Ramnik Xavier, MD

Institution: Massachusetts General Hospital
Research: Systems biology approaches to understand human disease signaling networks
Grants & Publications: Harvard Catalyst
Categories: MGH

The overall goal in the laboratory is to discover and understand the functions of important mediators and effectors involved in innate and adaptive immunity. Of particular interest are cellular components and regulatory networks that interact dynamically within temporal, spatial, and pathophysiological contexts of immunity. We utilize integrative systems approaches that closely couple genome-wide experimentation with high-throughput assays and computational methods.

Using the gut as a model system, we identify immune mechanisms that are perturbed in inflammatory bowel diseases (IBD) and type 1 diabetes (T1D). Recent work has focused on generating systems-wide maps within the gut that capture immune features and metabolic states at single-cell resolution. First, we transcriptionally profiled tens of thousands of individual gut epithelial cells to chart distinct cell types and their intrinsic cell states and responses to infections. We uncovered new cellular markers and programs, associated sensory molecules with cell types, and further defined principles of gut homeostasis and pathogenesis. We further utilized this data to identify intestinal stem cell (ISC) subsets enriched for MHC class II (MHCII) machinery and demonstrated that key cytokines affected MHCII+ ISC renewal and differentiation in opposing ways to orchestrate tissue-wide responses: pro-inflammatory signals promote differentiation, while regulatory cells and cytokines reduce it. A separate single-cell study examined the human colon mucosa during health and ulcerative colitis (UC), revealing 51 epithelial, stromal, and immune cell subsets. We associated inflammatory fibroblasts with resistance to anti-TNF treatment and revealed that many UC risk genes are cell type-specific and co-regulated in relatively few modules, suggesting that a limited set of cell types and pathways underlie UC. Lastly, we developed two single-nucleus RNA-sequencing methods—RAISIN-seq and MIRACL-seq—to transcriptionally profile the rare and diverse cells of the enteric nervous system (ENS) in humans at high resolution. We uncovered several neuro-epithelial, neuro-stromal, and neuro-immune interactions as well as strong expression in enteric neurons of risk genes for neuropathic, inflammatory, and extra-intestinal diseases. Collectively, these studies expose a rewiring of intra- and inter-cellular circuitry during intestinal inflammation and contribute to a more comprehensive understanding of the interplay between human genetics and mucosal immunity during health and complex diseases.

We also determine the influences of the gut microbiome on health and disease using human cohorts and computational models. Analyzing microbial strain-level variation in a longitudinal cohort of children predisposed to T1D, we revealed functional consequences of strain diversity on early microbiome development and disease susceptibility. Using the same cohort, we characterized the natural history of the early microbiome in connection to T1D diagnosis, antibiotic treatments, and probiotics. In pursuit of molecular mechanisms underlying interactions between the microbiome and the immune system, we identify microbially-derived metabolites, such as indoleacrylic acid and sphingolipids, that promote intestinal epithelial barrier function and mitigate inflammatory responses. Our metagenomic and metabolomic analyses of IBD cohorts uncovered over 2,700 gut metabolites that were differentially abundant in IBD. Furthermore, we link enzymatic activities of gut microbes to host metabolism; we recently identified cholesterol dehydrogenases harbored by a clade of bacteria that associates with lower cholesterol levels in humans. To generate unique hypotheses regarding immune mechanisms, we also established an integrative platform—an antigen prediction model coupled with high-throughput validation—to define the immunodominance landscape of microbes across a broad range of immune pathologies and an algorithm that identified bacterial genomic regions mediating host adaptation and antibiotic resistance. Together, these studies contribute to a comprehensive understanding of the functional roles played by the microbiome in maintaining mucosal homeostasis and promoting immunological disorders.

The laboratory ultimately aims to translate human genetics to functional biology and pathway medicine. Leveraging insight gained from our functional studies, we use chemical biology to test therapeutic hypotheses and inform drug discovery programs.