Reduction of butyric acid-producing bacteria in the ileal mucosa-associated microbiota is associated with the history of abdominal surgery in patients with Crohn’s disease

ABSTRACT

Fecal microbiota is a significant factor determining the cause, course, and prognosis of Crohn’s disease (CD). However, the factors affecting mucosa-associated microbiota (MAM) remain unclear. This retrospective study examined the differences in ileal MAM between CD patients and healthy controls and investigated the factors affecting MAM in CD patients to clarify potential therapeutic targets. Ileal MAM was obtained using brush forceps during endoscopic examination from 23 healthy controls and 32 CD patients (most were in remission). The samples’ microbiota was profiled using the Illumina MiSeq platform. Compared to controls, CD patients had significantly reduced α-diversity in the ileum and a difference in β-diversity. The abundance of butyric acid-producing bacteria in the ileal MAM was significantly lower in CD patients with a history of abdominal surgery than in those without. Because butyric acid is a major energy source in the intestinal epithelium, its metabolism via β-oxidation increases oxygen consumption in epithelial cells, reducing oxygen concentration in the intestinal lumen and increasing the abundance of obligate anaerobic bacteria. The suppression of obligate anaerobes in CD patients caused an overgrowth of facultative anaerobes. Summarily, reducing the abundance of butyric acid-producing bacteria in the ileal MAM may play an important role in CD pathophysiology.

KEYWORDS:

• Inflammatory bowel disease
• Crohn’s disease
• mucosa-associated microbiota
• butyric acid-producing bacteria
• abdominal surgery
• oxygen
• intestinal dysbiosis
• terminal ileum

Acknowledgments

We would like to thank Editage (www.editage.com) for English language editing.

Disclosure statement

Y.N. received scholarship funds from Taiyo Kagaku Co. Ltd. and EA Pharma. Co. Ltd., a collaborative research fund from Taiyo Kagaku Co., Ltd., and lecture fees from Mylan EPD Co. and Takeda Pharma. Co. Ltd., and Mochida Pharma. Co. Ltd., EA Pharma. Co., Ltd., Otsuka Pharma. Co. Ltd., and Miyarisan Pharma. Co. Ltd. This study was partially supported by these funds. Neither the funding agency nor any outside organization participated in the study design or had any competing interests. All companies approved the final version of the manuscript. All authors, except Y.N., received no financial support or otherwise from any organization that may have an interest in the submitted work. No other relationships or activities appear to have influenced the submitted work.

Author contributions

Osamu Handa and Akiko Shiotani substantially contributed to the conception, design acquisition of data, analysis, and interpretation of data for the work. Motoyasu Osawa, Hiroshi Matsumoto, and Eiji Umegaki contributed to the sample acquisition and analysis. Tingting Gu greatly contributed to the sample analysis. Osamu Handa was responsible for drafting the manuscript, while Akiko Shiotani, Hiroto Miura, Ryo Inoue, and Yuji Naito critically revised it for important intellectual content. All authors approved the final version of the manuscript for publication and agreed to be accountable for all aspects of the work. They also ensure that questions about the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Data availability statement

The data that support the findings of this study are available from the corresponding author, Osamu Handa, upon reasonable request.

Additional information

Funding

This work was supported by Japan Society for the Promotion of Science: [Grant Number Grant Number 22K06758]; MAFF Commissioned project study on “Project for the realization of foods and dietary habits to extend healthy life expectancy”: [Grant Number Grant Number JPJ009842]; Research Project Grant of Kawasaki Medical School: [Grant Number R03B-052].