Obesity is associated with insulin resistance and chronic inflammation in adipose tissue, muscle and liver and the mechanisms underlying this inflammation is not well understood. Endotoxin (lipopolysaccharide, LPS) is carried on gut-derived lipoproteins (chylomicrons) and provides a link between dietary fat and inflammation. During chylomicrons assembly, LPS and LPS binding protein (LBP) are attached to the particle. Plasma LPS in the chylomicron fraction transiently increases following a fatty meal. Chylomicron triglyceride is cleared from plasma by adipose and muscle lipoprotein lipase (LpL);remnant lipoproteins are then cleared by the liver. Strong associations between insulin resistance/diabetes and plasma LPS have been found. Further links between gut bacteria and insulin resistance are illustrated by many experiments in germ-free mice or in mice with microbiota transplants, which show changes in diet-induced obesity and insulin resistance. We hypothesize that the LPS on chylomicrons is delivered to adipose tissue, muscle and liver during chylomicron TG lipolysis, and the released LPS initiates a low-grade inflammatory reaction in these tissues that contributes to tissue inflammation and insulin resistance. A slow process of chylomicron lipolysis, with persistent remnant lipoproteinemia, may be associated with high exposure to LPS and consequent tissue inflammation. There is already an extensive literature in rodents demonstrating alterations in obesity, inflammation and insulin resistance with various immune modulations or manipulations of microbiota. These questions have not been well tested in humans. This study is intended to determine whether alteration of gut microbiota can impact human lipoprotein associated LPS and insulin resistance.
Specific Aim 1. We will determine whether an alteration in the gut microbiota achieved with rifaximin will decrease circulating LPS. We will measure plasma LPS both in the fasting state and after a lipid-rich meal in obese MetS subjects. The subjects will then be treated with the antibiotic rifaximin for 8 weeks to substantially reduce gut bacteria, which can be detected by current techniques.
Specific Aim 2. We will determine whether a change in the gut microbiota from rifaximin treatment will decrease adipose inflammation and improve insulin resistance. Subjects will undergo a baseline fat biopsy and a euglycemic clamp to measure peripheral and hepatic insulin sensitivity. They will then be treated with rifaximin and the insulin sensitivity testing ad biopsies will be repeated to determine if disruption of the microbiota reduces tissue inflammation and improves insulin sensitivity.
Obesity is closely linked with insulin resistance and diabetes and current research suggests that inflammation of fat plays a causal role in insulin resistance. Dietary fat causes an increase in plasma lipopolysaccharide, which circulates bound to lipoproteins, and we hypothesize that the LPS is transported to tissues and is responsible for much of the tissue inflammation associated with insulin resistance.