Research at The Kostic Lab is focused on understanding the metabolic symbiosis between humans and their gut microbiomes, and the leveraging of this knowledge to develop the next-generation of microbiome-based therapies for metabolic and immune diseases.
The Gut Microbiome & Exercise Capacity
Boosting exercise capacity by gut microbiome lactic acid fixation
The human gut microbiome encodes a vast metabolic repertoire with direct impacts on many aspects of host physiology. The Kostic Lab recently identified that lactate-utilizing bacteria are enriched in the gut microbiome of marathon runners, and that supplementation with lactate-utilizing bacteria can increase endurance exercise performance in a short-chain fatty acid dependent manner. In endurance exercise as glycogen stores become depleted and glucose is limiting, lactate from muscle can undergo gluconeogenesis in the liver to generate more glucose, but at a high energetic cost. Our research proposes an updated model in which muscle lactate becomes "fixed" by lactate-utilizing bacteria in the gut, which generate bioenergetic short-chain fatty acids free of cost to the host. Current research involves quantifying metabolic flux in this model as a function of microbiome composition and exercise quantity, and its potential therapeutic application to exercise resistance in type 1 and type 2 diabetes.
The Ancient Human Microbiome, Fiber, & Metabolic Health
Optimizing metabolism with the ancestral human gut microbiome
Members of the human gut microbiome have been observed to be vertically transmitted from mother to child, and there is evidence of co-speciation of gut microbes with primates. At the same time, the gut microbiome is malleable and can be reshaped by diet, immigration, and antibiotics. Identifying which gut microbes were part of human evolutionary history (or “ancestral”) and which have become lost may be instrumental in understanding human-microbiome relationships in health and disease. Our group has recently addressed this problem by reconstructing nearly 500 microbial genomes from eight paleofeces samples. These specimens are from different regions of North America and are 1000 to 2000 years old. Our work revealed that the ancient gut microbiome is much more similar to modern, non-industrialized people than industrialized people. In other words, these ancient microbiomes share features (i.e. species and genes) with the gut microbiomes of subsistence-farmers in Fiji, hunter-gatherers in Tanzania, and 2000-year-old Aztecs, and are conspicuously absent or very rare in modern Americans. Current research involves investigating the unique dietary fiber-utilizing capacity of the ancestral gut microbiome and its relevance to the obesity and diabetes epidemic, and the evolutionary histories of ancestral gut microbes.
Gut Microbiome-derived Extracellular Vesicles
Bacterial extracellular vesicles as a new modality for microbiome-host interaction
The gut microbiome is required to promote mucosal immune tolerance, intestinal barrier integrity, pancreatic beta-cell expansion and insulin secretion, among many other intestinal and extra-intestinal roles. How the microbiome mediates all these processes, being confined as it is to the lumen, is largely unknown. The Kostic Lab has recently demonstrated that extracellular vesicles (EVs) produced by members of the Bacteroidales are strong inducers of gut mucosal immune tolerance by regulating adenosine signaling. Bacterial EVs carry DNA, RNA, and protein cargo. It has recently been demonstrated that EVs from gut E. coli deliver functional molecules not only to intestinal cells, but also to the heart, liver, and brain. EVs from bacterial pathogens are relatively well-studied in their ability to deliver toxins and gene-silencing small RNAs that alter host cell function. Beyond facilitating natural microbiome influences on human physiology, microbiome EVs can be engineered to deliver targeted RNA and protein payloads in a highly regulatable manner.