Multiomics reveals microbial metabolites as key actors in intestinal fibrosis in Crohn’s disease
Intestinal fibrosis is the primary cause of disability in patients with Crohn's disease (CD), yet effective therapeutic strategies are currently lacking. Here, we report a multiomics analysis of gut microbiota and fecal/blood metabolites of 278 CD patients and 28 healthy controls, identifying characteristic alterations in gut microbiota (e.g., Lachnospiraceae, Ruminococcaceae, Muribaculaceae, Saccharimonadales) and metabolites (e.g., L-aspartic acid, glutamine, ethylmethylacetic acid) in moderate-severe intestinal fibrosis. By integrating multiomics data with magnetic resonance enterography features, putative links between microbial metabolites and intestinal fibrosis-associated morphological alterations were established. These potential associations were mediated by specific combinations of amino acids (e.g., L-aspartic acid), primary bile acids, and glutamine. Finally, we provided causal evidence that L-aspartic acid aggravated intestinal fibrosis both in vitro and in vivo. Overall, we offer a biologically plausible explanation for the hypothesis that gut microbiota and its metabolites promote intestinal fibrosis in CD while also identifying potential targets for therapeutic trials.
Authors
- Xiaodi Shen (ORCID: https://orcid.org/0000-0002-4754-8415)
- Yangdi Wang (ORCID: https://orcid.org/0000-0002-9731-2830)
- Ren Mao (ORCID: https://orcid.org/0000-0002-5523-8185)
- Shi‐Ting Feng (ORCID: https://orcid.org/0000-0002-0869-7290)
- Yijun Zhu (ORCID: https://orcid.org/0000-0003-2496-5395)
- Shixian Hu (ORCID: https://orcid.org/0000-0002-1190-0325)
- Zhenpeng Peng (ORCID: https://orcid.org/0000-0002-2304-5215)
- Canhui Sun (ORCID: https://orcid.org/0000-0001-5724-5410)
- Caiguang Liu (ORCID: https://orcid.org/0000-0003-4876-7000)
- R Zhang (ORCID: https://orcid.org/0000-0002-2815-4584)
- Ziping Li (ORCID: https://orcid.org/0009-0003-6147-6619)
- Zhoulei Li (ORCID: https://orcid.org/0000-0002-9426-0836)
- Minhu Chen (ORCID: https://orcid.org/0000-0003-2421-9966)
- Xinyue Wang (ORCID: https://orcid.org/0000-0003-1851-7430)
- Qingzhu Zheng
- Rui Feng (ORCID: https://orcid.org/0000-0002-4523-9344)
- Xiao Lin
- Jinjiang Lin (ORCID: https://orcid.org/0009-0008-3560-0184)
- Xuehua Li (ORCID: https://orcid.org/0000-0002-7476-2644)
- Weitao He
- Li Huang
- Luyao Wu
- Lili Huang (ORCID: https://orcid.org/0000-0002-7085-7646)
Institutions
- Sun Yat-sen University (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2024-09-13
- DOI
- https://doi.org/10.1038/s44321-024-00129-8
- Citations
- 13
- Primary Topic
- Gut microbiota and health
- Type
- article
- Field-Weighted Citation Impact
- 3.04
Funders
- National Natural Science Foundation of China
- National Key Research and Development Program of China
- Fundamental Research Funds for the Central Universities
- Special Project for Research and Development in Key areas of Guangdong Province
- Basic and Applied Basic Research Foundation of Guangdong Province