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Gut symbionts alleviate MASH through a secondary bile acid biosynthetic pathway

Cell

Volume 187, Issue 11, May 23, 2024, p2717-2734.e33

Qixing Nie, Xi Luo, Kai Wang, Yong Ding, Shumi Jia, Qixiang Zhao, Meng Li, Jinxin Zhang, Yingying Zhuo, Jun Lin, Chenghao Guo, Zhiwei Zhang, Huiying Liu, Guangyi Zeng, Jie You, Lulu Sun, Hua Lu, Ming Ma, Yanxing Ji, Ming Hua Zheng, Yanli Pang, Changtao Jiang

https://doi.org/10.1016/j.cell.2024.03.034

ABSTRACT: The gut microbiota has been found to play an important role in the progression of metabolic dysfunctionassociated steatohepatitis (MASH), but the mechanisms have not been established. Here, by developing a click-chemistry-based enrichment strategy, we identified several microbial-derived bile acids, including the previously uncharacterized 3-succinylated cholic acid (3-sucCA), which is negatively correlated with liver damage in patients with liver-tissue-biopsy-proven metabolic dysfunction-associated fatty liver disease (MAFLD). By screening human bacterial isolates, we identified Bacteroides uniformis strains as effective producers of 3-sucCA both in vitro and in vivo. By activity-based protein purification and identification, we identified an enzyme annotated as b-lactamase in B. uniformis responsible for 3-sucCA biosynthesis. Furthermore, we found that 3-sucCA is a lumen-restricted metabolite and alleviates MASH by promoting the growth of Akkermansia muciniphila. Together, our data offer new insights into the gut microbiota-liver axis that may be leveraged to augment the management of MASH.

摘要：腸道菌群已被發(fā)現(xiàn)在代謝功能障礙相關(guān)脂肪性肝炎 (MASH) 的進(jìn)展中發(fā)揮重要作用，但其機(jī)制尚未確定。在此，通過開發(fā)基于點(diǎn)擊化學(xué)的富集策略，我們鑒定出幾種微生物衍生的膽汁酸，包括之前未表征的3-琥珀酰膽酸 (3-sucCA)，它與肝組織活檢證實(shí)的代謝功能障礙相關(guān)脂肪肝疾病 (MAFLD) 患者的肝損傷呈負(fù)相關(guān)。通過篩選人體細(xì)菌分離株，我們鑒定出Bacteroides uniformis菌株在體外和體內(nèi)均為3-sucCA的有效生產(chǎn)者。通過基于活性的蛋白質(zhì)純化和鑒定，我們?cè)贐acteroides uniformis菌中鑒定出一種β-內(nèi)酰胺酶，該酶負(fù)責(zé)3-sucCA的生物合成。此外，我們發(fā)現(xiàn)3-sucCA是一種管腔限制性代謝物，可通過促進(jìn)Akkermansia muciniphila的生長(zhǎng)來緩解MASH ?？傊?，我們的數(shù)據(jù)為腸道菌群-肝臟軸提供了新的見解，或許可以用于增強(qiáng)MASH的管理。

Keywords: gut microbiota; bile acid; acylated bile acids; 3-sucCA; biosynthesis; BAS-suc; MAFLD

