Abstract
Decreases in short-chain-fatty-acids (SCFAs) are linked to inflammatory bowel disease (IBD). Yet, the mechanisms through which SCFAs promote wound healing, orchestrated by intestinal stem cells, are poorly understood. We discovered that, in mice with Citrobacter rodentium (CR)-induced infectious colitis, treatment with Pectin and Tributyrin diets reduced the severity of colitis by restoring Firmicutes and Bacteroidetes and by increasing mucus production. RNA-seq in young adult mouse colon (YAMC) cells identified higher expression of Lgr4, Lgr6, DCLK1, Muc2, and SIGGIR after Butyrate treatment. Lineage tracing in CR-infected Lgr5-EGFP-IRES-CreERT2/ROSA26-LacZ (Lgr5-R) mice also revealed an expansion of LacZ-labeled Lgr5(+) stem cells in the colons of both Pectin and Tributyrin-treated mice compared to control. Interestingly, gut microbiota was required for Pectin but not Tributyrin-induced Lgr5(+) stem cell expansion. YAMC cells treated with sodium butyrate exhibited increased Lgr5 promoter reporter activity due to direct Butyrate binding with Lgr5 at −4.0 Kcal/mol, leading to thermal stabilization. Upon ChIP-seq, H3K4me3 increased near Lgr5 transcription start site that contained the consensus binding motif for a transcriptional activator of Lgr5 (SPIB). Thus, a multitude of effects on gut microbiome, differential gene expression, and/or expansion of Lgr5(+) stem cells seem to underlie amelioration of colitis following dietary intervention.
Highlights
Introduction iationsThe gastrointestinal tract is home to trillions of microbes called microbiota [1] that protect against enteropathogens, contribute to normal immune function, and maintain homeostasis in the gut [1]
We found a significant increase in the Lgr5+ stem cell population in the colons of mice fed with Pectin and Tributyrin diets compared to controls
While both Pectin and Tributyrin diets increased Lgr5+ stem cells, treatment of Pectin-fed mice with antibiotics severely impacted Lgr5 expression, and there was no significant difference in mice fed with the Tributyrin diet and treated with antibiotics
Summary
The gastrointestinal tract is home to trillions of microbes called microbiota [1] that protect against enteropathogens, contribute to normal immune function, and maintain homeostasis in the gut [1]. Maintaining this functional balance is crucial for sustaining normal intestinal mucosa physiology, as disruptions have been linked to the pathophysiology of various gastrointestinal complications, including inflammatory bowel disease (IBD) [2]. The gut microbiota is known to secrete small molecules and metabolites such as shortchain-fatty-acids (SCFAs), which play an essential role in maintaining intestinal functions and homeostasis [3,4,5].
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