Chenthamarakshan Vasu, Ph.D.

Professor
Department: Microbiology & Immunology
Programs: Cellular Injury, Inflammation, Fibrosis, End Organ Disease

 

 

Research Interests:

The major research focus of Dr. Vasu’s laboratory is understanding the impact of gut mucosa-microbiota-dietary factor interactions on various inflammatory and autoimmune clinical conditions, including colitis, type 1 diabetes (T1D), and systemic lupus erythematosus (SLE). A series of gene knockout, specific pathogen-free (SPF), and germ-free (GF) mice are being used to investigate these questions.

Unhealthy changes in the gut microbiota can contribute to the pathogenesis of many diseases. Dr. Vau’s lab has reported that priming the gut by complex polysaccharide-shaped microbiota prior to clinical disease onset can profoundly suppress autoimmune and colitis severities. Accumulating evidence suggests that microbes and their metabolites critically modulate the pathophysiology of various diseases. However, the vast majority of microbial metabolites including those resulting from microbiota-diet interaction remain unknown and/or uncharacterized. Non-digestible, microbiota-accessible carbohydrates (MACs) including beta-glucans are thought to have major impact on microbiota composition and function. To fully explain the mechanisms associated with the host benefits of beta-glucan and other MAC-shaped microbiota and to develop nutraceutical approaches, it is important to identify metabolites generated from these polysaccharides and characterize their functional impacts. The project, DK136094, is involved in discovering novel BG and other MAC degradation-associated novel microbial metabolites. This project is focused on i) determining whether MAC degradation by human fecal microbiota produces distinct metabolite profiles and ii) identifying novel microbial metabolites of this process and characterizing their functions. Further, it is postulated that fecal microbes from autoimmune type 1 diabetes and systemic lupus erythematosus patients produce pro-inflammatory metabolites and that these inform whether the MAC-degradation process skews this pro-inflammatory metabolite profile to an immune regulatory phenotype. These studies are expected to demonstrate whether microbial fermentation of MACs generates metabolites with therapeutic value and could enhance gut health and prevent and/or treat immune-mediated disorders.

In a separate project, using preclinical models of lupus, Dr. Vasu’s lab has determined that pro-inflammatory events and gut permeability are initiated in the gut mucosa at juvenile age, long before the onset of systemic autoimmunity. Higher expression of X-linked TLR genes (Tlr7 and Tlr8) in intestinal epithelial and immune cells of lupus-prone females in the juvenile age induces profoundly high expression of inflammatory factors, leading to gut inflammation and permeability. Hence, this project is currently defining the requirement of TLR7 and TLR8 in gut inflammation and lupus autoimmunity and determining the requirement of interaction with microbiota for, and the role of X-linked TLR activation in, juvenile-onset gut inflammation. This study also elucidates the role of TLR7/8-gut microbiota interaction in initiating autoantibody production in the gut mucosal and systemic compartments using a series of gene knockout, germ-free, and conventional mouse models and clinical samples. Fecal IgA abundance and the degree of their nuclear antigen reactivity in lupus-prone mice and lupus-prone subjects correlate with the timing of eventual clinical disease onset and/or disease severity. This project is also determining the potential of oral treatment with antagonists against TLR7 and TLR8 in preventing/suppressing gut inflammation, systemic autoimmunity and disease incidence. These studies will not only identify early pro-inflammatory events that initiate systemic autoimmunity in lupus but will also introduce the possibility of a novel and rational oral therapy for suppressing intestinal inflammation to prevent SLE.

Publications:

PubMed Collection