Massachusetts General Hospital researchers have found how a variant in an important epigenetic enzyme – previously associated with Crohn’s disease and other immune disorders – interferes with the action of the innate immune system, potentially upsetting the balance between the microbial population of the gastrointestinal tract and the immune response.
Recent news from the Center for the Study of Inflammatory Bowel Disease at Massachusetts General Hospital.
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.
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.
Summary: Antigen Discovery and Specification of Immunodominance Hierarchies for MHCII-restricted Epitopes (Graham et.al)
by Katie E. Golden, MD
For well over a decade, the world of immunology has been gaining traction as a core focus to better understand, and cure, many human diseases. The science and medical community alike have gained appreciation for the role of immunological processes in infectious diseases, autoimmune diseases, and cancer. As the prevalence of these conditions increases, there has never a more critical time for researchers to better understand the immune system and its potential for therapeutics.
Behind the development of new and exciting immunotherapy and pharmaceutical interventions is rigorous, basic science research that forms the foundation upon which we can develop these advanced treatments. We still have a lot to learn about how the human immune system functions, how it can both keep us healthy or lead to disease, and how we can best study these mechanisms. In the newly published paper by Graham, et.al. in Nature Medicine, immunologists and researchers take on the difficult task of identifying the key components of immunologic processes.
In their investigation, the authors developed a way to identify the T cell epitopes that play a dominant role in antigenicity. More specifically, they outline a unique approach to identifying and predicting the specific molecules that initiate clinically significant immune responses. They focused on epitopes associated with major histocompatibility complex II (MHCII), which are the key proteins that bind the T cell to activate immune mechanisms implicated in both health and disease. Using a broad, unbiased survey of proteins, they developed a model that predicts dominant MHCII epitopes on a genome-wide scale.
This essentially provides researchers with the tool to take a collection of bacterial species, for example from the human gut microbiome, and create a map of the immunodominant epitopes. This is an important step in identifying the antigenic pathways that lead to development and propagation of disease (such as in Inflammatory Bowel Disease, in keeping with the microbiome example). When they put their model to the test, it accurately predicted novel T cell epitopes from both pathogenic and commensal bacteria.
Amidst a thirst for promising new immunotherapies to treat chronic and terminal disease, this paper is a powerful reminder of the role, and necessity, for developing new ways to study core immunologic mechanisms and pathways.
Summary: Compositional and Temporal Changes in the Gut Microbiome of Pediatric Ulcerative Colitis Patients Are Linked to Disease Course (Schirmer, et.al)
By Katie Golden
The incidence of Inflammatory Bowel Disease (IBD) is quickly rising, though despite the prevalence of disease, treatment options for patients are limited. Our current approach to treatment consists of pharmacologic immunosuppression, which is often only partially effective, or surgical removal of diseased portions of the intestine. These interventions often come with significant comorbidities for the patient, and are poorly tailored to their individual disease phenotypes as we still struggle to understand the pathophysiology of IBD.
The current research and future of IBD treatment is focused on understanding the interplay between the gut microbiome and the development and progression of disease. Research has consistently demonstrated how the microbiomes of IBD patients are less diverse compared to healthy control, and lack populations of protective, healthy bacteria. We have yet to understand, however, exactly how this dysbiosis of intestinal bacteria contributes to disease progression, and subsequently how it can be harnessed for treatment.
A new study, published in Cell Host & Microbe by Schirmer et.al., brings us one step closer to the future of a more tailored, elegant approach to IBD therapeutics. Investigators looked at pediatric patients diagnosed with Ulcerative Colitis (UC), a form of IBD, to understand the correlation between disease severity and microbiome characteristics, and how this changes over time with treatment. More specifically, researchers followed a population of newly diagnosed, treatment-naive children, treated with one of two immunosuppression regimens (corticosteroids or 5-ASA), and monitored changes in fecal microbial populations and disease progression. They collected stool samples and tissue biopsies before, during, and after treatment over the course of a year.
During their investigation, researchers uncovered several important associations between microbiome characteristics, disease severity, and response to treatment. In the pre-treatment population, they found that disease severity correlated with increased populations of oral cavity bacteria (that do not typically colonize the intestine) and depleted populations of protective, commensal bacteria (such as Ruminococcaceae and Lachnospiraceae species).
Several of these disease-associated microbiome characteristics, furthermore, were predictive of refractory disease and seen in patients who ultimately required colectomy for treatment. In patients who did respond to medical therapy, the investigators observed similar changes in microbiome characteristics over time in both treatment arms, challenging prior research that suggested treatment response was highly individualized. These findings provided an important step forward in predicting individual prognosis and response to treatment based on pre-treatment microbiome characteristics.
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.
CSIBD Investigators receive 2018 BMA Medical Book Award
Ramnik Xavier, Director of CSIBD, and Ashwin Ananthakrishnan, Technical Director of the Clinical Core, together with Daniel Podolsky at UT Southwestern received a Highly Commended certificate in the Internal Medicine category for their book, Inflammatory Bowel Diseases: A Clinician's Guide.
The annual BMA Medical Book Awards recognize outstanding contributions to medical literature, promoting excellence in medical publishing and demonstrating its importance to medical education and training. Prizes are awarded in 20 categories, and an overall BMA Medical Book of the Year Award is selected from the category winners.
Researchers produce the first draft cell atlas of the small intestine
(Courtesy of Broad Communications)
By surveying gene expression in over 53,000 cells from the small intestine, researchers have created a rich reference for understanding the biology of inflammatory bowel disease and food allergies, among other conditions.
Oral bacteria in the gut associated with inflammatory bowel disease
Bacteria living in the mouth are ingested with saliva, but normally do not persist in healthy intestine. In several disease states—inflammatory bowel disease (IBD), HIV infection, liver cirrhosis, colon cancer—orally-derived bacteria are found living in patients’ guts, leading researchers to hypothesize that oral bacteria colonizing the gut contribute to disease.
Collaborating with researchers in Japan, Dr. Ramnik Xavier and his laboratory at MGH recently published a study in Science demonstrating that certain strains of antibiotic-resistant oral bacteria colonize the gut and drive inflammation in genetically susceptible hosts. These bacteria were significantly more abundant in the guts of IBD and Crohn’s disease patients than of healthy individuals.
These findings highlight the disease potential of bacterial strains in susceptible hosts and the need to better understand the relationships between human hosts, their genomes, and resident bacterial communities. Read the study.