Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells

Campbell, Clarissa; McKenney, Peter T.; Konstantinovsky, Daniel; Isaeva, Olga I.; Schizas, Michail; Verter, Jacob; Mai, Cheryl; Jin, Wenbing; Guo, Chun-Jun; Violante, Sara; Ramos, Rúben J.; Cross, Justin R.; Kadaveru, Krishna; Hambor, John E.; Rudensky, Alexander Y.

doi:10.1038/s41586-020-2193-0

Cited by 534 publications

(429 citation statements)

References 34 publications

Supporting

Mentioning

385

Contrasting

Order By: Relevance

“…Bile acid hydroxylation patterns affect the binding and activation/inhibition of host nuclear receptors (67). HSDH enzymes may thus act in interkingdom-signaling, a hypothesis that has recent support based on the effect of oxidized and epimerized bile acids on the function of regulatory T cells (68,69). (70).…”

Section: Phylogenetic Analysis Of Cp12β-hsdhmentioning

confidence: 99%

Completion of the gut microbial epi-bile acid pathway

Doden

Wolf

Gaskins

et al. 2020

Preprint

View full text Add to dashboard Cite

Bile acids are detergent molecules that solubilize dietary lipids and lipid-soluble vitamins. Humans synthesize bile acids with α-orientation hydroxyl groups which can be biotransformed by gut microbiota to toxic, hydrophobic bile acids, such as deoxycholic acid (DCA). Gut microbiota are also capable of converting hydroxyl groups from the α-orientation through an oxo-intermediate to the β-orientation, resulting in more hydrophilic and less toxic bile acids. This interconversion is catalyzed by regio- (C-3 vs. C-7) and stereospecific (α vs. β) hydroxysteroid dehydrogenases (HSDHs). Recently, multiple human gut clostridia have been reported to encode 12α-HSDH, which interconverts DCA and 12-oxolithocholic acid (12-oxoLCA). Bile acid 12β-HSDH activity completes the epimerization of DCA by converting 12-oxoLCA to the 12β-bile acid known as epiDCA. While 12β-HSDH activity has been shown in cell extracts of Clostridium paraputrificum, the gene has not yet been reported. In order to identify the first gene encoding this activity, 6 candidate oxidoreductase genes from C. paraputrificum ATCC 25780 were cloned, overexpressed, purified, and screened for activity with 12-oxoLCA and epiDCA. LC-MS analysis was performed on reaction products from the enzyme encoded by DR024_RS09610, confirming the first 12β-HSDH gene discovered. The enzyme was more specific for bile acids lacking a 7-hydroxyl group than cholic acid derivatives containing a 7-hydroxyl. Phylogenetic analysis revealed previously unknown diversity for bile acid 12β-HSDH by experimentally validating two additional 12β-HSDHs within the tree from Eisenbergiella sp. OF01-20 and Olsenella sp. GAM18.

show abstract

Section: Phylogenetic Analysis Of Cp12β-hsdhmentioning

confidence: 99%

Completion of the gut microbial epi-bile acid pathway

Doden

Wolf

Gaskins

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The molecular mechanism by which the microbiome interacts with peripherally induced Treg (pTreg) is likely complex and multifactorial; however, part of the effect is mediated via the release of microbial fermentation products, such as butyrate and other short‐chain fatty acids 1–3 . In a string of recent studies, a role for host bile acids has also been shown to induce pTreg generation, with this function dependent on commensal colonization 4–6 . In the recent issue of Nature , Rudensky and colleagues dissect the molecular fermentation pathway where the gut microbiome converts an endogenous bile acid into an immunologically active bile acid with the capacity to induce pTreg in the gut 4 …”

Section: Figurementioning

confidence: 99%

“…In a string of recent studies, a role for host bile acids has also been shown to induce pTreg generation, with this function dependent on commensal colonization 4–6 . In the recent issue of Nature , Rudensky and colleagues dissect the molecular fermentation pathway where the gut microbiome converts an endogenous bile acid into an immunologically active bile acid with the capacity to induce pTreg in the gut 4 …”

Section: Figurementioning

confidence: 99%

“…To address this issue, Campbell et al 4 . set out to discover secondary bile acids capable of modulating pTreg generation in mice.…”

Section: Figurementioning

confidence: 99%

“…Campbell et al 4 formally linked microbial fermentation of isoDCA to colonic Treg expansion through the engineering of a minimal bacterial consortia. IsoDCA is generated from the primary bile acid cholic acid, with two structural changes required: cleavage of the 7α‐hydroxyl group and epimerization of the 3α‐hydroxyl group.…”

Section: Figurementioning

confidence: 99%

See 2 more Smart Citations

Bile acids mediate signaling between microbiome and the immune system

Liston

Whyte

2020

Immunol Cell Biol

View full text Add to dashboard Cite

Biomimetic Metal–Organic Framework Combats Biofilm‐Associated Infections via Hyperthermia‐Enhanced Bacterial Metabolic Interference and Autophagy‐Promoted Adaptive Immunity

Hu,

Ma,

Zhang

et al. 2023

Adv Funct Materials

View full text Add to dashboard Cite

Robust bacterial metabolism and the immunosuppression on peripheral immune cells cause biofilm‐associated infections (BAIs) extremely refractory to be eradicated via antibiotics alone. Herein, hierarchical mesoporous UiO‐66 metal–organic framework is decorated with selenite, polypyrrole, and macrophage membrane (MM) to develop a biomimetic nanosphere (USPM). Following the recruitment of USPM to the biofilm microenvironment (BME) via the pathogen‐targeting ability derived from MM. The BME‐responsive USPM can precisely release selenite to penetrate the loosened biofilm in synergy with near‐infrared‐induced mild photothermal therapy (mPTT). Selenite can quickly react with reducing substances to generate hydrogen selenide (H2Se) inside the biofilm. H2Se can competitively inhibit bacterial metabolic processes and disrupt biofilm metabolic homeostasis by cascade amplification effects. Furthermore, H2Se inside the biofilm further sensitizes photothermia to exert a precise local photothermal effect. Outside the biofilm, USPM can simultaneously promote the phagocytosis and autophagy of macrophages to kill and decompose the phagocytosed bacteria. Finally, the well‐decomposed bacterial antigens in macrophages can be presented to antigen‐presenting cells to arouse adaptive immune responses and enhance anti‐biofilm effectiveness further. Such powerful mPTT‐enhanced bacterial metabolic disruption and macrophagic autophagy‐promoted adaptive immune activation suggest an alternative therapeutic strategy to cure refractory BAIs.

show abstract

Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells

Cited by 534 publications

References 34 publications

Completion of the gut microbial epi-bile acid pathway

Completion of the gut microbial epi-bile acid pathway

Bile acids mediate signaling between microbiome and the immune system

Biomimetic Metal–Organic Framework Combats Biofilm‐Associated Infections via Hyperthermia‐Enhanced Bacterial Metabolic Interference and Autophagy‐Promoted Adaptive Immunity

Contact Info

Product

Resources

About