Colonic Epithelial Circadian Disruption Worsens Dextran Sulfate Sodium–Induced Colitis

Sarah B. Jochum; Phillip A. Engen; Maliha Shaikh; Ankur Naqib; Sherry Wilber; Shohreh Raeisi; Lijuan Zhang; Shiwen Song; Gabriella Sanzo; Vijit Chouhan; Frank Ko; Zoe Post; Laura Tran; Vivian Ramirez; Stefan J. Green; Khashayarsha Khazaie; Dana M. Hayden; Mark J. Brown; Robin M. Voigt; Christopher B. Forsyth; Ali Keshavarzian; Garth R. Swanson

doi:10.1093/ibd/izac219

Colonic Epithelial Circadian Disruption Worsens Dextran Sulfate Sodium–Induced Colitis

Sarah B. Jochum, Phillip A. Engen, Maliha Shaikh, Ankur Naqib, Sherry Wilber, Shohreh Raeisi, Lijuan Zhang, Shiwen Song, Gabriella Sanzo, Vijit Chouhan, Frank Ko, Zoe Post, Laura Tran, Vivian Ramirez, Stefan J. Green, Khashayarsha Khazaie, Dana M. Hayden, Mark J. Brown, Robin M. Voigt, Christopher B. ForsythAli Keshavarzian, Garth R. Swanson

Allergy, Asthma and Clinical Immunology

Research output: Contribution to journal › Article › peer-review

Abstract

Background: Disruption of central circadian rhythms likely mediated by changes in microbiota and a decrease in gut-derived metabolites like short chain fatty acids (SCFAs) negatively impacts colonic barrier homeostasis. We aimed to explore the effects of isolated peripheral colonic circadian disruption on the colonic barrier in a mouse model of colitis and explore the mechanisms, including intestinal microbiota community structure and function. Methods: Colon epithelial cell circadian rhythms were conditionally genetically disrupted in mice: TS4Cre-BMAL1lox (cBMAL1KO) with TS4Cre as control animals. Colitis was induced through 5 days of 2% dextran sulfate sodium (DSS). Disease activity index and intestinal barrier were assessed, as were fecal microbiota and metabolites. Results: Colitis symptoms were worse in mice with peripheral circadian disruption (cBMAL1KO). Specifically, the disease activity index and intestinal permeability were significantly higher in circadian-disrupted mice compared with control animals (TS4Cre) (P < .05). The worsening of colitis appears to be mediated, in part, through JAK (Janus kinase)-mediated STAT3 (signal transducer and activator of transcription 3), which was significantly elevated in circadian-disrupted (cBMAL1KO) mice treated with DSS (P < .05). Circadian-disrupted (cBMAL1KO) mice also had decreased SCFA metabolite concentrations and decreased relative abundances of SCFA-producing bacteria in their stool when compared with control animals (TS4Cre). Conclusions: Disruption of intestinal circadian rhythms in colonic epithelial cells promoted more severe colitis, increased inflammatory mediators (STAT3 [signal transducer and activator of transcription 3]), and decreased gut microbiota–derived SCFAs compared with DSS alone. Further investigation elucidating the molecular mechanisms behind these findings could provide novel circadian directed targets and strategies in the treatment of inflammatory bowel disease.

Original language	English (US)
Pages (from-to)	444-457
Number of pages	14
Journal	Inflammatory bowel diseases
Volume	29
Issue number	3
DOIs	https://doi.org/10.1093/ibd/izac219
State	Published - Mar 1 2023

Keywords

circadian disruption
metabolomics
microbiota
peripheral circadian disruption
ulcerative colitis

ASJC Scopus subject areas

Immunology and Allergy
Gastroenterology

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10.1093/ibd/izac219

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Jochum, S. B., Engen, P. A., Shaikh, M., Naqib, A., Wilber, S., Raeisi, S., Zhang, L., Song, S., Sanzo, G., Chouhan, V., Ko, F., Post, Z., Tran, L., Ramirez, V., Green, S. J., Khazaie, K., Hayden, D. M., Brown, M. J., Voigt, R. M., ... Swanson, G. R. (2023). Colonic Epithelial Circadian Disruption Worsens Dextran Sulfate Sodium–Induced Colitis. Inflammatory bowel diseases, 29(3), 444-457. https://doi.org/10.1093/ibd/izac219

