Being overweight and obese significantly increases the risk of developing numerous diseases, including cardiovascular disease (CVD), type 2 diabetes (T2D), and certain cancers. The microbial community (microbiota) that resides within the gut play a notable role in obesity and its associated pathologies (e.g. CVD, T2D), and is therefore a potential therapeutic target. Diet is known to determine whether the gut microbiota contributions to host metabolism are beneficial or detrimental. A westernized diet high in fat and sugar is associated with systemic inflammation, while fat intake increases lipopolysaccharide translocation through the gut membrane. In addition, gut microbial metabolism of choline and L-carnitine can produce trimethylamine, which has been shown to contribute to atherosclerosis after being oxidized in the liver to trimethylamine N-oxide (TMAO). In contrast, diets high in dietary fiber from fruits, vegetables, and whole grains are inversely associated with inflammation and can potentially reverse effects of a high fat diet. Fermentable fiber types can resist host digestion, but are then subsequently fermented by the gut microbiota to short-chain fatty acids (SCFAs), which are known to have metabolic and immunologic benefits. Accordingly, both epidemiologic associations and human intervention trials suggest an inverse association between fiber intake, reduced systemic inflammation, and improved lipid and glucose metabolism; however, results remain inconsistent. These discrepancies might be partly attributable to (I) the low fiber doses used in most studies, and (II) the high degree of inter-individual variation in the response to fiber, which may stem from the individualized responses of the microbiome to fiber. The emerging evidence that fiber and the gut microbiota interact to influence host physiology warrant human clinical research that investigates the capacity of chemically distinct fibers to modulate host metabolism and inflammation, and the mechanistic role of the gut microbiota in their physiological effects.
Our long-term goal is to contribute to such a framework through clinical research that applies a holistic approach to examining the effect of fiber on both the host and its gut microbiota. We hypothesize that fibers show structure-dependent effects on inflammatory, metabolic, and hormonal markers of obesity-associated pathologies that can be predicted through compositional, functional, and genetic characteristics of an individual's fecal microbiome. We propose the following specific aims:
AIM 1. Perform a parallel-arm exploratory intervention study in overweight and mildly obese individuals to determine the impact of high doses of chemically distinct fibers on host inflammatory markers, measures of insulin sensitivity, and other clinical outcomes.
The effect of two physicochemically distinct fermentable dietary fibers (acacia gum and resistant starch type 4) on clinical markers of metabolic disease will be compared against a relatively non-fermentable dietary fiber (microcrystalline cellulose - control). We will employ a three-arm, parallel-design, single-blind, placebo-controlled, stratified randomized exploratory trial. Fibers will be administered in relative pure form daily over six weeks without any further lifestyle adjustments. Doses used in the trial will be 25 g/day of fiber for women and 35 g/day for men (close to Health Canada's dietary recommendations). Although, the first two days of treatment will use half the daily treatment dose of fiber (women: 12.5 g/day; men: 17.5 g/day), to ease the incorporation of the fiber into the diet. Participants will be advised on how to incorporate the fibers into their diet, as to improve tolerance and compliance.
The impact of dietary fiber on a comprehensive set of well-established obesity-related biomarkers will be determined via quantification at baseline and post-dietary intervention. High sensitive C-reactive protein and other inflammatory markers (e.g. interleukin-6, interleukin-10), as well as established markers for metabolic syndrome (e.g. fasting glucose and triglycerides) will constitute as key endpoints of the exploratory trial. To gain further understanding on the mechanisms that mediate metabolic and inflammatory improvements; five primary gut hormones, including satiety/hunger signaling hormones (e.g. glucagon-like peptide-1, leptin, and ghrelin), will be included. Lifestyle indicators, compliance with treatment, and satiation will be further assessed through self-administered questionnaires.
AIM 2. Evaluate the short- and long-term impacts of chemically distinct types of dietary fiber on gut microbiota composition, genetic characteristics, and production of anti-inflammatory (SCFA) and pathogenic (TMAO) metabolites.
We will utilize Illumina 16S rRNA sequencing and whole metagenomic sequencing to characterize the fecal microbiota (that will be enriched for large bowel bacteria) of our exploratory trial participants at weeks 0, 1, and 6, to explore fiber-induced changes in gut microbiota composition and gene content. These methods will be used as a majority of gut microbiota are not currently culturable. To further investigate gut microbiota function, we will quantify specific bacterial associated metabolites in plasma (TMAO) and in feces (SCFAs and bile acids). In parallel, we will quantify the fecal metabolites after in vitro fermentation, to account for absorption in the human gut. This will allow us to gain insight into fiber-induced changes in gut microbiota composition, metabolism, and functionality that coincide with the physiological effects observed in the host.
AIM 3. Characterize associations between clinical outcomes and microbiome shifts and determine how well individual microbiome configurations predict impacts of dietary fiber.
With the establishment of a robust human exploratory trial, a well-defined set of host phenotypes, and participant microbiome characteristics, Aim 3 will statistically integrate these data to specifically test for associations between diet, the gut microbiome, and host metabolism, and evaluate if microbiome and host phenotypic signatures at baseline can predict clinical outcomes of dietary fibers
