Clostridium butyricum enhances colonization resistance against Clostridioides difficile by metabolic and immune modulation

Mao Hagihara; Tadashi Ariyoshi; Yasutoshi Kuroki; Shuhei Eguchi; Seiya Higashi; Takeshi Mori; Tsunemasa Nonogaki; Kenta Iwasaki; Makoto Yamashita; Nobuhiro Asai; Yusuke Koizumi; Kentaro Oka; Motomichi Takahashi; Yuka Yamagishi; Hiroshige Mikamo

doi:10.1038/s41598-021-94572-z

Clostridium butyricum enhances colonization resistance against Clostridioides difficile by metabolic and immune modulation

Sci Rep. 2021 Jul 22;11(1):15007. doi: 10.1038/s41598-021-94572-z.

Authors

Mao Hagihara^{1

2}, Tadashi Ariyoshi^{2

3}, Yasutoshi Kuroki^{2

3}, Shuhei Eguchi³, Seiya Higashi³, Takeshi Mori², Tsunemasa Nonogaki⁴, Kenta Iwasaki⁵, Makoto Yamashita², Nobuhiro Asai², Yusuke Koizumi², Kentaro Oka^{2

3}, Motomichi Takahashi^{2

3}, Yuka Yamagishi², Hiroshige Mikamo⁶

Affiliations

¹ Department of Molecular Epidemiology and Biomedical Sciences, Aichi Medical University, Nagakute, 480-1195, Japan.
² Department of Clinical Infectious Diseases, Aichi Medical University, Nagakute, 480-1195, Japan.
³ Miyarisan Pharmaceutical Co., Ltd., Saitama, 114-0016, Japan.
⁴ Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, 463-8521, Japan.
⁵ Departments of Kidney Disease and Transplant Immunology, Aichi Medical University, Nagakute, 480-1195, Japan.
⁶ Department of Clinical Infectious Diseases, Aichi Medical University, Nagakute, 480-1195, Japan. mikamo@aichi-med-u.ac.jp.

Abstract

Clostridioides difficile infection (CDI) represents the leading cause of nosocomial diarrhea worldwide and is associated with gut dysbiosis and intestinal damage. Clostridium butyricum MIYAIRI 588 (CBM 588) contributes significantly to reduce epithelial damage. However, the impacts of CBM 588 on antibacterial therapy for CDI are not clear. Here we show that CBM 588 enhanced the antibacterial activity of fidaxomicin against C. difficile and negatively modulated gut succinate levels to prevent C. difficile proliferation and downregulate tumor necrosis factor-α (TNF-α) producing macrophages in the colon lumina propria (cLP), resulting in a significant decrease in colon epithelial damage. Additionally, CBM 588 upregulated T cell-dependent pathogen specific immunoglobulin A (IgA) via interleukin (IL)-17A producing CD4⁺ cells and plasma B cells in the cLP, and Th17 cells in the cLP enhanced the gut epithelial barrier function. IL-17A and succinic acid modulations with CBM 588 enhance gut colonization resistance to C. difficile and protect the colon tissue from CDI.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Bacterial Agents / pharmacology
Anti-Bacterial Agents / therapeutic use
Antibiosis*
Clostridioides difficile / physiology*
Clostridium Infections / drug therapy
Clostridium Infections / metabolism
Clostridium Infections / microbiology*
Clostridium butyricum / physiology*
Disease Models, Animal
Disease Susceptibility
Energy Metabolism*
Female
Gastrointestinal Microbiome
Immunoglobulin A / immunology
Immunomodulation*
Interleukin-17 / biosynthesis
Mice
Models, Biological
T-Lymphocyte Subsets / immunology
T-Lymphocyte Subsets / metabolism

Substances

Anti-Bacterial Agents
IL17A protein, human
Immunoglobulin A
Interleukin-17