關(guān)鍵詞：腸道微生物群；膽汁酸；?；懼?；3-琥珀酰膽酸；生物合成；BAS-suc；代謝功能障礙相關(guān)脂肪肝疾病

SUMMARY: This study focused on the mechanism by which gut symbionts alleviate metabolic dysfunction-associated steatohepatitis (MASH). Employing a click chemistry-based enrichment strategy, a microbially derived bile acid-3-succinylated cholic acid (3-sucCA)-was identified. Levels of 3-sucCA were lower in patients with metabolically associated fatty liver disease (MAFLD) confirmed by liver tissue biopsy, and this bile acid exhibited a negative correlation with the degree of liver damage. The study further identified Bacteroides uniformis as the primary producer of 3-sucCA. Through activity-based protein purification and characterization, an enzyme annotated as a β-lactamase in this bacterium (designated BAS-suc) was found to be the key enzyme driving 3-sucCA biosynthesis. Additional experiments demonstrated that 3-sucCA is a gut lumen-restricted metabolite: it does not act directly on the bile acid receptors FXR and TGR5, but instead exerts its effects by promoting the growth of Akkermansia muciniphila. Specifically, 3-sucCA can activate the Amuc-NagB enzyme in Akkermansia muciniphila, facilitating glucosamination and peptidoglycan synthesis, which in turn accelerates the proliferation of Akkermansia muciniphila. The increased abundance of Akkermansia muciniphila enhances intestinal barrier function and reduces endotoxemia, thereby alleviating MASH via the LPS-TLR4 pathway. In animal models, supplementation with either 3-sucCA or 3-sucCA-producing Bacteroides uniformis (harboring the BAS-suc gene) reduced hepatic steatosis, inflammation, and fibrosis in mice. However, this protective effect was abolished when BAS-suc was knocked out in Bacteroides uniformis or when Akkermansia muciniphila was depleted. Analysis of clinical samples revealed that the fecal abundances of Bacteroides uniformis, Akkermansia muciniphila, and 3-sucCA content in MAFLD patients decreased with disease severity. Furthermore, the abundance of the bas-suc gene was positively correlated with both 3-sucCA levels and Akkermansia muciniphila abundance, while being negatively correlated with liver damage markers. In conclusion, this study uncovers a novel pathway: Bacteroides uniformis synthesizes 3-sucCA via BAS-suc, which in turn enriches Akkermansia muciniphila to alleviate MASH. This finding provides a microbial metabolic target for MASH therapy.

總結(jié)：該研究聚焦腸道共生菌緩解代謝相關(guān)脂肪性肝炎（MASH）的機(jī)制，通過點(diǎn)擊化學(xué)富集策略發(fā)現(xiàn)微生物衍生膽汁酸3-琥珀酰膽酸（3-sucCA），其在經(jīng)肝組織活檢證實(shí)的代謝相關(guān)脂肪性肝?。∕AFLD）患者中含量較低，且與肝損傷程度呈負(fù)相關(guān)。研究篩選出擬桿菌（Bacteroides uniformis）為3-sucCA的主要產(chǎn)生菌，通過基于活性的蛋白質(zhì)純化鑒定，發(fā)現(xiàn)該菌中一種β-內(nèi)酰胺酶（命名為BAS-suc）是3-sucCA生物合成的關(guān)鍵酶。進(jìn)一步實(shí)驗(yàn)表明，3-sucCA是腸腔限制性代謝物，不直接作用于膽汁酸受體FXR和TGR5，而是通過促進(jìn)阿克曼氏菌（Akkermansia muciniphila）生長(zhǎng)發(fā)揮作用——3-sucCA可激活阿克曼氏菌中Amuc-NagB酶，促進(jìn)葡萄糖胺化及肽聚糖合成，從而加速其增殖；阿克曼氏菌的增加能改善腸道屏障功能、降低內(nèi)毒素血癥，進(jìn)而通過LPS-TLR4通路緩解MASH。在動(dòng)物模型中，補(bǔ)充3-sucCA或能產(chǎn)生3-sucCA的擬桿菌Bacteroides uniformis（含BAS-suc基因），可減輕小鼠肝臟脂肪變性、炎癥和纖維化，而敲除BAS-suc 的擬桿菌或阿克曼氏菌，該保護(hù)作用消失。臨床樣本分析顯示，MAFLD患者糞便中擬桿菌、阿克曼氏菌豐度及3-sucCA含量均隨疾病嚴(yán)重程度降低，且BAS-suc基因豐度與3-sucCA、阿克曼氏菌豐度正相關(guān)，與肝損傷指標(biāo)負(fù)相關(guān)。綜上，該研究揭示了擬桿菌通過BAS-suc合成3-sucCA，進(jìn)而富集阿克曼氏菌緩解MASH的新通路，為MASH的治療提供了微生物代謝靶點(diǎn)。