The intestinal tract is inhabited by a large diverse community of microbes 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 benefits to the host, especially in terms of energy harvest, pathogen exclusion, and promotion of immune development. In contrast, disturbance of the microbiota-host relationship can drive chronic gut inflammation that can promote an array of chronic inflammatory diseases including metabolic syndrome. While host genetics are an important determinant of the host-microbiota relationship, the dramatic increase in incidence of numerous chronic inflammatory diseases, including inflammatory bowel disease (IBD) and metabolic syndrome over the last 60 years amidst relatively constant genetics, highlights the importance of understanding how non-genetic factors such as diet might alter the microbiota-host relationship to promote gut inflammation. Consequently, we and others have focused on how differences in macronutrient consumption influence the microbiota. However, dietary patterns can also be characterized by constituents other than macro and micronutrients. Post-mid-20th century dietary changes include consumption of an array of synthetic compounds that are added to many processed foods. The biologic effect of these food additives are not well described, particularly their potential to influence microbiota composition and/or its interaction with the host. One particularly disconcerting class of compounds are synthetic dietary emulsifiers including polysorbate 80 (P80) and carboxymethylcellulose (CMC). These detergent-like compounds, which are incorporated into a variety of processed foods, are not well-absorbed, thus allowing them to interact with the microbiota and gut mucosa. We have recently shown that, in mice, consumption of P80 and CMC, alters microbiota composition, pro- inflammatory potential and promotes microbiota encroachment into the colonic mucosa, low-grade inflammation, and metabolic syndrome 1. However, it is not known whether these compounds have similar effects in humans. Hence, addressing this critically important question is the central goal of this multi-PI Pilot and Feasibility Clinical/Translational research proposal. Our initial focus will be on CMC, which, despite never being tested in humans and not widely studied in animals, is generally regarded as safe (GRAS) by the US FDA, allowing it to be widely and unrestrictedly used in a broad variety of processed foods. Specifically, we will: 1) Establish a tractable and physiologic means of administering and measuring CMC consumption in healthy volunteers. 2) Examine extent to which CMC consumption impacts human gut microbiota composition, gene expression, and/or localization. 3) Explore effects of CMC consumption on a range of inflammatory and metabolic parameters that characterize metabolic syndrome. Such experiments will establish feasibility of performing a larger trial that might allow our discoveries made in mouse studies to translate into knowledge that can improve human digestive and metabolic health. !

Public Health Relevance

) Research performed in mice indicates that a class of food additives, namely synthetic dietary emulsifiers, alter the gut microbiota in a manner that promotes intestinal inflammation, and such inflammation can manifest as inflammatory bowel disease (IBD), but more commonly lacks the form of low-grade inflammation that associates with metabolic syndrome. However, the extent to which these observations are applicable to humans is not known but, rather, will be addressed by this proposal. The answer to this question will impact upon the understanding of a range of human diseases associated with, and driven by, inflammation, including IBD, obesity, type 2 diabetes and cancer.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Hamilton, Frank A
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Georgia State University
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United States
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