Metabolic Syndrome and Obesity

Gut microbiota is an integral part of the human digestive system and can play important roles in all aspects of energy metabolism, including:

• • Energy intake, i.e., appetite and eating behavior
  • Energy harvest – microbiota help to digest food, especially complex polysaccharides, and generate consumable calories as short chain fatty acids acetate, propionate, and butyrate
  • Energy expenditure, i.e., regulation of metabolic rate
  • Energy distribution and storage, e.g., regulation of body adiposity

Anatomically, humans are hindgut fermenters. That means that the upper digestive tract, which is composed of stomach, pancreas, liver, and small bowel carries out digestion and absorption of most nutrients. After that, undigested remnants, primarily complex polysaccharides, are fermented by the commensal microbes in the large intestine. Many end-products of microbial metabolism in the colon can interact directly with the host. Receptors for short-chain fatty acids (GPR40, GPR41, GPR43, GRP120) are expressed throughout the body, including intestinal, muscle, fat, immune, and nerve cells.

Over the past century the function of microbiota in the large intestine has been altered significantly by changes in diet and widespread use of antibiotics. Energy rich, processed foods are largely digested and absorbed in the small intestine, leaving fewer nutrients for the microbiota in the large intestine. Antibiotic usage in medicine and farming practices may have directly altered microbial community composition in our population. Studies of fecal microbiota in ancestral communities, e.g., Native Americans in the Amazon and certain African tribes, show significantly higher diversity of microorganisms compared to those found in individuals from Western cities. The metabolic capacity of ancestral microbiota to produce short chain fatty acids is significantly greater. Moreover, microbiota of obese individuals in the Western countries is characterized by lower microbial diversity than that of their lean counterparts, and lower ability to produce short chain fatty acids.

Our hypothesis is that beneficial effects of high fiber diet can be optimized by having the right microbiota that is diverse and highly capable to ferment complex carbohydrates to short chain fatty acids. We will be testing this hypothesis with an interventional trial that will involve a combination of optimized diet and fecal microbiota transplantation. Multiple investigators from different colleges and departments across the University (Medical School, BioTechnology Institute, College of Food and Nutrition) are participating in this project, which is supported by MnDRIVE Transdisciplinary Research Program. In addition, we are conducting microbiota research in collaboration with our colleagues in Bariatric Surgery to understand the contribution of microbial metabolism to outcomes of obesity surgery and our colleagues in the Department of Psychiatry to understand how gut microbiota can affect eating behavior.

Figure 1

Hypothesis for the Bio-Remediation Trial using FMT and Controlled Diet to benefit energy metabolism in pre-diabetic individuals.

Optimal production of short chain fatty acids, which can improve handling of glucose by the human body, depends on the right diet and the right microbiota. Greater production of short chain fatty acids by microbiota can strengthen the gut barrier, lower inflammation, increase intestinal gluconeogenesis, decrease liver glucose production, and change appetite. These beneficial changes can result in improved insulin sensitivity and lower circulating levels of glucose.