Jochum, SB, Engen, PA, Shaikh, M, Naqib, A, Wilber, S, Raeisi, S, Zhang, L, Song, S, Sanzo, G, Chouhan, V, Ko, F, Post, Z, Tran, L, Ramirez, V, Green, SJ, Khazaie, K, Hayden, DM, Brown, MJ, Voigt, RM, Forsyth, CB, Keshavarzian, A & Swanson, GR 2023, 'Colonic Epithelial Circadian Disruption Worsens Dextran Sulfate Sodium–Induced Colitis', Inflammatory bowel diseases, vol. 29, no. 3, pp. 444-457. https://doi.org/10.1093/ibd/izac219

@article{b3c13b1b68b048a3a80c0faf6aea7dcc,

title = "Colonic Epithelial Circadian Disruption Worsens Dextran Sulfate Sodium–Induced Colitis",

abstract = "Background: Disruption of central circadian rhythms likely mediated by changes in microbiota and a decrease in gut-derived metabolites like short chain fatty acids (SCFAs) negatively impacts colonic barrier homeostasis. We aimed to explore the effects of isolated peripheral colonic circadian disruption on the colonic barrier in a mouse model of colitis and explore the mechanisms, including intestinal microbiota community structure and function. Methods: Colon epithelial cell circadian rhythms were conditionally genetically disrupted in mice: TS4Cre-BMAL1lox (cBMAL1KO) with TS4Cre as control animals. Colitis was induced through 5 days of 2% dextran sulfate sodium (DSS). Disease activity index and intestinal barrier were assessed, as were fecal microbiota and metabolites. Results: Colitis symptoms were worse in mice with peripheral circadian disruption (cBMAL1KO). Specifically, the disease activity index and intestinal permeability were significantly higher in circadian-disrupted mice compared with control animals (TS4Cre) (P < .05). The worsening of colitis appears to be mediated, in part, through JAK (Janus kinase)-mediated STAT3 (signal transducer and activator of transcription 3), which was significantly elevated in circadian-disrupted (cBMAL1KO) mice treated with DSS (P < .05). Circadian-disrupted (cBMAL1KO) mice also had decreased SCFA metabolite concentrations and decreased relative abundances of SCFA-producing bacteria in their stool when compared with control animals (TS4Cre). Conclusions: Disruption of intestinal circadian rhythms in colonic epithelial cells promoted more severe colitis, increased inflammatory mediators (STAT3 [signal transducer and activator of transcription 3]), and decreased gut microbiota–derived SCFAs compared with DSS alone. Further investigation elucidating the molecular mechanisms behind these findings could provide novel circadian directed targets and strategies in the treatment of inflammatory bowel disease.",

keywords = "circadian disruption, metabolomics, microbiota, peripheral circadian disruption, ulcerative colitis",

author = "Jochum, {Sarah B.} and Engen, {Phillip A.} and Maliha Shaikh and Ankur Naqib and Sherry Wilber and Shohreh Raeisi and Lijuan Zhang and Shiwen Song and Gabriella Sanzo and Vijit Chouhan and Frank Ko and Zoe Post and Laura Tran and Vivian Ramirez and Green, {Stefan J.} and Khashayarsha Khazaie and Hayden, {Dana M.} and Brown, {Mark J.} and Voigt, {Robin M.} and Forsyth, {Christopher B.} and Ali Keshavarzian and Swanson, {Garth R.}",

note = "Publisher Copyright: {\textcopyright} 2022 Crohn{\textquoteright}s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn{\textquoteright}s & Colitis Foundation.",

year = "2023",

month = mar,

day = "1",

doi = "10.1093/ibd/izac219",

language = "English (US)",

volume = "29",

pages = "444--457",

journal = "Inflammatory bowel diseases",

issn = "1078-0998",

publisher = "John Wiley and Sons Inc.",

number = "3",

}

TY - JOUR

T1 - Colonic Epithelial Circadian Disruption Worsens Dextran Sulfate Sodium–Induced Colitis

AU - Jochum, Sarah B.

AU - Engen, Phillip A.

AU - Shaikh, Maliha

AU - Naqib, Ankur

AU - Wilber, Sherry

AU - Raeisi, Shohreh

AU - Zhang, Lijuan

AU - Song, Shiwen

AU - Sanzo, Gabriella

AU - Chouhan, Vijit

AU - Ko, Frank

AU - Post, Zoe

AU - Tran, Laura

AU - Ramirez, Vivian

AU - Green, Stefan J.

AU - Khazaie, Khashayarsha

AU - Hayden, Dana M.

