Interplay of Gut Microbiota and Host Epithelial Mitochondrial Dysfunction Is Necessary for the Development of Spontaneous Intestinal Inflammation in Mice

Authors

• Kibrom M Alula
• Alexander S Dowdell
• Brittany LeBere
• J Scott Lee
• Cassandra L Levens
• Kristine A Kuhn
• Benny A Kaipparettu
• Winston E Thompson
• Richard S Blumberg
• Sean P Colgan
• Arianne L Theiss

Language

English

Publication Date

11-17-2023

Journal

Microbiome

DOI

10.1186/s40168-023-01686-9

PMID

37978573

PMCID

PMC10655390

PubMedCentral® Posted Date

11-17-2023

PubMedCentral® Full Text Version

Post-print

Abstract

Background: Intestinal epithelial cell (IEC) mitochondrial dysfunction involvement in inflammatory bowel diseases (IBD), including Crohn's disease affecting the small intestine, is emerging in recent studies. As the interface between the self and the gut microbiota, IECs serve as hubs of bidirectional cross-talk between host and luminal microbiota. However, the role of mitochondrial-microbiota interaction in the ileum is largely unexplored. Prohibitin 1 (PHB1), a chaperone protein of the inner mitochondrial membrane required for optimal electron transport chain function, is decreased during IBD. We previously demonstrated that mice deficient in PHB1 specifically in IECs (Phb1i∆IEC) exhibited mitochondrial impairment, Paneth cell defects, gut microbiota dysbiosis, and spontaneous inflammation in the ileum (ileitis). Mice deficient in PHB1 in Paneth cells (epithelial secretory cells of the small intestine; Phb1∆PC) also exhibited mitochondrial impairment, Paneth cell defects, and spontaneous ileitis. Here, we determined whether this phenotype is driven by Phb1 deficiency-associated ileal microbiota alterations or direct effects of loss of PHB1 in host IECs.

Results: Depletion of gut microbiota by broad-spectrum antibiotic treatment in Phb1∆PC or Phb1i∆IEC mice revealed a necessary role of microbiota to cause ileitis. Using germ-free mice colonized with ileal microbiota from Phb1-deficient mice, we show that this microbiota could not independently induce ileitis without host mitochondrial dysfunction. The luminal microbiota phenotype of Phb1i∆IEC mice included a loss of the short-chain fatty acid butyrate. Supplementation of butyrate in Phb1-deficient mice ameliorated Paneth cell abnormalities and ileitis. Phb1-deficient ileal enteroid models suggest deleterious epithelial-intrinsic responses to ileal microbiota that were protected by butyrate.

Conclusions: These results suggest a mutual and essential reinforcing interplay of gut microbiota and host IEC, including Paneth cell, mitochondrial health in influencing ileitis. Restoration of butyrate is a potential therapeutic option in Crohn's disease patients harboring epithelial cell mitochondrial dysfunction.

Keywords

Humans, Animals, Mice, Crohn Disease, Gastrointestinal Microbiome, Ileitis, Inflammation, Inflammatory Bowel Diseases, Paneth Cells, Butyrates, Mitochondria, Intestinal Mucosa, Inflammatory bowel disease, Crohn’s disease, Short-chain fatty acids, Butyrate, Enteroids, Mitochondria, Antimicrobial peptides

Published Open-Access

yes

Recommended Citation

Alula, Kibrom M; Dowdell, Alexander S; LeBere, Brittany; et al., "Interplay of Gut Microbiota and Host Epithelial Mitochondrial Dysfunction Is Necessary for the Development of Spontaneous Intestinal Inflammation in Mice" (2023). Faculty, Staff and Students Publications. 8104.
https://digitalcommons.library.tmc.edu/baylor_docs/8104