The intestinal tract is inhabited by a large diverse community of bacteria collectively referred to as the gut microbiota. When maintained in a stable manner, at an appropriately safe distance from gut epithelial cells, the microbiota provides a benefit to the host, especially in terms of energy harvest, pathogen exclusion, and promotion of immune development. However, research performed under this grant has led to us hypothesize that disturbance of the microbiota-host relationship, promoted by genetic and non-genetic factors, can drive chronic gut inflammation that can manifest as inflammatory bowel disease (IBD) or metabolic syndrome. The recently completed grant whose funding this application seeks to reinstate, has largely focused on understanding how a genetic innate immune deficiency can result in chronic gut inflammation. Yet, the dramatic increase in incidence of numerous chronic inflammatory diseases, including IBD and metabolic syndrome over the last 60 years amidst relatively constant genetics highlights the importance of understanding mechanisms by which non-genetic factors might alter the microbiota-host relationship to promote gut inflammation. Hence, the goal of this renewal application is to investigate disturbance of the microbiota-host relationship by a ubiquitous class of food additives, namely emulsifiers, whose penetrance in the world's food supply roughly parallel's increases in chronic inflammatory diseases. Our focus on emulsifiers is based on the notion that these detergent-like molecules have been suggested to promote bacterial translocation across gut mucosa and, moreover, our recent findings that, in mice, administration of 2 common synthetic emulsifiers, namely polysorbate 80 (P80) and carboxymethylcellulose (CMC), via diet, at concentrations below that which they are approved for use in processed foods, promote colitis in mice with a genetically predisposed to this disorder (IL-10-/- and TLR5-/-) and, moreover, drive metabolic syndrome in 2 distinct WT mouse strains (C57BL/6 and Swiss-Webster). Such emulsifier-induced metabolic syndrome requires the presence of a microbiota in that neither P80 nor CMC promote low-grade inflammation or metabolic syndrome in germfree mice. While human studies (that we will propose elsewhere) will ultimately be required to define the role of emulsifiers in driving the increased incidence of IBD and metabolic syndrome, we submit that understanding mechanisms by which emulsifiers promote inflammatory diseases in our model systems can guide such studies and, moreover, broadly enhance our understanding of fundamental mechanisms by which any factor that disturbs the microbiota-gut relationship can promote chronic inflammatory diseases. Hence, this proposal seeks to investigate our hypothesis that emulsifiers promote pathobiont penetration through the mucus layer thus inducing inflammation that changes microbiota composition to further drive inflammation and its consequences.

Public Health Relevance

Humanity is facing an epidemic of chronic inflammatory diseases of the gut, including 'classic' inflammatory diseases such as inflammatory bowel disease and the cluster of very common metabolic diseases collectively referred to as metabolic syndrome, the hallmarks of which include obesity, insulin resistance, hyperglycemia, hyperlipidemia, and hepatic steatosis. Metabolic syndrome greatly increases risk of developing diabetes, cardiovascular disease, and liver dysfunction. The severe impact of IBD on the life of young persons and the high incidence of metabolic syndrome and its highly morbid, chronic, and very costly downstream diseases threaten to overwhelm the world's healthcare systems and economies thus making it an enormous public health problem in dire need of reckoning. This proposal seeks to investigate mechanisms by which alterations in the gut microbiota might promote metabolic syndrome. Specifically, it examines how a common component of processed foods, namely emulsifiers, can disturb the microbiota-gut relationship and drive inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK083890-09
Application #
9547380
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Perrin, Peter J
Project Start
2009-04-01
Project End
2019-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
9
Fiscal Year
2018
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
Singh, Vishal; Yeoh, Beng San; Chassaing, Benoit et al. (2018) Dysregulated Microbial Fermentation of Soluble Fiber Induces Cholestatic Liver Cancer. Cell 175:679-694.e22
Fields, Christopher T; Chassaing, Benoit; Paul, Matthew J et al. (2018) Vasopressin deletion is associated with sex-specific shifts in the gut microbiome. Gut Microbes 9:13-25
Etienne-Mesmin, Lucie; Chassaing, Benoit; Adekunle, Oluwaseyi et al. (2018) Toxin-positive Clostridium difficile latently infect mouse colonies and protect against highly pathogenic C. difficile. Gut 67:860-871
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
Fields, Christopher T; Chassaing, Benoit; Castillo-Ruiz, Alexandra et al. (2018) Effects of gut-derived endotoxin on anxiety-like and repetitive behaviors in male and female mice. Biol Sex Differ 9:7
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

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