AU - Brown, Mark J.

AU - Voigt, Robin M.

AU - Forsyth, Christopher B.

AU - Keshavarzian, Ali

AU - Swanson, Garth R.

PY - 2023/3/1

Y1 - 2023/3/1

N2 - Background: Disruption of central circadian rhythms likely mediated by changes in microbiota and a decrease in gut-derived metabolites like short chain fatty acids (SCFAs) negatively impacts colonic barrier homeostasis. We aimed to explore the effects of isolated peripheral colonic circadian disruption on the colonic barrier in a mouse model of colitis and explore the mechanisms, including intestinal microbiota community structure and function. Methods: Colon epithelial cell circadian rhythms were conditionally genetically disrupted in mice: TS4Cre-BMAL1lox (cBMAL1KO) with TS4Cre as control animals. Colitis was induced through 5 days of 2% dextran sulfate sodium (DSS). Disease activity index and intestinal barrier were assessed, as were fecal microbiota and metabolites. Results: Colitis symptoms were worse in mice with peripheral circadian disruption (cBMAL1KO). Specifically, the disease activity index and intestinal permeability were significantly higher in circadian-disrupted mice compared with control animals (TS4Cre) (P < .05). The worsening of colitis appears to be mediated, in part, through JAK (Janus kinase)-mediated STAT3 (signal transducer and activator of transcription 3), which was significantly elevated in circadian-disrupted (cBMAL1KO) mice treated with DSS (P < .05). Circadian-disrupted (cBMAL1KO) mice also had decreased SCFA metabolite concentrations and decreased relative abundances of SCFA-producing bacteria in their stool when compared with control animals (TS4Cre). Conclusions: Disruption of intestinal circadian rhythms in colonic epithelial cells promoted more severe colitis, increased inflammatory mediators (STAT3 [signal transducer and activator of transcription 3]), and decreased gut microbiota–derived SCFAs compared with DSS alone. Further investigation elucidating the molecular mechanisms behind these findings could provide novel circadian directed targets and strategies in the treatment of inflammatory bowel disease.

AB - Background: Disruption of central circadian rhythms likely mediated by changes in microbiota and a decrease in gut-derived metabolites like short chain fatty acids (SCFAs) negatively impacts colonic barrier homeostasis. We aimed to explore the effects of isolated peripheral colonic circadian disruption on the colonic barrier in a mouse model of colitis and explore the mechanisms, including intestinal microbiota community structure and function. Methods: Colon epithelial cell circadian rhythms were conditionally genetically disrupted in mice: TS4Cre-BMAL1lox (cBMAL1KO) with TS4Cre as control animals. Colitis was induced through 5 days of 2% dextran sulfate sodium (DSS). Disease activity index and intestinal barrier were assessed, as were fecal microbiota and metabolites. Results: Colitis symptoms were worse in mice with peripheral circadian disruption (cBMAL1KO). Specifically, the disease activity index and intestinal permeability were significantly higher in circadian-disrupted mice compared with control animals (TS4Cre) (P < .05). The worsening of colitis appears to be mediated, in part, through JAK (Janus kinase)-mediated STAT3 (signal transducer and activator of transcription 3), which was significantly elevated in circadian-disrupted (cBMAL1KO) mice treated with DSS (P < .05). Circadian-disrupted (cBMAL1KO) mice also had decreased SCFA metabolite concentrations and decreased relative abundances of SCFA-producing bacteria in their stool when compared with control animals (TS4Cre). Conclusions: Disruption of intestinal circadian rhythms in colonic epithelial cells promoted more severe colitis, increased inflammatory mediators (STAT3 [signal transducer and activator of transcription 3]), and decreased gut microbiota–derived SCFAs compared with DSS alone. Further investigation elucidating the molecular mechanisms behind these findings could provide novel circadian directed targets and strategies in the treatment of inflammatory bowel disease.

KW - circadian disruption

KW - metabolomics

KW - microbiota

KW - peripheral circadian disruption

KW - ulcerative colitis

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U2 - 10.1093/ibd/izac219

DO - 10.1093/ibd/izac219

M3 - Article

C2 - 36287037

AN - SCOPUS:85149187216

SN - 1078-0998

VL - 29

SP - 444

EP - 457

JO - Inflammatory bowel diseases

JF - Inflammatory bowel diseases

IS - 3

ER -

Colonic Epithelial Circadian Disruption Worsens Dextran Sulfate Sodium–Induced Colitis

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