The impact of high-fiber diets in the colonic epithelial microenvironment

Author(s)

Renan Oliveira Corrêa

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2022-03-30

Examining board members

Marco Aurélio Ramirez Vinolo; Pedro Manoel Mendes de Moraes Vieira; Renata Sesti Costa; Ana Maria Caetano de Faria; Larissa Dias da Cunha

• Advisor: Marco Aurélio Ramirez Vinolo

Abstract

The intestinal epithelium is a single-layer barrier composed of several cell types, all originated from the intestinal stem cells (ISCs) located at the bottom of the crypts. Although several studies have demonstrated that distinct dietary approaches can regulate the function of the ISCs and niche cells, the impact of fiber-enriched diets on the intestinal stem cell compartment, mainly in homeostasis, remains unclear. Here we found that the consumption of the soluble fiber inulin increased proliferation in the colon, generating deeper crypts and longer intestines in steady state, a phenotype not observed in control or cellulose (insoluble fiber)-enriched diets. Inulin upregulated the expression of several genes related to cell division in the intestinal epithelial cells, besides enhancing the function, but not the number, of Lgr5+ ISCs in the colon. The composition of the gut microbiota was also modulated by inulin, with increased abundance of several bacterial groups, including species with the ability to break down inulin. The presence of the microbiota was essential for enhancing epithelial proliferation, as no phenotype was observed in germ-free mice, nor in mice treated with antibiotics. Fecal microbial transplantation revealed that only the presence of the inulin-modulated microbiota was enough to induce colon proliferation, although a stronger phenotype could be seen when this microbiota was combined with the consumption of inulin. Interestingly, even in mice colonized with a synthetic microbiota composed of only 14 bacterial species, inulin was still able to induce the increased proliferation, showing that as long the microbial community contains important groups that can degrade inulin, the phenotype can still be induced. Our data also showed that bacterial metabolites short-chain fatty acids (SCFAS) are dispensable for the enhanced proliferation in the colon in this model. Inulin increased the levels of these metabolites, but so did the conventional chow without inducing colonic proliferation. Besides, proliferation was seen in knockout mice for FFAR2, one of the main receptors for SCFAs. On the other hand, the cytokine IL-22 played a pivotal role in this sense. More ILC3 and Th17 were found in the lamina propria of inulin-fed mice, as well as increased production of IL-22, and enhanced responsiveness of the epithelium to this cytokine. More importantly, there was a complete lack of phenotype in Il22-deficient mice. Finally, our results also indicated that the ?? T cells are also important players in our model, since inulin failed to increase proliferation in animals lacking most T and B lymphocytes (Rag1-deficient), but also in those lacking only the ?? T population (Tcrd-deficient). Together, our data demonstrate that inulin impacts ISCs stemness by modulating the communication between the gut microbiota and the immune cells in IL-22 dependent way (AU)

• FAPESP's process: 16/23142-3 - Interaction between HIF-1 and short-chain fatty acids in the intestine: what is the role of HIF-1 acetylation?
• Grantee: Renan Oliveira Corrêa
• Support Opportunities: Scholarships in Brazil - Doctorate