Fenofibrate promotes PPARα-targeted recovery of the intestinal epithelial barrier at the host-microbe interface in dogs with diabetes mellitus

Abstract Diabetes mellitus (DM) is associated with a dysfunctional intestinal barrier and an increased risk for systemic infection and inflammation in people, though the pathogenic mechanisms leading to this are poorly understood. Using a canine model of DM, we showed that the peroxisomal proliferat...

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Autores principales:	Katti R. Crakes, Jully Pires, Nina Quach, Riley E. Ellis-Reis, Rachel Greathouse, Kathyrnne A. Chittum, Jörg M. Steiner, Patricia Pesavento, Stanley L. Marks, Satya Dandekar, Chen Gilor
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/fc8522dc657f47b5bd02084f12d335f5
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spelling	oai:doaj.org-article:fc8522dc657f47b5bd02084f12d335f52021-12-02T14:33:51ZFenofibrate promotes PPARα-targeted recovery of the intestinal epithelial barrier at the host-microbe interface in dogs with diabetes mellitus10.1038/s41598-021-92966-72045-2322https://doaj.org/article/fc8522dc657f47b5bd02084f12d335f52021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-92966-7https://doaj.org/toc/2045-2322Abstract Diabetes mellitus (DM) is associated with a dysfunctional intestinal barrier and an increased risk for systemic infection and inflammation in people, though the pathogenic mechanisms leading to this are poorly understood. Using a canine model of DM, we showed that the peroxisomal proliferator-activated receptor-α agonist fenofibrate modulates plasma lipid profiles and markers of intestinal barrier function. A 3-week course of fenofibrate reduced fasting interstitial glucose and inflammatory cytokine IL-8 and TNF-α concentrations, which correlated with reduced triglyceride levels. The lipidomic profile exhibited significantly lower levels of triacylglycerols, phosphatidylethanolamines, diacylglycerols, and ceramides following fenofibrate administration. On histopathological analysis, we observed an aberrant amount of intraepithelial CD3+ T lymphocytes (IEL) in the small intestine of dogs with spontaneous and induced-DM. Fenofibrate reduced IEL density in the duodenum of dogs with DM and enhanced markers of intestinal barrier function in vivo and in vitro. There were minimal changes in the intestinal microbial composition following fenofibrate administration, suggesting that repair of intestinal barriers can be achieved independently of the resident microbiota. Our findings indicate that lipid metabolism is critical to functionality of the intestinal epithelium, which can be rescued by PPARα activation in dogs with DM.Katti R. CrakesJully PiresNina QuachRiley E. Ellis-ReisRachel GreathouseKathyrnne A. ChittumJörg M. SteinerPatricia PesaventoStanley L. MarksSatya DandekarChen GilorNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Katti R. Crakes Jully Pires Nina Quach Riley E. Ellis-Reis Rachel Greathouse Kathyrnne A. Chittum Jörg M. Steiner Patricia Pesavento Stanley L. Marks Satya Dandekar Chen Gilor Fenofibrate promotes PPARα-targeted recovery of the intestinal epithelial barrier at the host-microbe interface in dogs with diabetes mellitus
description	Abstract Diabetes mellitus (DM) is associated with a dysfunctional intestinal barrier and an increased risk for systemic infection and inflammation in people, though the pathogenic mechanisms leading to this are poorly understood. Using a canine model of DM, we showed that the peroxisomal proliferator-activated receptor-α agonist fenofibrate modulates plasma lipid profiles and markers of intestinal barrier function. A 3-week course of fenofibrate reduced fasting interstitial glucose and inflammatory cytokine IL-8 and TNF-α concentrations, which correlated with reduced triglyceride levels. The lipidomic profile exhibited significantly lower levels of triacylglycerols, phosphatidylethanolamines, diacylglycerols, and ceramides following fenofibrate administration. On histopathological analysis, we observed an aberrant amount of intraepithelial CD3+ T lymphocytes (IEL) in the small intestine of dogs with spontaneous and induced-DM. Fenofibrate reduced IEL density in the duodenum of dogs with DM and enhanced markers of intestinal barrier function in vivo and in vitro. There were minimal changes in the intestinal microbial composition following fenofibrate administration, suggesting that repair of intestinal barriers can be achieved independently of the resident microbiota. Our findings indicate that lipid metabolism is critical to functionality of the intestinal epithelium, which can be rescued by PPARα activation in dogs with DM.
format	article
author	Katti R. Crakes Jully Pires Nina Quach Riley E. Ellis-Reis Rachel Greathouse Kathyrnne A. Chittum Jörg M. Steiner Patricia Pesavento Stanley L. Marks Satya Dandekar Chen Gilor
author_facet	Katti R. Crakes Jully Pires Nina Quach Riley E. Ellis-Reis Rachel Greathouse Kathyrnne A. Chittum Jörg M. Steiner Patricia Pesavento Stanley L. Marks Satya Dandekar Chen Gilor
author_sort	Katti R. Crakes
title	Fenofibrate promotes PPARα-targeted recovery of the intestinal epithelial barrier at the host-microbe interface in dogs with diabetes mellitus
title_short	Fenofibrate promotes PPARα-targeted recovery of the intestinal epithelial barrier at the host-microbe interface in dogs with diabetes mellitus
title_full	Fenofibrate promotes PPARα-targeted recovery of the intestinal epithelial barrier at the host-microbe interface in dogs with diabetes mellitus
title_fullStr	Fenofibrate promotes PPARα-targeted recovery of the intestinal epithelial barrier at the host-microbe interface in dogs with diabetes mellitus
title_full_unstemmed	Fenofibrate promotes PPARα-targeted recovery of the intestinal epithelial barrier at the host-microbe interface in dogs with diabetes mellitus
title_sort	fenofibrate promotes pparα-targeted recovery of the intestinal epithelial barrier at the host-microbe interface in dogs with diabetes mellitus
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/fc8522dc657f47b5bd02084f12d335f5
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Fenofibrate promotes PPARα-targeted recovery of the intestinal epithelial barrier at the host-microbe interface in dogs with diabetes mellitus

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