Promotion of Intestinal Epithelial Cell Turnover by Commensal Bacteria: Role of Short-Chain Fatty Acids

Abstract

The life span of intestinal epithelial cells (IECs) is short (3–5 days), and its regulation is thought to be important for homeostasis of the intestinal epithelium. We have now investigated the role of commensal bacteria in regulation of IEC turnover in the small intestine. The proliferative activity of IECs in intestinal crypts as well as the migration of these cells along the crypt-villus axis were markedly attenuated both in germ-free mice and in specific pathogen–free (SPF) mice treated with a mixture of antibiotics, with antibiotics selective for Gram-positive bacteria being most effective in this regard. Oral administration of chloroform-treated feces of SPF mice to germ-free mice resulted in a marked increase in IEC turnover, suggesting that spore-forming Gram-positive bacteria contribute to this effect. Oral administration of short-chain fatty acids (SCFAs) as bacterial fermentation products also restored the turnover of IECs in antibiotic-treated SPF mice as well as promoted the development of intestinal organoids in vitro. Antibiotic treatment reduced the phosphorylation levels of ERK, ribosomal protein S6, and STAT3 in IECs of SPF mice. Our results thus suggest that Gram-positive commensal bacteria are a major determinant of IEC turnover, and that their stimulatory effect is mediated by SCFAs.

Intestinal Epithelial and Intraepithelial T Cell Crosstalk Mediates a Dynamic Response to Infection

“…Although previous studies have demonstrated that “natural” IELs do not require commensal bacteria to populate the intestinal epithelium (Bandeira et al, 1990), we observed that γδ IEL distribution along the small intestine, positioning in the villi, motility above the basement membrane and villus-crypt bidirectional displacement are largely dependent on stimulation by the microbiota and enteric pathogens. It is possible that IELs physiologically sense EC proliferation, since our estimated IEL vertical downward displacement nearly offsets the EC growth rate described in SPF mice (approximately 6 µm/hour) (Park et al, 2016). Likewise, this coordination seems to be directed by gut microbiota, since both γδ IEL vertical displacement and epithelial cell turnover are reduced in mice devoid of microbiota (Park et al, 2016).…”

“…It is possible that IELs physiologically sense EC proliferation, since our estimated IEL vertical downward displacement nearly offsets the EC growth rate described in SPF mice (approximately 6 µm/hour) (Park et al, 2016). Likewise, this coordination seems to be directed by gut microbiota, since both γδ IEL vertical displacement and epithelial cell turnover are reduced in mice devoid of microbiota (Park et al, 2016). The microbiota-dependent preferential localization of γδ IELs in the upper third of villi also corresponds to the increased microbial concentration reported in that region, which has lower concentrations of anti-microbial peptides (AMPs) produced by Paneth cells in the crypts (Hooper and Macpherson, 2010).…”

Sensitive and Simplified Detection of Antibiotic Influence on the Dynamic and Versatile Changes of Fecal Short-Chain Fatty Acids

“…Few studies systematically explored the influences of antibiotics on fecal SCFAs [44], and none on the influences of cefdinir or azithromycin. A very recent report showed that the microbiota of preterm infant involves a concomitant alteration in the levels of SCFAs [45].…”

Evolutionary and ecological forces that shape the bacterial communities of the human gut

“…The rate of epithelial turnover is at least partially dependent on gut bacteria since bacterial-produced short chain fatty acids promote epithelial turnover. 64 However, responses to microbial metabolites can be very cell type specific. When intestinal stem cells, a tissue compartment that is normally isolated from short chain fatty acids, encounter butyrate, their proliferation is slowed which delays tissue repair and turnover.…”