High-fat diet modifies the PPAR-γ pathway leading to disruption of microbial and physiological ecosystem in murine small intestine

Abstract

Diet is among the most important factors contributing to intestinal homeostasis, and basic functions performed by the small intestine need to be tightly preserved to maintain health. Little is known about the direct impact of high-fat (HF) diet on small-intestinal mucosal defenses and spatial distribution of the microbiota during the early phase of its administration. We observed that only 30 d after HF diet initiation, the intervillous zone of the ileum—which is usually described as free of bacteria—became occupied by a dense microbiota. In addition to affecting its spatial distribution, HF diet also drastically affected microbiota composition with a profile characterized by the expansion of Firmicutes (appearance of Erysipelotrichi), Proteobacteria (Desulfovibrionales) and Verrucomicrobia, and decrease of Bacteroidetes (family S24-7) and Candidatus arthromitus. A decrease in antimicrobial peptide expression was predominantly observed in the ileum where bacterial density appeared highest. In addition, HF diet increased intestinal permeability and decreased cystic fibrosis transmembrane conductance regulator (Cftr) and the Na-K-2Cl cotransporter 1 (Nkcc1) gene and protein expressions, leading to a decrease in ileal secretion of chloride, likely responsible for massive alteration in mucus phenotype. This complex phenotype triggered by HF diet at the interface between the microbiota and the mucosal surface was reversed when the diet was switched back to standard composition or when mice were treated for 1 wk with rosiglitazone, a specific agonist of peroxisome proliferator-activated receptor-γ (PPAR-γ). Moreover, weaker expression of antimicrobial peptide-encoding genes and intervillous bacterial colonization were observed in Ppar-γ–deficient mice, highlighting the major role of lipids in modulation of mucosal immune defenses.

Peroxisome Proliferator-Activated Receptor Modulation during Metabolic Diseases and Cancers: Master and Minions

“…In agreement with what reported in the previous chapters, high-fat diet is associated with increased colorectal cancer incidence, probably because many of its effects on stem and progenitor cell compartment are driven by a robust PPAR- δ program and contribute to the early steps of intestinal tumorigenesis [79]. In addition, recent evidence suggests that high-fat diet modifies the PPAR γ pathway leading to disruption of microbial and physiological ecosystem in murine small intestine [80]. …”

Intestinal microbiota contributes to colonic epithelial changes in simulated microgravity mouse model

“…Although molecules that are expressed by bacteria from this phylum have not been reported to suppress epithelial cell turnover or defense response, the results from cohousing and fecal transplantation experiments indicate a causal relationship between HU-induced dysbiosis and altered epithelial homeostasis. Because similar dysbiosis has been linked to a variety of diseases, such as diabetes, obesity, chronic inflammation, or even cancer (54,55,63,64), it will be worthwhile to investigate whether this altered epithelium-microbiota interaction may lead to certain types of chronic inflammation locally or systemically.…”

Targeting PPARγ in the epigenome rescues genetic metabolic defects in mice

“…The exact mechanism for insulin sensitization by rosiglitazone remains elusive, but PPARγ in adipose tissue is the likely target (18), though roles for PPARγ in other tissues like liver, immune cells, and neurons have also been proposed. Furthermore, a recent study even suggests that rosiglitazone reverses HFD-mediated changes in the small intestinal microbiota (19). TZDs have effects on adipocytes, but also increase the number of alternatively activated antiinflammatory macrophages in adipose tissue and reduce markers of inflammation (20).…”