The primary research goal of the Xavier Laboratory at Massachusetts General Hospital and the Broad Institute is to discover and understand the function of important mediators and effectors involved in both the innate and adaptive immune systems. Of particular interest are the cellular components and regulatory networks that interact dynamically within temporal, spatial, and patho-physiological contexts of innate immunity. A second area of focus is to examine the pathway defects associated with genetic variants in inflammatory bowel disease and identify novel small molecules that interrupt signal transduction pathways associated with disease risk. We are pursuing integrative systems approaches that closely couple genome-wide experimentation with high-throughput assays and computational methods. Furthermore, we are pursuing studies of the microbiome in autoimmunity and inflammatory bowel disease.
NEWS AND EVENTS
Therapeutic Opportunities in Inflammatory Bowel Disease: Mechanistic Dissection of Host-Microbiome Relationships.Mechanistic and functional links between host-microbiome interplay and irritable bowel disease pathology are building, presenting exciting but challenging opportunities to manipulate the microbiome for therapeutic benefit. A summary of the review is available here.
In the News - from the NIH Director's blog. In his May 29, 2019 blog, Dr. Francis Collins highlights the latest finding from the Human Microbiome Project published in a landmark set of papers in Nature. One of the studies features the work of the Inflammatory Bowel Disease Multi’omics Data team led by Ramnik Xavier and Curtis Huttenhower. Their multi-omic approach offers the most comprehensive view to date of functional imbalances associated with changes in the microbiome during IBD flares.
Gut sphingolipids send signals about health and disease. Sphingolipids, a signaling molecule and structural component of both bacterial and mammalian cell membranes, play a central role in regulating inflammation, immunity, growth, and cell survival. To date, the specific roles of bacterial sphingolipids in regulating innate immunity or metabolism in the mammalian gut have been largely unknown. Reporting in Cell Host & Microbe, Eric Brown, Ramnik Xavier, Hera Vlamakis, Clary Clish and colleagues describe sphingolipid metabolite alterations in stool as a defining signature in inflammatory bowel disease in humans and further demonstrate in mice that bacterial sphingolipid production plays a significant role in the host’s gut health and disease.
Switching ON resistance. Diversity in bacterial populations promotes fitness and survival. In a study to better understand phase variation, a process used by bacteria to introduce diversity, a team led by Xiaofang Jiang, Brantley Hall, Eric Alm and Ramnik Xavier reports in Science the development of an algorithm to survey bacterial genomes for invertible promoters that cause phase variation. From in vivo studies in humans, they observed these invertible promoters turn on and off at the beginning and end of antibiotic treatment, respectively, highlighting a mechanism that allows bacteria to be equipped and prepared for sudden environmental stresses. A full summary is available here.
Eavesdropping on gut gossip. The gut's intestinal stem cells (ISCs) "talk" to other cell types to help maintain a robust and healthy cellular community. In this week's Cell, Moshe Biton, Adam Haber, Noga Rogel, Aviv Regev, Ramnik Xavier, and colleagues dive into one such conversation, between ISCs and T helper (Th) cells. They found that some ISCs express MCH II (a surface complex that activates Th cells), while Th cells produce cytokines (chemical messages) that influence ISCs’ behavior. The crosstalk may help maintain the right balance of immune activity in the gut, as well as a hardy stem cell pool. Read more in a Broad news story.
Like taking microbes from a baby. In search of microbial triggers for type 1 diabetes (T1D), a team led by Tommi Vatanen, Curtis Huttenhower, and Ramnik Xavier analyzed nearly 11,000 metagenomes in stool samples from children at risk for T1D, collected monthly starting at three months of age. Known as The Environmental Determinants of Diabetes in the Young (TEDDY) study, it produced the most shotgun metagenomic microbiome profiles published for a single target population to date. Appearing in Nature, the work finds that the microbiome gains adult-like functions as early as one year of age, and suggests that short-chain fatty acids may protect against early-onset T1D.
Peptide presentation prognosticator produced. We don't fully understand the immune system's rules for determining whether a peptide from a bacterium and other source will 1) be presented to T cells, and 2) spark an immune response. To help bring new clarity, Dan Graham, Chengwei Luo, Ramnik Xavier, and colleagues profiled the "peptidome" of potential antigens bound to MHC class II (a protein complex that presents peptides to T cells) in mice. They used their data to build and train BOTA, a machine learning algorithm that predicts antigenic peptides based on bacterial whole genome data. Learn more in Nature Medicine and in a Broad news story. A comprehensive summary of the study can be found here.
Director, Center for Computational and Integrative Biology
Ramnik Xavier is a core institute member of the Broad Institute of MIT and Harvard and co-director of the Broad’s Infectious Disease and Microbiome Program. He is the Kurt Isselbacher Professor of Medicine at Harvard Medical School; director of the Center for Computational and Integrative Biology and member of the Department of Molecular Biology at Massachusetts General Hospital (MGH); and co-director of the Center for Microbiome Informatics and Therapeutics at MIT.
