A meta-analysis of the gut microbiome in inflammatory bowel disease patients identifies disease-associated small molecules

• Published in: Cell host & microbe Vol. 33; no. 2; pp. 218 - 234.e12
• Main Authors: Elmassry, Moamen M., Sugihara, Kohei, Chankhamjon, Pranatchareeya, Kim, Yeji, Camacho, Francine R., Wang, Shuo, Sugimoto, Yuki, Chatterjee, Seema, Chen, Lea Ann, Kamada, Nobuhiko, Donia, Mohamed S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.02.2025
• Subjects: Animals; biosynthetic gene clusters; Clostridium - genetics; Clostridium - metabolism; colitis; Crohn Disease - microbiology; Disease Models, Animal; fatty acid amides; Fatty Acids - chemistry; Fatty Acids - metabolism; Feces - chemistry; Feces - microbiology; Gastrointestinal Microbiome - genetics; human microbiome; Humans; inflammatory bowel disease; Inflammatory Bowel Diseases - microbiology; meta-analysis; Metagenomics; Mice; microbiome-derived small molecules; Multigene Family; fatty acid amides; microbiome-derived small molecules; biosynthetic gene clusters; colitis; human microbiome; meta-analysis; inflammatory bowel disease
• ISSN: 1931-3128; 1934-6069; 1934-6069
• DOI: 10.1016/j.chom.2025.01.002

Gut microbiome changes have been associated with several human diseases, but the molecular and functional details underlying these associations remain largely unknown. Here, we performed a meta-analysis of small molecule biosynthetic gene clusters (BGCs) in metagenomic samples of the gut microbiome from inflammatory bowel disease (IBD) patients and matched healthy subjects and identified two Clostridia-derived BGCs that are significantly associated with Crohn’s disease (CD), a main IBD type. Using synthetic biology, we discovered and solved the structures of six fatty acid amides as the products of the CD-enriched BGCs, which we subsequently detected in fecal samples from IBD patients. Finally, we show that the discovered molecules disrupt gut permeability and exacerbate disease in chemically or genetically susceptible mouse models of colitis. These findings suggest that microbiome-derived small molecules may play a role in the etiology of IBD and represent a generalizable approach for discovering molecular mediators of disease-relevant microbiome-host interactions. [Display omitted] •Biosynthetic gene clusters (BGCs) were discovered from the human gut microbiome•A meta-analysis approach identified BGCs that are enriched in Crohn’s disease•Two disease-enriched BGCs produce a unique set of fatty acid amides (ebf-ecf-FAAs)•ebf-ecf-FAAs exist in patient fecal samples and exacerbate colitis in mouse models Elmassry et al. employed computational and experimental approaches to identify gut microbiome-encoded biosynthetic gene clusters that are enriched in Crohn’s disease patients and the small molecules they produce, which exacerbated disease when introduced to mouse models of colitis.