2020

Highlight: Pathway Paradigms Revealed from the Genetics of Inflammatory Bowel Disease

By Katie E. Golden, MD


In a recently published paper in Nature, CSIBD faculty provide a comprehensive review of the scientific advances that have brought us to our current understanding of inflammatory bowel disease (IBD) pathophysiology, and how this has provided valuable insights into the metabolic pathways that contribute to microbiome-related disorders on a larger scale. Their in-depth survey illustrates how the evolution of genetics-based research has built a valuable framework to explore the clinical implications of the molecular pathways that contribute to IBD development and progression.

Our understanding of inflammatory bowel disease (IBD) has dramatically evolved over the last decade as a result of advanced genetic, immunology, and microbiome research. We have moved away from a traditional model that categorizes the disease into two subtypes (Ulcerative Colitis and Crohn’s Disease), to understand IBD as a heterogeneous condition with varied phenotypes resulting from a complex interaction between genetic and environmental factors. Investigating the underlying pathophysiology of an inherently complex condition has demanded the development of innovative research technology, particularly in functional genetics, which in turn has resulted in broader applications to human health and disease.

In a recently published paper, authors Graham and Xavier provide an eloquent and comprehensive review of the scientific advances that have brought us to our current understanding of IBD pathophysiology, and how this has provided valuable insights into the metabolic pathways that contribute to microbiome-related disorders on a larger scale. Their in-depth survey of the most relevant IBD discoveries inspires an appreciation of how the evolution of genetics-based research has successfully built a valuable framework for the biomedical research community to explore the clinical implications of the molecular pathways that contribute to disease development and progression.

The inherent complexity of IBD has long been apparent from the observed phenotypic variation, unpredictable treatment response from patient to patient, and even the extra-intestinal systemic manifestations of the disease. Identifying causal genes and their variants within risk loci was only the first step; scientists had to understand how genetic variants translated to causal disease mechanisms to make a clinical impact. This pressure inspired the development of exome sequencing, CRISPR technology, and single-cell genomics to capture in vivo data demonstrating how intestinal microbiota affect transcriptional activity. This expansion of functional genomics yielded a blueprint of IBD pathology as a complicated interplay between gut mucosal immunity and aberrant antimicrobial responses.

The elaboration of cellular and molecular pathways that lead to IBD pathogenesis has created opportunities for therapeutic intervention, as well as biomarker development to predict and monitor disease severity and treatment response. This includes the identified roles of epithelial barrier function, mucosal immunity and stem cell response, microbe-sensing pathways, and cytokine networks that have important implications for both intestinal homeostasis as well as systemic inflammatory responses. In reviewing these discoveries, Graham and Xavier move us beyond the oversimplification of IBD as a genetic disease that is triggered by environmental conditions, to help us understand how it arises from a complicated relationship between host genetics, a dynamic microbiome that influences host metabolism, and resultant dysregulation of mucosal epithelium and immunity.

Read the review.

Celebrate International Women's Day by Sharing Pioneering Work from CSIBD Investigator Kate Jeffrey

Courtesy of the Kenneth Rainin Foundation

With her lab at Harvard Medical School and Massachusetts General Hospital, immunologist Dr. Kate Jeffrey has embarked on a new frontier to research the human virome. It holds promise for treatment breakthroughs for Inflammatory Bowel Disease.

Watch the video to learn about her breakthrough moment.

The Kenneth Rainin Foundation and the CSIBD are proud to celebrate International Women’s Day on March 8 and honor the achievements of women like Dr. Jeffrey around the world.


A Requirement for Argonaute 4 in Mammalian Antiviral Defense

Mammals have four RNA interference (RNAi) and micro RNA (miRNA) effector proteins: Argonautes 1–4, AGO1–AGO4 for short. A recent study in Cell Reports by Adiliaghdam et al. sought to determine their individual functions during viral infections, revealing that cells deficient in AGO4 are more susceptible to viral infection than those deficient in AGO1 or AGO3. Moreover, AGO4-deficient mice infected with influenza displayed a significantly higher viral burden and titers in vivo. Together, the authors establish a unique and essential role for AGO4 in mammalian antiviral defense. 

Read the study.


RICOPILI: Rapid Imputation for COnsortias PIpeLIne

Challenges in analyzing genome-wide association studies (GWAS) arise in the rapid processing of large-scale, multi-cohort GWAS. To address these, Lam et al. introduced RICOPILI, an open-sourced pipeline that integrates quality control, imputation and association analysis. RICOPILI features technical and genomic quality control in case-control and trio cohorts, genome-wide phasing and imputation, association analysis, meta-analysis, polygenic risk scoring, and replication analysis. Its framework allows scalable processing of GWAS data and is computationally efficient with portability to a wide range of high-performance computing environments. The design, implementation, and comparisons with other GWAS pipelines were published in Bioinformatics.

Read the study.


