The Mechanism of Oral Melatonin Ameliorates Intestinal and Adipose Lipid Dysmetabolism Through Reducing Escherichia Coli-Derived LipopolysaccharideSummary

Background & Aims: Gut microbiota have been reported to be sensitive to circadian rhythms and host lipometabolism, respectively. Although melatonin-mediated beneficial efforts on many physiological sites have been revealed, the regulatory actions of oral melatonin on the communication betwee...

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Autores principales:	Bohan Rong, Qiong Wu, Russel J. Reiter, Chao Sun
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Melatonin Gut Microbiota Circadian Rhythm Disruption Lipid Metabolism ANGPTL Diseases of the digestive system. Gastroenterology RC799-869
Acceso en línea:	https://doaj.org/article/6cb17c47ecf34c53b2dd68c98b8d238f
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spelling	oai:doaj.org-article:6cb17c47ecf34c53b2dd68c98b8d238f2021-11-12T04:38:39ZThe Mechanism of Oral Melatonin Ameliorates Intestinal and Adipose Lipid Dysmetabolism Through Reducing Escherichia Coli-Derived LipopolysaccharideSummary2352-345X10.1016/j.jcmgh.2021.06.024https://doaj.org/article/6cb17c47ecf34c53b2dd68c98b8d238f2021-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2352345X21001399https://doaj.org/toc/2352-345XBackground & Aims: Gut microbiota have been reported to be sensitive to circadian rhythms and host lipometabolism, respectively. Although melatonin-mediated beneficial efforts on many physiological sites have been revealed, the regulatory actions of oral melatonin on the communication between gut microbiota and host are still not clear. Angiopoietin-like 4 (ANGPTL4) has been shown to be strongly responsible for the regulation of systemic lipid metabolism. Herein, we identified that oral melatonin improved lipid dysmetabolism in ileum and epididymal white adipose tissue (eWAT) via gut microbiota and ileac ANGPTL4. Methods: Analyses of jet-lag (JL) mice, JL mice with oral melatonin administration (JL+MT), and the control for mRNA and protein expression regarding lipid uptake and accumulation in ileum and eWAT were made. Gut microbiome sequencing and experimental validation of target strains were included. Functional analysis of key factors/pathways in the various rodent models, including the depletion of gut microbiota, mono-colonization of Escherichia coli, and other genetic intervention was made. Analyses of transcriptional regulation and effects of melatonin on E coli-derived lipopolysaccharide (LPS) in vitro were made. Results: JL mice have a higher level of ileal lipid uptake, fat accumulation in eWAT, and lower level of circulating ANGPTL4 in comparison with the control mice. JL mice also showed a significantly higher abundance of E coli and LPS than the control mice. Conversely, oral melatonin supplementation remarkably reversed these phenotypes. The test of depletion of gut microbiota further demonstrated that oral melatonin-mediated improvements on lipometabolism in JL mice were dependent on the presence of gut microbiota. By mono-colonization of E coli, LPS has been determined to trigger these changes similar to JL. Furthermore, we found that LPS served as a pivotal link that contributed to activating toll-like receptor 4 (TLR4)/signal transducer and activator of transcription 3 (STAT3_/REV-ERBα) signaling to up-regulate nuclear factor interleukin-3-regulated protein (NFIL3) expression, resulting in increased lipid uptake in ileum. In MODE-K cells, the activation of NFIL3 has further been shown to inhibit ANGPTL4 transcription, which is closely associated with lipid uptake and transport in peripheral tissues. Finally, we confirmed that melatonin inhibited LPS via repressing the expression of LpxC in E coli. Conclusions: Overall, oral melatonin decreased the quantity of E coli-generated LPS, which alleviated NFIL3-induced transcriptional inhibition of ANGPTL4 through TLR4/IL-22/STAT3 signaling in ileum, thereby resulting in the amelioration of ileal lipid intake and lower fat accumulation in eWAT. These results address a novel regulation of oral melatonin originating from gut microbiota to host distal tissues, suggesting that microbe-generated metabolites are potential therapies for melatonin-mediated improvement of circadian rhythm disruption and related metabolic syndrome.Bohan RongQiong WuRussel J. ReiterChao SunElsevierarticleMelatoninGut MicrobiotaCircadian Rhythm DisruptionLipid MetabolismANGPTLDiseases of the digestive system. GastroenterologyRC799-869ENCellular and Molecular Gastroenterology and Hepatology, Vol 12, Iss 5, Pp 1643-1667 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Melatonin Gut Microbiota Circadian Rhythm Disruption Lipid Metabolism ANGPTL Diseases of the digestive system. Gastroenterology RC799-869
