Absence of neurotensin attenuates intestinal dysbiosis and inflammation by maintaining Mmp7/α-defensin axis in diet-induced obese mice

Jing Li, Xian Li, Jun Song, Baoxiang Yan, Stephanie A. Rock, Jianhang Jia, Jinpeng Liu, Chi Wang, Todd Weiss, Heidi L. Weiss, Tianyan Gao, Ashfaqul Alam, B. Mark Evers

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

We previously reported that high levels of plasma neurotensin (NT), a gut hormone released from enteroendocrine cells of the small bowel, contribute to obesity and comorbid conditions. Gut microbiota has been implicated in the obesity development. Paneth cells are critical in maintaining gut microbiota composition and homeostasis by releasing antimicrobial proteins including α-defensins. The purpose of our current study was to determine the possible role of NT in gut microbiota composition and α-defensin gene expression associated with obesity. Here we show that the ratio of Firmicutes/Bacteroidetes (F/B ratio) and intestinal proinflammatory cytokines is significantly increased in NT+/+ mice fed with a high-fat diet (HFD) which were improved in NT-deficient mice. HFD disrupted the intestinal Mmp7/α-defensin axis, which was completely prevented in NT−/− mice. In addition, NT treatment inhibited DEFA5 expression and concurrent NF-κB activity, which was blocked by a pan PKC inhibitor (Gö6983) or an inhibitor for atypical PKCs (CRT0066854). More importantly, the shRNA-mediated knockdown of atypical PKCτ reversed NT-attenuated DEFA5 expression and increased NF-κB activity. NT contributes to the HFD-induced disruption of gut microbiota composition and α-defensin expression. PKCτ/λ plays a central role in NT-mediated α-defensin gene expression which might be mediated through the inhibition of NF-κB signaling pathways in Paneth cells.

Original languageEnglish
Pages (from-to)8596-8610
Number of pages15
JournalFASEB Journal
Volume34
Issue number6
DOIs
StatePublished - Jun 1 2020

Bibliographical note

Funding Information:
The authors thank Donna Gilbreath in the University of Kentucky Markey Cancer Center's Research Communications Office for manuscript preparation, the Biostatistics and Bioinformatics Shared Resource Facility for statistical analyses (supported by NCI P30 CA177558). This research was supported by the Biospecimen Procurement & Translational Pathology Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30 CA177558) and NIH grants R01 DK112034 and R01 DK48498 (to BME) and K01 DK114391 (to MAA).

Publisher Copyright:
© 2020 Federation of American Societies for Experimental Biology

Keywords

  • NF-κB
  • PKCτ/λ
  • Paneth cells
  • obesity

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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