Global IBD care in the 21st century

The changing global landscape of inflammatory bowel diseases (IBD) will impact their future burden on care. In a review published in Clinical Gastroenterology and Hepatology, Ananthakrishnan et al. highlight recent trends in epidemiological patterns of IBD, explore modifiable environmental exposures that may reduce incidence of IBD, and discuss the evolving healthcare burden of IBD – offering an outline of key research and clinical steps toward sustainable global IBD care.

Read the review.


Sulfur-metabolizing gut bacteria linked to colorectal cancer risk in men

Colorectal cancer (CRC) is the third most frequently occurring and third most lethal form of cancer in the US. As a genetic predisposition is unclear in most new cases, lifestyle changes are considered a top priority for disease prevention. Nguyen et al. investigate the impact of diet, specifically on the composition and function of the gut microbiome, on CRC risk in a cohort of men enrolled in the prospective Health Professionals Follow-up Study. The results, published in Gastroenterology, associated a dietary pattern (high in processed meats and low-calorie drink and low in vegetables and legumes) with sulfur-metabolizing bacteria, which have been implicated in CRC development and are known to produce genotoxic metabolites. The authors were further able to demonstrate that the presence of these bacteria was coupled to their metabolic activities. Overall, this study provides a rationale for dietary modification as a means of modulating the gut microbiome to mediate disease risk.

Read the study.


Summary: Growth Effects of N-acylethanolamines on Gut Bacteria Reflect Altered Bacterial Abundances in Inflammatory Bowel Disease

By Katie E. Golden, MD

In a recently published study that takes a closer look at the role of the metabolome in the progression of inflammatory bowel disease (IBD), researchers identify a specific lipid metabolite that is abnormally abundant in IBD patients. Their subsequent investigations reveal how this metabolite stimulates the growth of species that are well established to be overrepresented in IBD patients. Remarkably, when they treated healthy stool samples with these specific lipids, they observed taxonomic shifts in bacterial populations that mirrored microbiome composition in IBD.

As our understanding of the pathophysiologic picture of inflammatory bowel disease (IBD) is evolving, current research is illustrating an increasingly complex relationship between gut microorganisms and the host’s immune system that drives disease. While the earliest microbiome research focused on the microbial taxonomic changes in IBD, scientists are now recognizing that the gut metabolome is of equal importance. Small molecules, derived from the environment as well as host and bacterial cellular processes, are proving to be an integral component of the dynamic microbiome that is so intimately linked to intestinal homeostasis and dysbiosis.

In a recent study published in Nature Microbiology, Fornelos et al. identify specific metabolites that play a role in the pathophysiology of IBD. The authors first identified lipid metabolites (N-acylethanolamines, or NAEs) that are differentially abundant in IBD, and then analyzed how they affect the growth of intestinal bacteria. They found that NAEs stimulated the growth of species that are well established to be aberrantly abundant in IBD patients, and furthermore restricted the growth of species that are depleted in disease. To analyze these findings under further scientific rigor, they treated healthy stool samples ex vivo with NAEs and analyzed bacterial populations changes. In comparison to controls, the investigators observed taxonomic shifts in bacterial populations that mirrored microbiome composition in IBD. More specifically, metagenomic analysis revealed two bacterial shifts that are well-established changes characteristically seen in IBD: enhanced growth of Enterobacteriaceae, as well as proliferation of Proteobacteria at the expense of Bacteroides species.

Their results implicated enhanced NAE production as an important contributor to the pathologic bacterial growth that underlies IBD. In the final phase of their investigation, they used metatranscriptomic analysis to analyze exactly how NAEs alter bacterial cellular processes. They found that the bacterial respiratory chain played a critical role in the metabolism of the metabolites, which in turn induced upregulated cellular metabolism of facultative aerobes (Enterobacteriaceae), and a subsequent pro-inflammatory feedback loop that further increased NAE production. Their work not only advances our understanding of the metabolome’s role in disease, but also successfully identifies the potential for NAEs as both a therapeutic target and a biomarker of disease severity in IBD patients.

Read the study.


2019

Summary: Cryo-electron Microscopy Structures of Human Oligosaccharyltransferase Complexes OST-A and OST-B

By Katie E. Golden, MD

In a recent paper published in Science, investigators expand on prior CSIBD research to define the chemical structure of two important glycosylation enzymes. By combining advanced cryo-electron microscopy with traditional western blot analysis, scientists identify the subtle structural differences in two related human oligosaccharyltransferase complexes that accounts for their unique cellular functions.

Back in 2016, CSIBD researchers proposed a mechanism by which a gene-dense locus on chromosome 11, TMEM258, plays an important role in the pathogenesis of inflammatory bowel disease. They illustrated how it is a component of the oligosaccharyltransferase (OST) complex that is required for protein glycosylation, and without it, mice models demonstrated severe colonic inflammation.

