Humanity is facing an epidemic of interrelated obesity-associated disorders collectively referred to as metabolic syndrome (Met Syn). Central features of Met Syn include insulin-resistance, hyperlipidemia, hepatic steatosis and hypertension, all of which can progress to highly morbid and costly diseases such as diabetes, cardiovascular disease, and liver failure. Met Syn is associated with systemic chronic low-grade inflammation (LGI). LGI is not merely a marker of Met Syn but, rather, LGI interferes with a panoply of metabolic signaling pathways, including insulin and leptin signaling, such that chronic LGI promotes Met Syn. Thus, better understanding of the underlying causes of LGI is germane to managing the Met Syn epidemic. Proposed causes of LGI include the notion that obesity itself leads to lipid overload, resulting in endoplasmic reticulum stress that induces the pro-inflammatory gene expression that defines LGI. However, the grant this application seeks to renew has shown that LGI, and subsequently Met Syn, can also originate from poor management of gut microbiota, which is, in fact, required for many aspects of Met Syn. While our hypothesis that alterations in microbiota promote LGI/Met Syn originated from study of mice with a genetically engineered innate immune deficiency, namely lack of the flagellin receptor toll-like receptor 5 (TLR5) it has since proven applicable to understanding how diet, particularly industrialization of the food supply, might be altering the microbiota-host relationship in a manner that promotes LGI and, subsequently, Met Syn. Indeed, we?ve found that a central feature of Met Syn in both mice and humans, is infiltration of bacteria into the normally near-sterile inner mucus layer. Such microbiota encroachment can activate pro-inflammatory signaling in the intestine and/or result in translocation of bacteria, and their products, into liver and adipose tissue thus driving LGI in these organs. In contrast, obese humans lacking microbiota encroachment also lacked Met Syn . Moreover, in mice, ablation of microbiota via antibiotics, germfree status, or maintaining gnotobiotic mice with the pathobiont-free microbiome, results in a seemingly analogous state of ?healthy obesity? in response to a western-style diet (WSD). Together, these results underscore our central hypothesis that microbiota encroachment is a pivotal event in driving LGI and, subsequently Met Syn. This hypothesis holds that preventing or reversing microbiota encroachment will ameliorate Met Syn. Hence, we will propose to identify encroaching bacteria (Aim 1) and define how they drive LGI and impact metabolism (Aim 2). Furthermore, we will develop means to train the immune system to reduce microbiota encroachment and ameliorate Met Syn (Aim 3).

Public Health Relevance

Humanity is facing an epidemic of interrelated obesity-associated metabolic disorders including insulin resistance, hyperglycemia, hyperlipidemia, and hepatic steatosis, collectively referred to as metabolic syndrome (Met Syn). Estimates for incidence of Met Syn range from 50-80 million Americans, many of whom will develop morbid diseases including type 2 diabetes, cardiovascular disease, and liver failure. This project seeks to better understand mechanisms that drive Met Syn thus paving the way to develop novel means to combat this public health emergency.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK099071-08A1
Application #
10151289
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Shea-Donohue, Terez
Project Start
2013-08-01
Project End
2024-11-30
Budget Start
2021-01-04
Budget End
2021-11-30
Support Year
8
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Georgia State University
Department
Miscellaneous
Type
Organized Research Units
DUNS #
837322494
City
Atlanta
State
GA
Country
United States
Zip Code
30302
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Zou, Jun; Chassaing, Benoit; Singh, Vishal et al. (2018) Fiber-Mediated Nourishment of Gut Microbiota Protects against Diet-Induced Obesity by Restoring IL-22-Mediated Colonic Health. Cell Host Microbe 23:41-53.e4
Chassaing, Benoit; Van de Wiele, Tom; De Bodt, Jana et al. (2017) Dietary emulsifiers directly alter human microbiota composition and gene expression ex vivo potentiating intestinal inflammation. Gut 66:1414-1427
Etienne-Mesmin, Lucie; Chassaing, Benoit; Gewirtz, Andrew T (2017) Tryptophan: A gut microbiota-derived metabolites regulating inflammation. World J Gastrointest Pharmacol Ther 8:7-9
Viennois, Emilie; Merlin, Didier; Gewirtz, Andrew T et al. (2017) Dietary Emulsifier-Induced Low-Grade Inflammation Promotes Colon Carcinogenesis. Cancer Res 77:27-40
Etienne-Mesmin, Lucie; Chassaing, Benoit; Adekunle, Oluwaseyi et al. (2017) Genome Sequence of a Toxin-PositiveClostridium difficileStrain Isolated from Murine Feces. Genome Announc 5:
Chassaing, Benoit; Vijay-Kumar, Matam; Gewirtz, Andrew T (2017) How diet can impact gut microbiota to promote or endanger health. Curr Opin Gastroenterol 33:417-421
Zhang, Benyue; Oyewole-Said, Damilola; Zou, Jun et al. (2017) TLR5 signaling in murine bone marrow induces hematopoietic progenitor cell proliferation and aids survival from radiation. Blood Adv 1:1796-1806
Chassaing, Benoit; Raja, Shreya M; Lewis, James D et al. (2017) Colonic Microbiota Encroachment Correlates With Dysglycemia in Humans. Cell Mol Gastroenterol Hepatol 4:205-221
Miles, Jennifer P; Zou, Jun; Kumar, Matam-Vijay et al. (2017) Supplementation of Low- and High-fat Diets with Fermentable Fiber Exacerbates Severity of DSS-induced Acute Colitis. Inflamm Bowel Dis 23:1133-1143

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