Pro-restitutive Bacteroides thetaiotaomicron reprograms the transcriptome of intestinal epithelial cells by modulating the expression of genes essential for proliferation and migration.

Abstract

The mammalian intestine harbors a highly complex, very diverse, and numerically vast community of symbiotic microorganisms, which profoundly influence the development and maintenance of the intestinal barrier function. Alterations in microbial composition, known as dysbiosis, are observed in Inflammatory Bowel Disease (IBD), colorectal cancer (CRC), and gastrointestinal infections; however, the exact causal relationship between these changes and the resolution of intestinal inflammation and the repair of damaged mucosa remains unclear. Notably, IBD is not only marked by dysbiosis but also by changes in microbial metabolic pathways and metabolite landscape in the intestinal lumen. The small molecules and microbial metabolites present in the intestinal lumen have emerged as potential regulators of gut pathology, cancer, and mucosal repair. Investigating how altered microbiota and microbial metabolic activities influence intestinal epithelial cells (IEC) can provide insights into their role in the regeneration of mucosal epithelia and restoration of gut barrier functions. This knowledge can be harnessed to promote intestinal homeostasis, prevent relapse, and prolong remission of IBD. To dissect the complex interplay between the gut microbiome and IEC, we focused on the overrepresented bacterium Bacteroides thetaiotaomicron. Here, we show that B. thetaiotaomicron and Akkermansia muciniphila, the dominant members of gut microbiota, expand during the repair & resolution phase of the chemically induced acute murine colitis. Furthermore, our bioinformatics analysis demonstrated that the elevated relative abundance of B. thetaiotamicron was also accompanied by rewiring of bacterial metabolic programs towards the essential amino acid metabolism, polyamine synthesis and utilization, stress response mechanisms, cell envelope biogenesis, and nutrient scavenging. Our RNA sequencing and transcriptomic analysis of primary human colonic epithelial cells cocultured with B. thetaiotaomicron showed that B. thetaiotaomicron stimulates the expression of genes and pathways involved in different cellular functions, including proliferation, differentiation, adhesion, lipid metabolism, migration, chemotaxis, and receptor expression. Our study emphasizes the crucial functions of the gut microbiome and metabolic activities in regulating the functions of intestinal epithelial cells during the repair of injured gut mucosa. Thus, these microorganisms and their metabolism hold promise as potential therapeutic agents.