REG3γ-deficient mice have altered mucus distribution and increased mucosal inflammatory responses to the microbiota and enteric pathogens in the ileum

Abstract

REG3γ is considered to have a protective role against infection with Gram-positive bacteria due to its bactericidal activity, but evidence from in vivo studies is lacking. We generated a REG3γ(-/-) mouse, and investigated the effect of lack of REG3γ on intestinal mucus distribution, spatial compartmentalization of bacteria, and expression of innate immunity genes. Infection studies were also performed with Gram-positive and Gram-negative pathogens to investigate the antimicrobial role of REG3γ. REG3γ(-/-) mice display altered mucus distribution, increased bacterial contact with the epithelium, and elevated inflammatory markers in the ileum without histological evidence of pathology. Infection response pathway genes were differentially expressed in both Listeria monocytogenes and Salmonella enteritidis infected REG3γ(-/-) and wild-type (wt) mice. Higher amounts of myeloperoxidase and interleukin-22 transcripts were present in the ileal mucosa of REG3γ(-/-) than wt mice, but translocation to the organs was unaffected. We concluded that REG3γ has a protective role against mucosal infection with pathogenic Listeria and Salmonella in vivo. REG3γ is equally distributed throughout the mucus and its absence results in increased epithelial contact with the microbiota resulting in low-grade inflammation. REG3γ can bind to Gram-negative and Gram-positive bacteria and influence mucus distribution in the ileum, properties which may contribute to mucosal protection.

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

“…The decrease in AMP gene expression was correlated to the uncontrolled bacterial colonization, regardless if the duodenum or ileum were considered. This finding supports a model where impairment in AMP gene expression and production is associated with an expansion of the microbiota to otherwise preserved territories (63,64). In the ileum of HFfed mice, the decrease in AMP, such as α-defensins, lysozyme, and phospholipase A2 could explain colonization of the intervillous space by the microbiota.…”

A single-cell survey of the small intestinal epithelium

“…9a, top left and Supplementary Table 9) were enriched for pathways involved in defense response to bacterium (FDR<0.001, hypergeometric test Extended Data Fig. 9c), including Reg3b and Reg3g 39 , protective genes in Salmonella infection (Fig. 6c).…”

Bile Acid Administration Elicits an Intestinal Antimicrobial Program and Reduces the Bacterial Burden in Two Mouse Models of Enteric Infection

“…Intestinal AMPPs, immunoglobulins, and a healthy mucus layer are all important factors in the defense against enteric infections (20,(56)(57)(58)(59)(60)(61). CDCA administration, which increased AMPP production, the mucosal B cell fraction, and Muc2 expression, also accelerated the clearance of Citrobacter rodentium infection and limited the systemic spread of Salmonella Typhimurium.…”