Western diet induces Paneth cell defects through microbiome alterations and farnesoid X receptor and type I interferon activation

Ta Chiang Liu, Justin T. Kern, Umang Jain, Naomi M. Sonnek, Shanshan Xiong, Katherine F. Simpson, Kelli L. VanDussen, Emma S. Winkler, Talin Haritunians, Atika Malique, Qiuhe Lu, Yo Sasaki, Chad Storer, Michael S. Diamond, Richard D. Head, Dermot P.B. McGovern, Thaddeus S. Stappenbeck

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Intestinal Paneth cells modulate innate immunity and infection. In Crohn's disease, genetic mutations together with environmental triggers can disable Paneth cell function. Here, we find that a western diet (WD) similarly leads to Paneth cell dysfunction through mechanisms dependent on the microbiome and farnesoid X receptor (FXR) and type I interferon (IFN) signaling. Analysis of multiple human cohorts suggests that obesity is associated with Paneth cell dysfunction. In mouse models, consumption of a WD for as little as 4 weeks led to Paneth cell dysfunction. WD consumption in conjunction with Clostridium spp. increased the secondary bile acid deoxycholic acid levels in the ileum, which in turn inhibited Paneth cell function. The process required excess signaling of both FXR and IFN within intestinal epithelial cells. Our findings provide a mechanistic link between poor diet and inhibition of gut innate immunity and uncover an effect of FXR activation in gut inflammation.

Original languageEnglish
Pages (from-to)988-1001.e6
JournalCell Host and Microbe
Volume29
Issue number6
DOIs
StatePublished - Jun 9 2021

Keywords

  • cell-intrinsic
  • high fat diet
  • metabolism
  • microbiota
  • myeloid cells
  • obesity
  • organoids
  • transcriptomics

Fingerprint

Dive into the research topics of 'Western diet induces Paneth cell defects through microbiome alterations and farnesoid X receptor and type I interferon activation'. Together they form a unique fingerprint.

Cite this