Walter Lab: Gut microbiome and its interactions with metabolic disease

Walter Laboratory: Gut microbiome, diet, and the host metabolome A relationship between metabolic syndrome (obesity, type 2 diabetes, etc.), the gut microbiota, and systemic inflammation has been implicated. Alterations of the gut microbiota have been associated with obesity, type 2 diabetes, and related metabolic diseases, and the mechanistic importance of the gut microbiota has been demonstrated in animal models of disease. Diet has the potential to induce compositional and functional changes in the human gut microbiota, and by doing so, improve host metabolism and immune functions. The long term goal of Jens Walter’s group is to study the potential of specifically designed diets that modulate the gut microbiome to induce metabolic and immunological improvements in humans and prevent metabolic disease. Inflammation, and Immunity: Junior investigator Dr. Daniel Peterson (Food Science) will test the hypothesis that dietary components contribute to aberrations of the homeostatic interactive relationship between the gut microbiota and the immune system resulting in the low grade inflammatory response that contributes to the pathogenesis of metabolic syndrome (i.e. obesity, inflammation, insulin resistance, type 2 diabetes and atherosclerosis).

Dietary modulation of the human gut microbiota with resistant starch (RS) Weeks Fibersym® RW induces intensive phylum level alterations to the human fecal microbiota, increasing levels of the phyla Bacteriodetes and Actinobacteria (e.g. bifidobacteria) while reducing the level of Firmicutes. Most importantly, these are community shifts that have been associated with lean human subjects that harbor a microbiome with a decreased capacity for energy harvest (Ley et al., 2006; Turnbaugh et al., 2009), weight loss (Nadel et al., 2009), and metabolic improvements in animal models of type 2 diabetes and hypercholesterolemia (Cani et al., 2007; Martínez et al., 2009) Martínez et al., In Press

RS4 induces compositional changes of the human gut microbiota that have been associated with benefits in host metabolism and energy balance ** * * ** ** Martínez et al., In Press Control RS4 ** ** Cani et al., 2007 Martínez et al., 2009 Ley et al., 2005; Turnbaugh et al., 2006

Can we prevent metabolic disease through a targeted modulation of the gut microbiome? One of the long term goals of the Walter Lab is to identify the links between dietary factors, the gut microbiome, and host metabolism in order that improved strategies can be developed to prevent disease. The findings on the modulation of the human fecal microbiota through resistant starches in our previous study clearly warrant an intervention study with the aims to assess the potential of RS to induce metabolic benefits in human subjects, and to provide mechanistic insights into the interrelationships between host metabolism and gut microbiome. I hypothesize that resistant starches, and especially RS4 (Fibersym® RW), as part of a dietary program for weight loss, will contribute to weight loss and improve both metabolic and immunological markers of the metabolic syndrome. I further hypothesize that these improvements are partially caused by a modulation of the metabolism of the gut microbiome. Specifically I propose: Perform a randomized, parallel-arm, controlled human trial to determine the impact of RS on weight loss in overweight individuals Characterize the impact of RS on gut microbiota composition, function (metagenome), and metabolism (SCFA) in these subjects Determine the impact of RS on metabolic markers of glucose and lipid metabolism and immunological markers of inflammation Correlate gut microbiota composition and function with metabolic and immunological markers to identify putative causative associations

Approach Design Randomized, parallel-arm, controlled trial with free-living, overweight to obese adults (N~200, BMI=25-45) Intervention A daily does of 30 gram resistant starch (Fibersym® RW, included in 100 gram crackers) or native starch (as control) as part of a reduced energy diet program (-500 kcal/day deficit) that encourages limiting consumption of food high in energy and fat and portion control. Main outcome measures Fecal microbiome analysis: Composition (by 454 sequencing of 16S rRNA tags), function (whole metagenome 454 sequencing), and metabolism (SCFA analysis). Human subjects: Weight, waist circumference, blood pressure, GI symptoms, and Bristol stool scale. Blood samples: Total cholesterol, HDL and LDL cholesterol, fasting plasma lipid profiles, fasting glucose and insulin, hs-crp, inflammatory cytokines.

Experimental design Weeks -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 Recruitment Run-in Treatment Semi weekly visit to lab. Food will be provided and compliance will be assessed. Subjects will be surveyed to address overall well being, weight, waist circumference, body fat, blood pressure, GI symptoms, and Bristol stool scale. Visit to lab for blood sample and delivery of fecal sample. Visit to lab during which 3-d diet records will be prepared.

Challenges Where to do human trial? UNL? Collaborator at K-state? (Jens Walter has several projects with Dr. Mark Haub, Department of Human Nutrition, K-state) Clinical research service center? (Is probably to expensive) Suggested infrastructure at UNL: Metabolic core facility with trained staff (Nurse, Research Dietitian).