Enteric nervous system damage caused by abnormal intestinal butyrate metabolism may lead to functional constipation

Abstract

Functional constipation (FC) is a high morbidity gastrointestinal disease for which dysfunction in the enteric nervous system is a major pathogenesis mechanism. To enhance our understanding of the involvement of intestinal microbiota and its metabolites in the pathogenesis of FC, we conducted a shotgun metagenomic sequencing analysis of gut microbiota and serum short-chain fatty acids (SCFAs) analysis in 460 Chinese women with different defecation frequencies. We observed that the abundance ofFusobacterium_varium, a butyric acid-producing bacterium, was positively correlated (P = 0.0096) with the frequency of defecation; however, the concentrations of serum butyric acid was negatively correlated (P = 3.51E-05) with defecation frequency. These results were verified in an independent cohort (6 patients with FC and 6 controls). To further study the effects of butyric acid on intestinal nerve cells, we treated mouse intestinal neurons in vitro with various concentrations of butyrate (0.1, 0.5, 1, and 2.5 mM). We found that intestinal neurons treated with 0.5 mM butyrate proliferated better than those in the other treatment groups, with significant differences in cell cycle and oxidative phosphorylation signal pathways. We suggest that the decreased butyrate production resulting from the reduced abundance of Fusobacterium in gut microbiota affects the proliferation of intestinal neurons and the energy supply of intestinal cells. However, with FC disease advancing, the consumption and excretion of butyric acid reduce, leading to its accumulation in the intestine. Moreover, the accumulation of an excessively high amount of butyric acid inhibits the proliferation of nerve cells and subsequently exacerbates the disease.

Association between gut microbiota and Hirschsprung disease: a bidirectional two-sample Mendelian randomization study

“…In our MR results, some SCFA-producing bacteria, such as Peptococcus ( Wang H. et al, 2023 ), Ruminococcus2 ( Wu et al, 2023 ), Clostridiaceae1 ( Vojinovic et al, 2019 ), and Ruminococcaceae ( D'Amato et al, 2020 ; Zhou et al, 2022 ) were identified to be protective to HSCR, some of which in HSCR was significantly decreased, and were correlated with SCFAs. Animal studies suggested that SCFAs could independently stimulate the enteric neural stem cell phenotype, thereby improving enteric neural disorders ( Fung et al, 2021 ; Tian et al, 2023 ; Wang L. et al, 2023 ). Recent studies revealed that SCFA promoted enterochromaffin cells (ECs) to secrete 5-hydroxytryptamine (5-HT; Atarashi et al, 2013 ; Furusawa et al, 2013 ; Reigstad et al, 2015 ; Yano et al, 2015 ), which is regulated by the calcitonin selective reuptake transporter (SERT) of epithelial cells and plays crucial roles in enteric neuroregeneration and neuroprotection ( Bian et al, 2007 ).…”

Causal relationship between gut microbiota and constipation: a bidirectional Mendelian randomization study

“…This elucidates the crucial role that microbial metabolites play in intestinal health and suggests that boosting the production of beneficial SCFAs may offer a therapeutic strategy for managing constipation. This in-depth analysis enhances our comprehension of how genetic predispositions and gut microbiota configurations impact constipation, significantly broadening our understanding of the microbiome’s role in gastrointestinal health ( Wang L. et al, 2023 ). In addition, previous research has highlighted that butyrate-producing flora can enhance colonic motility and alleviate constipation by inducing the release of serotonin or by stimulating cholinergic pathways through butyrate production.…”

Microbiota treatment of functional constipation: Current status and future prospects

“…Butyrate maintains intestinal barrier integrity, prevents bacterial endotoxin and inflammatory responses, and reduces interference with intestinal motility[ 11 ]. One study observed that the abundance of Fusobacterium , which is a butyric acid–producing bacteria, is positively correlated with defecation frequency[ 12 ]. Several studies observed the increasing abundance of butyric acid–producing bacteria in the intestine of patients with FC; however, the concentration of butyric acid has yet to be detected[ 9 , 10 ].…”