient

Cited by 2 publications

References 95 publications

Microbially catalyzed conjugation of GABA and tyramine to bile acids

Microbially catalyzed conjugation of GABA and tyramine to bile acids

Microbially-catalyzed conjugation of GABA and tyramine to bile acids

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