Premium
Butyrate Priming Improves Gut Health by Modulating Host Protease Activity in Murine Non‐Alcoholic Fatty Liver Disease
Author(s) -
Mondal Ayan,
Seth Ratanesh,
Bose Dipro,
Nagarkatti Mitzi,
Nagarkatti Prakash,
Chatterjee Saurabh
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.07464
Subject(s) - proteases , proinflammatory cytokine , biology , granzyme b , inflammation , cathepsin , occludin , cathepsin b , immunology , immune system , microbiology and biotechnology , biochemistry , t cell , tight junction , enzyme
Reports from clinical investigations implicate a strong association of non‐alcoholic fatty liver disease (NAFLD) and inflammatory bowel diseases (IBD). Recently we reported a rapid alteration of gut microbiome in murine NAFLD model that resulted in gut leaching, tight junction protein alteration and intestinal inflammation. Advancing our present understanding, we show that altered gut microbiome in murine NAFLD significantly decreased microbial proteases content in the host gut micro‐environment. Dysbiosis significantly increased expression of host proteases derived from gut immune cells which were associated with intestinal inflammation and gut leaching. Results also showed significant upregulated expression of a disintegrin and metalloproteinase 17 (ADAM17) and serine proteases Granzyme M, Cathepsin G and Proteinase 3 in intestines of NAFLD mice. Increased expression of these proteases were associated with activation of protease activated receptor 1 (PAR1), significant over production of pro inflammatory cytokines TNFα and IL‐1β, decreased expression of Occludin, and increased expression of Claudin2. Most interestingly administration of butyrate to NAFLD mouse group significantly increased microbial protease content in gut, decreased expression of ADAM17, Granzyme M and Cathepsin G, and increased expression of protective matrix metalloproteinases 7 and 2 (MMP7 and MMP2). Decreased expression of ADAM17, Granzyme M and Cathepsin G improved gut leaching by upregulation of Occludin and down regulation of Claudin 2 expression, decreased PAR1 expression, and decreased TNFα and IL‐1β secretion. Furthermore, increased expression of MMP 2 and MMP 7 showed elevated expression of anti‐inflammatory cytokines IL‐4 and IL‐10 in small intestine. Thus, in conclusion our present study demonstrates that butyrate plays a crucial role in gut homeostasis by a previously unknown function of modulating host protease activity in NAFLD and can be of significant therapeutic value. Support or Funding Information This project has been supported by NIH grants # 2P01AT003961 (Project 4) and #P20GM103641‐07(Project3) to Dr. Saurabh Chatterjee