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The impact of dietary fat and exercise on intestinal homeostasis: a quest for anti-inflammatory mechanisms

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Title
The impact of dietary fat and exercise on intestinal homeostasis: a quest for anti-inflammatory mechanisms
Name (type = personal)
NamePart (type = family)
Wisniewski
NamePart (type = given)
Paul
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Wisniewski, Paul.
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author
Name (type = personal)
NamePart (type = family)
Campbell
NamePart (type = given)
Sara C.
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Sara C. Campbell
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
chair
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
NamePart
School of Graduate Studies
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RoleTerm (authority = RULIB)
school
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Text
Genre (authority = marcgt)
theses
OriginInfo
DateCreated (encoding = w3cdtf); (keyDate = yes); (qualifier = exact)
2020
DateOther (encoding = w3cdtf); (qualifier = exact); (type = degree)
2020-05
Language
LanguageTerm (authority = ISO 639-3:2007); (type = text)
English
Abstract (type = abstract)
Excess consumption of saturated fat has shown to increase risk of colorectal cancer (CRC) development as well exacerbate inflammatory bowel disease (IBD) progression. In contrast, physical exercise has shown to significantly reduce the risk of CRC development and ameliorate symptoms of IBD. Although exercise has shown to exert profound anti-inflammatory effects in the colon, what is not well known are the exact mechanisms by which these health benefits are conferred. Of note are three primary processes that have been implicated in modulating intestinal inflammatory responses in the context of large bowel disorders. These include the production of intestinal mucus, the induction of the unfolded protein response (UPR) in the advent of endoplasmic reticulum (ER) stress, and the activation of inflammasomes which foster a microbe-host mutualism. The impact of dietary fat intake and physical activity on mucus thickness, the UPR and inflammasome activation where explored to elucidate putative mechanisms by which diet and exercise promote or disrupt intestinal homeostasis. In aim 1, we examined the extent to which 12 weeks of a 45% high-fat diet (HFD) contributes to colon inflammation and microbiota localization and whether voluntary wheel running could confer a therapeutic effect in 6-week-old male and female C57BL/6NTac mice. Voluntary wheel running attenuated HFD-induced colon inflammation in female mice only while no differences in microbiota localization were observed between treatment groups. In addition, sedentary male mice consuming a control low 10% fat diet demonstrated a greater degree of inflammation compared to their female counterparts. These findings demonstrate that 12 weeks of a 45% HFD is not sufficient to induce any structural changes to intestinal mucus but have shown that regular physical activity can ameliorate colon inflammation. In aim 2, we replicated aim 1 in a second cohort of 6-week-old male and female C57BL/6NTac mice using a 60% HFD in order to accelerate the occurrence of overt colon pathologies and to compare our findings from aim 1. In addition, we explored the effects of dietary fat and voluntary wheel running on colonic epithelial ER stress and the UPR. In contrast to aim 1, voluntary wheel running attenuated HFD-induced colon inflammation in both male and female mice. In agreement with aim 1, a similar increase in inflammation in sedentary male mice fed a control 10% fat diet was observed. Female mice demonstrated an inherent increase in colon IL-10 concentrations, an improved proliferative phenotype and an increase in goblet cell density compared to males. Voluntary wheel running contributed to a significantly improved proliferative phenotype compared to exercised mice. Sedentary and exercised male mice consuming a 60% HFD exhibited a unique compensatory response characterized by an increase in inner mucus layer thickness and mucin 2 production. While a 60% HFD modulated the gene expression of ER stress sensors activating transcription factor 6 (Atf6) and inositol-requiring kinase 1β (IRE1β) in female mice, a 60% HFD increased the phosphorylation of eukaryotic initiating factor-2α (eIF2α) in male mice which was attenuated by a control 10% fat diet and voluntary wheel running. Findings from this aim further corroborate the efficacy of exercise in contributing to colon health and suggests that females may possess an inherent resistance against the development of colon pathologies. In addition, we are the first to demonstrate that voluntary wheel running attenuates HFD-induced colonic epithelial ER stress in male mice. Utilizing the same cohort of animals from aim 2, aim 3 investigated the contribution of dietary fat and voluntary wheel running towards the transcription of inflammasome components and activation of caspase-1. Large increases in the gene expression of inflammasome components including the NOD-like receptor family pyrin domain containing (NLRP)3 and NLRP6 sensors, the adaptor PYD and CARD domain containing (Pycard), and caspase-1 where observed in sedentary female mice fed an HFD and in exercised female mice fed either diet relative to the sedentary control fed a 10% fat diet. This occurred in tandem with a non-significant increase in caspase-1 activation. In males, a non-significant and modest decrease in caspase-1 activation was observed, however. These findings illustrate putative sex differences in inflammasome activation in response to dietary fat and voluntary wheel running, but more rigorous analyses are required.
Subject (authority = RUETD)
Topic
Kinesiology and Applied Physiology
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Title
Rutgers University Electronic Theses and Dissertations
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ETD
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ETD_10587
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application/pdf
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text/xml
Extent
1 online resource (xv, 127 pages)
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
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School of Graduate Studies Electronic Theses and Dissertations
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rucore10001600001
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Identifier (type = doi)
doi:10.7282/t3-wyq9-jq41
Genre (authority = ExL-Esploro)
ETD doctoral
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RightsDeclaration (ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Wisniewski
GivenName
Paul
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2020-02-16 13:19:35
AssociatedEntity
Name
Paul Wisniewski
Role
Copyright holder
Affiliation
Rutgers University. School of Graduate Studies
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Author Agreement License
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I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
RightsEvent
Type
Embargo
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2020-05-31
DateTime (encoding = w3cdtf); (qualifier = exact); (point = end)
2021-05-31
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after May 31st, 2021.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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2020-02-25T15:32:04
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2020-02-25T15:32:04
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