Xavier Lab Areas of Interest
Massachusetts General Hospital and its collaborating institutions are important destinations for world-class care for patients with IBD, allergic disease of the gut and autoimmunity. As part of the initiative to link bench and bedside, we invite patients to participate in research efforts by providing clinical samples to both basic and translational researchers. The Xavier lab participates in many such cohort-building efforts, such as PRISM, SHARE, 500FG, and others. Insights from patient samples have led to advances in our understanding of both genetic and environmental risk factors for IBD and autoimmune disorders, responses to treatment, and the role of the microbiome in IBD and autoimmunity.
Examples of ongoing clinical cohort studies
Recent products of cohort studies
The immune system is implicated in a vast array of diseases along a spectrum of hyperinflammatory, hyperimmune, and autoimmune states. Among these diseases, inflammatory bowel diseases (IBDs), comprising Crohn’s disease and ulcerative colitis, are of particular interest in our lab. More than a million individuals in the United States have a form of IBD. These diseases have no known cause, but significant progress is underway in understanding the underlying mechanisms of these disorders. Our current model of IBD is based on a combination of increased genetic risk and an immune system that overreacts to environmental and microbial stresses.
To uncover basic mechanisms of IBD that can be used to develop treatment, our research takes three general and complementary approaches: using insights from human genetics to understand the biological mechanisms underlying disease, using genetic and chemical screens to identify the function of genes implicated in IBD risk, and gathering primary data from patients themselves. These approaches are guided by the lab’s central philosophy, which is to understand compelling biological and clinical questions, and drive innovation through development, optimization, and adaptation of new technologies.
Dr. Xavier is also a leader in the Broad Institute’s efforts to sequence thousands of exomes of IBD patients and healthy individuals in a project funded by the Helmsley Trust.
Genetics and pathways
Among complex diseases, genetics has been particularly successful in the identification of genes/genetic loci associated with risk of IBD. With this rapid progress, however, it has become clear that a major challenge in the study of complex genetic traits is to determine how disease genes and their corresponding alleles exert their influence on the biology of health and disease. Our working model is that alleles associated with predisposition to IBD — and more importantly, protection from IBD — will identify key pathways in the pathogenesis of IBD. We propose that defining these pathways will provide new insights into each disease state.
Innate and adaptive immunity
In research driven by insights from human genetics, we use functional genomics to discover and understand the function of important mediators and effectors involved in innate and adaptive immunity.
To this end, we are pursuing integrative systems approaches that closely couple genome-wide experimentation with high-throughput assays, chemical biology, and computational methods. Using these techniques, we are interested in understanding the role of regulatory circuits in mucosal immunity, in particular using (1) insights from human genetics and whole-genome sequencing to understand regulatory mechanisms in innate and adaptive immunity, (2) chemical approaches to controlling cellular disease phenotypes suggested by human genetics, and (3) harnessing computational approaches to uncover both broad and precise patterns of pathway activation in the context of disease and treatment.
Genes and Pathways
One approach to discovering the key mediators of innate and adaptive immunity focuses on defining immune-related genes and placing them in their proper pathways. Current areas of focus using this approach are studies of (1) autophagy (Lassen et al., 2014), (2) host defense and the inflammatory response (Conway et al., 2012), and (3) tolerance and regulatory cells (Khor et al., 2015, recently highlighted in Nature Immunology and selected as an “Editors’ Choice” by Science Translational Medicine).
Chemical approaches to controlling cellular disease phenotypes suggested by human genetics
Using chemical (e.g., small molecule) screening approaches, we can gain insight into disease gene function and place risk genes into signal transduction pathways. Chemical screens have the additional potential to identify small molecule probes and early therapeutic leads, as recently demonstrated by Kuo et al. (paper; press release).
We use the power of computational biology to uncover patterns in complex pathway analysis, as well as to integrate multiple ’omics data types to decipher human disease.
The goal of the microbiome program in the Xavier lab is to use informatics to understand the function of the human microbiome in health and disease. We are particularly interested in identifying microbial small molecules with immunomodulatory activities and to characterize their mechanisms of immune modulation.
Commensal gut microbiota are both ecologically and functionally perturbed during immune-mediated diseases such as inflammatory bowel diseases (IBD) and type 1 diabetes (T1D). Using these diseases as models for understanding the human microbiome’s role in complex inflammatory disease, our recent studies have characterized the microbiome of treatment-naïve Crohn’s disease, and identified trends in the development of the human infant gut microbiome along with specific alterations that precede T1D onset and distinguish T1D progressors from nonprogressors.