Emerging data show that the gut and the gut microbiome play key roles in metabolic health. From glucose and lipid metabolism to fatty liver disease, obesity, and other conditions, intestinal immunity is an important modulator of both metabolic health and metabolic disease.
“Increased risk and severity of infection is often an overlooked complication of diabetes,” said Jonathan D. Schertzer, PhD, Assistant Professor of Biochemistry and Biomedical Sciences at the Farncombe Family Digestive Health Research Institute at McMaster University in Hamilton, Ontario. “It was not clear if obesity, glucose, or insulin provided the key link between diabetes and infection. We found that elevated blood glucose is sufficient to increase the severity of certain bacterial infections in the gut, at least in our mouse models. We can bring glucose levels back down and the increased severity goes away.”
Dr. Schertzer opened Friday’s cross-disciplinary symposium The Role of the Intestinal Immune System in Metabolic Disease. The session’s presenters discussed research that has dramatic implications for the treatment and prevention of diabetes complications.
Elevated blood glucose seen in diabetes triggers multiple pathogenic pathways. One of those pathways can lead to over-proliferation of stem cells in the gut, which disrupts the formation of the barrier wall that blocks intestinal pathogens. The defective barrier wall leaves the host more susceptible to infection and more likely to develop severe infection.
“We have also found that prior antibiotic use can increase risk for certain gut infections,” Dr. Schertzer said. “The elevated blood glucose seen in obesity and antibiotic use are both risk factors for increased infections and increased severity of infection. If you put those two together, they could synergize and elevate risk for severe outcomes even more.”
Antibiotic use has long been recognized as a risk factor for the development of Clostridium difficile (C. diff) infection in hospitalized patients.
“Antibiotics alter the gut microbiota, which alters the profile of bile acids present in the gut,” said Casey M. Theriot, PhD, Assistant Professor of Infectious Disease at the College of Veterinary Medicine at North Carolina State University. “Some of the most important bacterial derived metabolites in the gut are secondary bile acids. We think they create an environment that inhibits the growth of C. diff and the production of toxins. Antibiotics alter the microbiota, which alters secondary bile acids and changes the gut environment in ways that can favor C. diff.”
Fecal microbiota transplant is one way to restore a more normal gut microbiota. Dr. Theriot’s lab is engineering bacteria to do the job more precisely.
“Alterations to the microbial community influence bile acid metabolism and are associated with the development of obesity, metabolic syndrome, and diabetes,” he said. “We are designing Lactobacillus to rationally design the bile acid pool in the gut and throughout the body. Altering bile acids allows you to alter the gut microbiota and host signaling, which can modulate host physiology. There’s a lot of crosstalk between different gut bacteria, metabolites, and the host that we don’t understand yet, but we have the ability to shape host physiology by shaping the gut microbiota and bile acid metabolism.”
Peter A. Crawford, MD, PhD, is investigating how intestinal immunity affects liver fibrosis in the setting of non-alcoholic fatty liver disease (NAFLD), one of the important chronic complications of diabetes. At least 10 percent of patients with NAFLD progress to nonalcoholic steatohepatitis (NASH), which is emerging as a leading cause of cirrhosis, an indication for liver transplantation, and a leading cause of hepatocellular carcinoma.
“There’s a great deal of effort to uncover the signaling processes that drive this more aggressive form of NAFLD,” said Dr. Crawford, Director of the Cardiovascular Metabolism Program and Associate Professor of Internal Medicine at the Center for Metabolic Origins of Disease at the Sanford Burnham Prebys Medical Discover Institute. “We have found that disruption in the exchange of ketone bodies between hepatocytes and macrophages predisposes the liver to develop accelerated scar formation, or fibrosis.”
Cells typically metabolize glucose and lipids. When carbohydrates are in short supply, cells metabolize ketone bodies, which are a byproduct of lipid metabolism in the liver. What was not recognized, Dr. Crawford said, is that ketone bodies may also be important regulators of liver function.
“This exchange between macrophages and hepatocytes may be an important way of preserving and protecting individuals from progressing to more serious consequences of steatohepatitis,” he said. “Other proximate cell types, including stellate cells, which lay down the collagen seen in liver scarring, are also important to consider in this exchange of nutrients as signals. We need to understand how changes in this metabolic pathway might predict progression of NASH or be leveraged to protect from progression.”
Sean S. Davies, PhD, Associate Professor of Pharmacology at Vanderbilt University School of Medicine, is engineering a familiar probiotic, E. coli Nissle 1917, used to treat traveler’s diarrhea, to alter appetite, obesity, and metabolic consequences such as NAFLD and atherosclerosis. In LDL receptor knockout mice, bacteria modified to produce N-acyl-phosphatidylethanolamine have dramatic anti-inflammatory and pro-metabolic effects.
LDL receptor knockout mice model important aspects of fatty liver disease and atherosclerosis in humans, including steatohepatitis and the early stages of unstable atherosclerotic plaque formation.
“We see a dramatic decrease in liver triglycerides, which are the starting point for fatty liver disease,” Dr. Davies said. “We also see marked decreases in inflammation in the liver and reduced markers of fibrosis.
“In atherosclerosis, we see significantly less necrosis in lesions after treatment with our bacteria,” he continued. “It’s the necrotic lesions that in humans eventually rupture and cause myocardial infarctions. There are also increases in metabolic rate and in fatty acid oxidation in the liver. These bacteria are quite safe in mice, but we need more work to assure safety and better understand mechanisms before we can take them into humans.”