Welcome to the Laboratory of Ashutosh Mangalam, PhD, at the University of Iowa Department of Pathology.
The major goal of my research is to develop better treatment options to cure multiple sclerosis (MS). To achieve this goal, my research program focuses on three major interconnected themes: i) to understand the role of gut microbiome and metabolome in the etiopathogenesis of MS; ii) test therapeutic efficacy of human gut derived bacteria as drug (BRUG) in animal models of MS; and iii) utilize transgenic mice expressing MS susceptible and resistant HLA class II molecules (HLA transgenic mice) to understand the mechanisms of disease pathogenesis.
Our fecal microbiota profiling study showed that MS patients had depletion of certain bacteria whereas enrichment of others (PMID: 27346372). The gut microbiota help in maintaining our health by regulating various functions, including: food metabolism, energy homeostasis, maintenance of the intestinal barrier, inhibition of colonization by pathogenic organisms and shaping of both the mucosal and systemic immune responses. Alteration of the gut microbiota and resulting changes in its metabolic network perturb this homeostasis, often leading to intestinal and systemic disorders such as MS (Figure below). Our microbiome study showed that MS patients have alteration in gut bacteria involved in metabolism of phytoestrogens, fibres/carbohydrates, bile acids and tryptophans. Therefore, multiple projects in the laboratory are investigating the mechanism through which gut bacteria regulate host physiology, e.g. numbers of bacteria responsible for metabolism of phytoestrogens (specifically Prevotella, Parabacteroides, and Adlercreutzia) are depleted in MS patients. As a proof of concept, we isolated Prevotella histicola from healthy individual (one of the bacteria linked with phytoestrogen metabolism) and observed that it can induce regulatory CD4 T cells as well as suppress disease in experimental autoimmune encephalomyelitis (EAE), an animal model of MS (PMID: 28793252). Based on these two observations we are testing the hypothesis that a decrease in microbial flora associated with metabolism of plant lignan and isoflavone might be responsible for pro-inflammatory state and predisposition to disease.
We have extended our human microbiome study to recruit new cohort of MS patients to confirm our earlier findings as well as identify and characterize the specific bacteria which might be responsible for predisposition to the disease. We are also testing whether combination therapy of commensal bacteria and currently used MS drug is a better treatment option than either of them alone.
In another project, we are utilizing transgenic mice expressing autoimmune prone HLA class-II molecules to understand their role in selection of gut flora and its effect on development of adaptive immune system.