RT Journal Article
SR Electronic
T1 Microbial metabolite butyrate-prodrug polymeric micelles demonstrate therapeutic efficacy in pre-clinical models of food allergy and colitis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.05.01.490224
DO 10.1101/2022.05.01.490224
A1 Ruyi Wang
A1 Shijie Cao
A1 Mohamed Elfatih H. Bashir
A1 Lauren A. Hesser
A1 Yanlin Su
A1 Sung Min Choi Hong
A1 Andrew Thompson
A1 Elliot Culleen
A1 Matthew Sabados
A1 Nicholas P. Dylla
A1 Evelyn Campbell
A1 Riyue Bao
A1 Eric B. Nonnecke
A1 Charles L. Bevins
A1 D. Scott Wilson
A1 Jeffrey A. Hubbell
A1 Cathryn R. Nagler
YR 2022
UL http://biorxiv.org/content/early/2022/07/30/2022.05.01.490224.abstract
AB The microbiome modulates host immunity and aids in maintenance of tolerance in the gut, where microbial and food-derived antigens are abundant. Modern lifestyle practices, including diet and antibiotic use, have depleted beneficial taxa, specifically butyrate-producing Clostridia. This depletion is associated with the rising incidence of inflammatory bowel diseases, food allergy, and other noncommunicable chronic diseases. Although butyrate is known to play important roles in regulating gut immunity and maintaining epithelial barrier function, its clinical translation is challenging due to its offensive odor and quick absorption in the upper gut. Here, we have developed two polymeric micelle systems, one with a neutral charge (NtL-ButM) and one with a negative charge (Neg-ButM) that release butyrate from their polymeric core in different regions of the gastrointestinal tract when administered intragastrically to mice. We show that these butyrate-containing micelles, used in combination, restore a barrier-protective response in mice treated with either dextran sodium sulfate or antibiotics. Moreover, butyrate micelle treatment protects peanut-allergic mice from an anaphylactic reaction to peanut challenge and rescues their antibiotic-induced dysbiosis by increasing the abundance of Clostridium Cluster XIVa. Butyrate micelle treatment also reduces the severity of colitis in a murine model. By restoring microbial and mucosal homeostasis, these butyrate-prodrug polymeric micelles may function as a new, antigen-agnostic approach for the treatment of allergic and inflammatory disease.Competing Interest StatementC.R.N. and J.A.H. are founders and shareholders in ClostraBio, Inc, which is developing the technology described herein. R.W., S.C., M.E.H.B., D.S.W., C.R.N. and J.A.H. are inventors on patents filed by the University of Chicago describing the micelles reported herein.