Microbial assimilatory sulfate reduction-mediated H2S: an overlooked role in Crohn's disease development.

IF 13.8 1区 生物学 Q1 MICROBIOLOGY
Wanrong Luo, Min Zhao, Mohammed Dwidar, Yang Gao, Liyuan Xiang, Xueting Wu, Marnix H Medema, Shu Xu, Xiaozhi Li, Hendrik Schäfer, Minhu Chen, Rui Feng, Yijun Zhu
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Abstract

Background: H2S imbalances in the intestinal tract trigger Crohn's disease (CD), a chronic inflammatory gastrointestinal disorder characterized by microbiota dysbiosis and barrier dysfunction. However, a comprehensive understanding of H2S generation in the gut, and the contributions of both microbiota and host to systemic H2S levels in CD, remain to be elucidated. This investigation aimed to enhance comprehension regarding the sulfidogenic potential of both the human host and the gut microbiota.

Results: Our analysis of a treatment-naive CD cohorts' fecal metagenomic and biopsy metatranscriptomic data revealed reduced expression of host endogenous H2S generation genes alongside increased abundance of microbial exogenous H2S production genes in correlation with CD. While prior studies focused on microbial H2S production via dissimilatory sulfite reductases, our metagenomic analysis suggests the assimilatory sulfate reduction (ASR) pathway is a more significant contributor in the human gut, given its high prevalence and abundance. Subsequently, we validated our hypothesis experimentally by generating ASR-deficient E. coli mutants ∆cysJ and ∆cysM through the deletion of sulfite reductase and L-cysteine synthase genes. This alteration significantly affected bacterial sulfidogenic capacity, colon epithelial cell viability, and colonic mucin sulfation, ultimately leading to colitis in murine model. Further study revealed that gut microbiota degrade sulfopolysaccharides and assimilate sulfate to produce H2S via the ASR pathway, highlighting the role of sulfopolysaccharides in colitis and cautioning against their use as food additives.

Conclusions: Our study significantly advances understanding of microbial sulfur metabolism in the human gut, elucidating the complex interplay between diet, gut microbiota, and host sulfur metabolism. We highlight the microbial ASR pathway as an overlooked endogenous H2S producer and a potential therapeutic target for managing CD. Video Abstract.

微生物同化硫酸盐还原介导的 H2S:在克罗恩病发病过程中被忽视的作用。
背景:肠道中的 H2S 失衡会诱发克罗恩病(CD),这是一种以微生物群失调和屏障功能障碍为特征的慢性炎症性胃肠道疾病。然而,对肠道内 H2S 生成的全面了解以及微生物群和宿主对克罗恩病全身 H2S 水平的贡献仍有待阐明。这项研究旨在进一步了解人类宿主和肠道微生物群的硫化物生成潜力:结果:我们对治疗无效的 CD 队列的粪便元基因组和活检元转录组数据进行了分析,发现宿主内源性 H2S 生成基因的表达量减少,而微生物外源性 H2S 生成基因的丰度增加,这与 CD 有关。之前的研究主要关注微生物通过亚硫酸盐还原酶产生 H2S,而我们的元基因组分析表明,鉴于同化硫酸盐还原(ASR)途径的高流行率和高丰度,它在人体肠道中的作用更为重要。随后,我们通过实验验证了我们的假设,即通过删除亚硫酸盐还原酶和 L-半胱氨酸合成酶基因,产生 ASR 缺失的大肠杆菌突变体 ∆cysJ 和 ∆cysM。这种改变极大地影响了细菌的亚硫酸盐生成能力、结肠上皮细胞活力和结肠粘蛋白硫酸化,最终导致小鼠模型的结肠炎。进一步的研究发现,肠道微生物群通过ASR途径降解硫多糖并同化硫酸盐以产生H2S,这凸显了硫多糖在结肠炎中的作用,并提醒人们不要将硫多糖用作食品添加剂:我们的研究大大加深了人们对人体肠道微生物硫代谢的了解,阐明了饮食、肠道微生物群和宿主硫代谢之间复杂的相互作用。我们强调微生物ASR途径是一个被忽视的内源性H2S生产者,也是治疗CD的潜在治疗靶点。视频摘要。
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来源期刊
Microbiome
Microbiome MICROBIOLOGY-
CiteScore
21.90
自引率
2.60%
发文量
198
审稿时长
4 weeks
期刊介绍: Microbiome is a journal that focuses on studies of microbiomes in humans, animals, plants, and the environment. It covers both natural and manipulated microbiomes, such as those in agriculture. The journal is interested in research that uses meta-omics approaches or novel bioinformatics tools and emphasizes the community/host interaction and structure-function relationship within the microbiome. Studies that go beyond descriptive omics surveys and include experimental or theoretical approaches will be considered for publication. The journal also encourages research that establishes cause and effect relationships and supports proposed microbiome functions. However, studies of individual microbial isolates/species without exploring their impact on the host or the complex microbiome structures and functions will not be considered for publication. Microbiome is indexed in BIOSIS, Current Contents, DOAJ, Embase, MEDLINE, PubMed, PubMed Central, and Science Citations Index Expanded.
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