spellingShingle	Melatonin Gut Microbiota Circadian Rhythm Disruption Lipid Metabolism ANGPTL Diseases of the digestive system. Gastroenterology RC799-869 Bohan Rong Qiong Wu Russel J. Reiter Chao Sun The Mechanism of Oral Melatonin Ameliorates Intestinal and Adipose Lipid Dysmetabolism Through Reducing Escherichia Coli-Derived LipopolysaccharideSummary
description	Background & Aims: Gut microbiota have been reported to be sensitive to circadian rhythms and host lipometabolism, respectively. Although melatonin-mediated beneficial efforts on many physiological sites have been revealed, the regulatory actions of oral melatonin on the communication between gut microbiota and host are still not clear. Angiopoietin-like 4 (ANGPTL4) has been shown to be strongly responsible for the regulation of systemic lipid metabolism. Herein, we identified that oral melatonin improved lipid dysmetabolism in ileum and epididymal white adipose tissue (eWAT) via gut microbiota and ileac ANGPTL4. Methods: Analyses of jet-lag (JL) mice, JL mice with oral melatonin administration (JL+MT), and the control for mRNA and protein expression regarding lipid uptake and accumulation in ileum and eWAT were made. Gut microbiome sequencing and experimental validation of target strains were included. Functional analysis of key factors/pathways in the various rodent models, including the depletion of gut microbiota, mono-colonization of Escherichia coli, and other genetic intervention was made. Analyses of transcriptional regulation and effects of melatonin on E coli-derived lipopolysaccharide (LPS) in vitro were made. Results: JL mice have a higher level of ileal lipid uptake, fat accumulation in eWAT, and lower level of circulating ANGPTL4 in comparison with the control mice. JL mice also showed a significantly higher abundance of E coli and LPS than the control mice. Conversely, oral melatonin supplementation remarkably reversed these phenotypes. The test of depletion of gut microbiota further demonstrated that oral melatonin-mediated improvements on lipometabolism in JL mice were dependent on the presence of gut microbiota. By mono-colonization of E coli, LPS has been determined to trigger these changes similar to JL. Furthermore, we found that LPS served as a pivotal link that contributed to activating toll-like receptor 4 (TLR4)/signal transducer and activator of transcription 3 (STAT3_/REV-ERBα) signaling to up-regulate nuclear factor interleukin-3-regulated protein (NFIL3) expression, resulting in increased lipid uptake in ileum. In MODE-K cells, the activation of NFIL3 has further been shown to inhibit ANGPTL4 transcription, which is closely associated with lipid uptake and transport in peripheral tissues. Finally, we confirmed that melatonin inhibited LPS via repressing the expression of LpxC in E coli. Conclusions: Overall, oral melatonin decreased the quantity of E coli-generated LPS, which alleviated NFIL3-induced transcriptional inhibition of ANGPTL4 through TLR4/IL-22/STAT3 signaling in ileum, thereby resulting in the amelioration of ileal lipid intake and lower fat accumulation in eWAT. These results address a novel regulation of oral melatonin originating from gut microbiota to host distal tissues, suggesting that microbe-generated metabolites are potential therapies for melatonin-mediated improvement of circadian rhythm disruption and related metabolic syndrome.
format	article
author	Bohan Rong Qiong Wu Russel J. Reiter Chao Sun
author_facet	Bohan Rong Qiong Wu Russel J. Reiter Chao Sun
author_sort	Bohan Rong
title	The Mechanism of Oral Melatonin Ameliorates Intestinal and Adipose Lipid Dysmetabolism Through Reducing Escherichia Coli-Derived LipopolysaccharideSummary
title_short	The Mechanism of Oral Melatonin Ameliorates Intestinal and Adipose Lipid Dysmetabolism Through Reducing Escherichia Coli-Derived LipopolysaccharideSummary
title_full	The Mechanism of Oral Melatonin Ameliorates Intestinal and Adipose Lipid Dysmetabolism Through Reducing Escherichia Coli-Derived LipopolysaccharideSummary
title_fullStr	The Mechanism of Oral Melatonin Ameliorates Intestinal and Adipose Lipid Dysmetabolism Through Reducing Escherichia Coli-Derived LipopolysaccharideSummary
title_full_unstemmed	The Mechanism of Oral Melatonin Ameliorates Intestinal and Adipose Lipid Dysmetabolism Through Reducing Escherichia Coli-Derived LipopolysaccharideSummary
title_sort	mechanism of oral melatonin ameliorates intestinal and adipose lipid dysmetabolism through reducing escherichia coli-derived lipopolysaccharidesummary
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/6cb17c47ecf34c53b2dd68c98b8d238f
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The Mechanism of Oral Melatonin Ameliorates Intestinal and Adipose Lipid Dysmetabolism Through Reducing Escherichia Coli-Derived LipopolysaccharideSummary

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