Antagonism Between Gut Ruminococcus gnavus and Akkermansia muciniphila Modulates the Progression of Chronic Hepatitis B

IF 7.1 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Cellular and Molecular Gastroenterology and Hepatology Pub Date : 2024-01-01 DOI:10.1016/j.jcmgh.2023.12.003

Huey-Huey Chua , Ya-Hui Chen , Li-Ling Wu , Hung-Chih Yang , Chia-Ray Lin , Huey-Ling Chen , Jia-Feng Wu , Mei-Hwei Chang , Pei-Jer Chen , Yen-Hsuan Ni

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Abstract

Background & Aims

A long immune-tolerant (IT) phase lasting for decades and delayed HBeAg seroconversion (HBe-SC) in patients with chronic hepatitis B (CHB) increase the risk of liver diseases. Early entry into the immune-active (IA) phase and HBe-SC confers a favorable clinical outcome with an unknown mechanism. We aimed to identify factor(s) triggering IA entry and HBe-SC in the natural history of CHB.

Methods

To study the relevance of gut microbiota evolution in the risk of CHB activity, fecal samples were collected from CHB patients (n = 102) in different disease phases. A hepatitis B virus (HBV)-hydrodynamic injection (HDI) mouse model was therefore established in several mouse strains and germ-free mice, and multiplatform metabolomic and bacteriologic assays were performed.

Results

Ruminococcus gnavus was the most abundant species in CHB patients in the IT phase, whereas Akkermansia muciniphila was predominantly enriched in IA patients and associated with alanine aminotransferase flares, HBeAg loss, and early HBe-SC. HBV-HDI mouse models recapitulated this human finding. Increased cholesterol-to-bile acids (BAs) metabolism was found in IT patients because R gnavus encodes bile salt hydrolase to deconjugate primary BAs and augment BAs total pool for facilitating HBV persistence and prolonging the IT course. A muciniphila counteracted this activity through the direct removal of cholesterol. The secretome metabolites of A muciniphila, which contained small molecules structurally similar to apigenin, lovastatin, ribavirin, etc., inhibited the growth and the function of R gnavus to allow HBV elimination.

Conclusions

R gnavus and A muciniphila play opposite roles in HBV infection. A muciniphila metabolites, which benefit the elimination of HBV, may contribute to future anti-HBV strategies.

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肠道反刍球菌和粘液杏球菌之间的拮抗作用可调节慢性乙型肝炎的病情发展

背景& 目的慢性乙型肝炎（CHB）患者持续数十年之久的免疫耐受期（IT）和延迟的 HBeAg 血清转换（HBe-SC）会增加罹患肝病的风险。早期进入免疫活性（IA）期和 HBe-SC 期会带来良好的临床结局，但其机制尚不清楚。为了研究肠道微生物群演变与慢性乙型肝炎活动风险的相关性，我们收集了处于不同疾病阶段的慢性乙型肝炎患者（102 人）的粪便样本。结果在IT期的CHB患者中，gnavus反刍球菌是最丰富的物种，而Akkermansia muciniphila则主要富集于IA期患者，并与ALT异常、HBeAg丢失和早期HBe-SC有关。HBV-HDI 小鼠模型再现了人类的这一发现。在 IT 患者中发现胆固醇转化为胆汁酸（BAs）的新陈代谢增加，因为 R. gnavus 编码的胆盐水解酶可使初级胆汁酸脱钩，增加胆汁酸总量，从而促进 HBV 的持续存在并延长 IT 病程。A. muciniphila 通过直接清除胆固醇来抵消这种活性。A. muciniphila 的分泌物代谢物含有结构类似于芹菜素、洛伐他汀、利巴韦林等的小分子，可抑制 R. gnavus 的生长和功能，从而消除 HBV。有利于消除 HBV 的 A. muciniphila 代谢物可能有助于未来的抗 HBV 策略。

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来源期刊

Cellular and Molecular Gastroenterology and Hepatology Medicine-Gastroenterology

CiteScore

13.00

自引率

2.80%

发文量

246

审稿时长

42 days

期刊介绍： "Cell and Molecular Gastroenterology and Hepatology (CMGH)" is a journal dedicated to advancing the understanding of digestive biology through impactful research that spans the spectrum of normal gastrointestinal, hepatic, and pancreatic functions, as well as their pathologies. The journal's mission is to publish high-quality, hypothesis-driven studies that offer mechanistic novelty and are methodologically robust, covering a wide range of themes in gastroenterology, hepatology, and pancreatology. CMGH reports on the latest scientific advances in cell biology, immunology, physiology, microbiology, genetics, and neurobiology related to gastrointestinal, hepatobiliary, and pancreatic health and disease. The research published in CMGH is designed to address significant questions in the field, utilizing a variety of experimental approaches, including in vitro models, patient-derived tissues or cells, and animal models. This multifaceted approach enables the journal to contribute to both fundamental discoveries and their translation into clinical applications, ultimately aiming to improve patient care and treatment outcomes in digestive health.