Ultra-processed food consumption, gut microbiota, and glucose homeostasis in mid-life adults

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Project Summary Advancing age is associated with gut dysbiosis, low-grade chronic inflammation, progressive insulin resistance, and increased risk of type 2 diabetes (T2D). Prediabetes is present in 45-50% of middle-aged/older adults, and declines in glucose tolerance are evident in the third or fourth decade of life. Thus, there is an urgent need to identify new approaches for the prevention of type 2 diabetes among middle-aged adults. Observational research has linked intake of ultra-processed foods (UPF), which comprise ~60% of total energy intake in US adults, with increased risk of T2D. Ex vivo and animal research suggests that components of UPF alter gut microbiota composition and initiate a cascade of events leading to intestinal inflammation and impaired glycemic control. Whether mid-life adults (aged 45-65 yrs) are susceptible to the adverse impact of UPF consumption on glucose homeostasis is unknown. The overall objective of this R21 proposal is to establish proof-of-concept for an impairment in glucose homeostasis following increases in UPF consumption in mid-life adults, in order to conduct a larger, more comprehensive and mechanistic trial in the future. In addition, we will investigate changes in gut microbial composition and function, intestinal inflammation and permeability, serum endotoxin concentrations, and inflammatory cytokines as potential mechanisms by which UPF consumption influences glucose homeostasis. To this end, following a two- week eucaloric lead-in diet, 42 healthy mid-life adults (45-65 yrs) will be randomly assigned to either a 6-week diet emphasizing UPF or minimally processed foods (no UPF). Participants will be fed a eucaloric diet (50% carbohydrate, 35% fat,15% protein) matched for dietary soluble and insoluble fiber, added sugar, mono- and polyunsaturated fat, saturated fat, antioxidant nutrients, sodium, pre- and probiotics, and overall diet quality, for the duration of the study to avoid potential confounds of weight change and other dietary factors which may influence study outcomes. Measurements of insulin sensitivity and beta cell function via IVGTT, 24-hr and postprandial glycemic control using continuous glucose monitoring (CGM), gut microbiota composition/function, fecal short chain fatty acids (SCFA), intestinal inflammation, intestinal permeability, serum endotoxin, and inflammatory cytokines will be made before and following the 6-week high UPF or no UPF diet period. This innovative study may contribute importantly to an emerging integrative physiological understanding of the adverse effects of UPF consumption in an understudied population, mid-life adults. Our proposal is responsive to PA-18-850 Prevention Research in Mid- life Adults, specifically the focus on “how age-related perturbations in the microbiome” may predispose mid-life adults to chronic disease. This research may also have clinical and public health impact by informing US dietary and T2D prevention and treatment guidelines which do not currently address total UPF consumption or older adults due to a lack of rigorously designed controlled trials.