Wendy S. Garrett
The Mucosal Immune System and Gut Microbiota
Our experimental questions are grounded in understanding how interactions between intestinal microbial communities and the immune system contribute to the pathophysiology of both inflammatory bowel disease and colorectal cancer.
Gut Microbiota in Disease
Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract and it afflicts 1.5 million people in the US. While alterations in the intestinal microbiota have been described in patients with inflammatory bowel disease (IBD), it has been difficult to identify specific species or consortia that instigate or perpetuate IBD. Our studies in mouse models have provided us with insight into how select species can work in concert with the gut microbiota to induce spontaneous intestinal inflammation. Recent work from our group has identified bacterial taxa that are not only over-enriched and appear to drive inflammation in our model but also taxa that are under-enriched or deficient. We are determining the stimuli and sensing pathways linking these microbes to inflammation and unraveling how these microbial consortia instigate and perpetuate chronic colitis. Collaboratively with physicians and scientists that treat and study human IBD, we are interrogating the role of IBD patient gut microbes in disease pathogenesis using mouse models.
Colorectal cancer is the second leading cause of cancer-related death in the US and the gut microbiota plays an important role in colorectal cancer. In mouse models, select species have been identified that drive inflammation and promote carcinogenesis. In human populations, select taxa within the fecal microbiota have been identified that are enriched in patients with adenomas and carcinomas. We are characterizing the microbes present within colorectal tumors and in the colonic lumen to define microbial contributions to carcinogenesis. The altered vasculature, patterns of immune cell infiltration, metabolic requirements, and altered cell surface protein glycosylation of colon cancers present a distinctive ecologic niche for microbes. Using mouse models of colorectal cancer and collaboratively studying human colorectal cancers, we are investigating microbial communities associated with colorectal cancer. We aim to understand both how microbes promote carcinogenesis and also what tumor-specific factors create a niche that is permissive for some but not all microbes. Our ultimate goal is to leverage our understanding of tumors and their microbes to design microbiota-based therapeutics for colorectal cancer.
Myeloid cells in IBD and Colorectal CancerMyeloid cells encompass dendritic cells, macrophages, and neutrophils. A common feature of myeloid subsets is that their functional fate is strongly influenced by their local tissue environment. At mucosal sites, the microbiota constitute an important part of the environment for these cells. Myelomonocytic cell populations can play crucial roles in chronic inflammation in IBD and colorectal cancer. Monocytes can drive proliferation of malignant cells, angiogenesis, and stromal remodeling; subvert adaptive immune responses; promote metastasis; and are thus an important therapeutic target in cancer treatment. Gut microbial communities can influence monocyte population dynamics and monocytes can drive neoplastic inflammation. To understand these interactions, we are investigating monocyte subsets, their functions, and responses to the microbiota in colitis and in evolving colorectal tumors.
Diet, the Gut Microbiota, and Disease
We are studying the effects of dietary interventions such as fermented dairy products and risk-associated foods like red meat on the microbiota in the context of colitis and colon cancer. Fermented dairy products often contain so called beneficial microbes and we are investigating how such foods and their bacteria interact and modulate immune and gut microbiota function. In contrast, compelling epidemiologic data has linked a high intake of red meat with colorectal cancer. Complementary to work aimed at understanding the role of gut microbes in colonic carcinogenesis, we are interested in understanding how the gut microbiota may mediate the neoplastic effects of red meat intake. Our laboratory employs mouse models where we can manipulate genetic and environmental factors that complicate human studies of the microbiota and diet. In addition, we make use of mice where we can design their gut microbial communities by first generating and breeding mice without any microbes and then adding back select microbes. These so-called germ-free mice can also be transplanted with human fecal samples to begin to unravel associations observed between human microbial communities, diet, and diseases like colorectal cancer and IBD.
Reciprocal Interactions between the Gut Microbiota and Immune System
The dependence of mucosal and systemic immune system development on gut microbes has been noted for over 50 years, since the development of germ-free animal models. Recent studies by several groups have determined that select bacterial species influence the development of adaptive immune cell subsets, in particular gut T cell subsets. As a result of our interest in myeloid cells and the dendritic cell phenotypes in the mouse models of colitis we study, we are focused on understanding microbiota-based cues for myeloid subset development and function in the colon. We are also particularly interested in understanding how host immunity shapes the gut microbiota. We are actively investigating how microbial communities sense and respond to pro- and anti-inflammatory factors produced by adaptive and innate immune cells.