In a more recent paper published in Science, researchers use cryo-electron microscopy to define the chemical structure of two human OST complexes that play an important role in secretory protein modification. This is not only an exciting discovery that builds on the work by Graham et al. in 2016, but is also an important example of advanced basic science research that unmasks physiologic mechanisms with potential clinical relevance.

To break it down, when proteins are translated from genetic material in the cell, those proteins need to be modified before they are functional. A process called N-glycosylation is one of the most common ways that proteins are modified, and is catalyzed by OST complexes located in the endoplasmic reticulum (a specialized membrane found inside mammalian cells that aids in protein synthesis). Humans have two distinct OST complexes: OST-A and OST-B. Despite similar molecular structures, these complexes have distinct functions in the glycosylation process. In this most recent paper by Ramírez et al., the authors discovered the specific catalytic subunits (STT3A and STT3B) that account for the unique substrate affinities of each complex. OST-A associates with the translocon and binds unfolded proteins to process the N-glycosylation sites needed for protein modification. OST-B, contrastingly, does not associate with the translocon but has a stronger affinity for glycosylation sites and is thus able to bind and process proteins that are partially folded and modified.

While the above is an oversimplification of a complicated process, this paper decisively identifies the subtle but specific structural changes that translate to unique enzymatic function. Given the ubiquitous nature of these cellular processes, Ramírez and his team have laid important groundwork for the design of N-glycosylation inhibitors, which could ultimately be used to augment specific disease processes in the clinical setting.

Read the study by Graham et al.

Read the study by Ramírez et al.


Migratory DCs activate TGF-β to precondition naïve T cell fate

The function of epithelial resident memory T (eTRM) cells is key to protect against previously encountered pathogens, but how eTRM cells are formed remained unclear. Mani et al. address this question in a study published in Science using a mouse model of skin vaccination. The authors show that during homeostasis, resting naïve CD8+ T cells in the lymph nodes are epigenetically primed to become eTRM cells through the activation of cytokine transforming growth factor β (TGF-β) by migratory dendritic cells. These results present a contrasting view of the preimmune T cell repertoire, in which naïve T cell fate potential is preconditioned and not less uniform than expected.

Read the study.


BIO-ML: not your entomologist’s library

To facilitate mechanistic research aimed at understanding how the gut microbiome interacts with its human host, the CSIBD, Center for Microbiome Informatics and Therapeutics, and Broad Institute established the Broad Institute-OpenBiome Microbiome Library (BIO-ML). This phylogenetically diverse collection of gut bugs — described by Poyet et al. in Nature Medicine — contains thousands of bacterial isolates from healthy donors with corresponding longitudinal multi’omic data. As the microbiome field moves from characterization of structure and composition toward functional studies during health and disease, BIO-ML provides an unparalleled resource of clinically-relevant human gut strains, including hundreds implicated in inflammatory bowel diseases, for hypothesis-driven studies and microbiome-based therapeutic advancements.

Read the study.


Assessing the impact of biologic therapy initiation on fatigue in IBD patients

A new study by Borren et al. published in the Journal of Crohn’s and Colitis examined the effects of biologic therapies used to treat inflammatory bowel diseases (IBD) on the persistent fatigue often experienced by patients. The study followed 326 IBD patients initiating either anti-TNF, vedolizumab, or ustekinumab over a one-year period. At therapy initiation, 198 patients (61%) reported significant fatigue, which was associated with female sex, depressive symptoms, active disease, and disturbed sleep. After 14, 30, and 54 weeks, 86 (70%), 55 (63%), and 44 (61%) of these patients remained fatigued. Clinical remission at each of these time points was associated with lower likelihood of fatigue; however, a significant proportion of patients continued to experience persistent fatigue after a year of biologic therapy.

Read the study.


Ulcerative colitis rewires the human gut

The human gut represents a circuit – a network of interconnected components, in this case various types of cells, that performs a function. Disruptions in the circuit cause malfunctions, or diseases such as the chronic inflammatory condition ulcerative colitis (UC). Mapping the gut as a circuit holds diagnostics and therapeutic value; comparisons between healthy and disease states expose pathological disturbances and potential therapeutic entry points. In a study published in Cell, Smillie et al. generated such maps by analyzing single cells from the colons of healthy individuals and UC patients. The authors classified new cell types, associating them with disease and resistance to treatment, and pinpointed populations in which susceptibility genes function. This work provides new insights into complex interactions underlying UC that will lead to a better understanding of gut health and inflammation.

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Human Microbiome Project profiles Inflammatory Bowel Disease activity

Inflammatory bowel diseases (IBD) are characterized by chronic inflammation of the digestive tract, often involving periods of remission and relapse. Genetics, environment, and the gut microbiome – the community of microorganisms inhabiting the human intestines – contribute to these complex diseases and are the subjects of extensive research. As part of the Integrative Human Microbiome Project that aims to determine how microbiomes influence human health and disease, Lloyd-Price et al. collected data from 132 individuals for one year to survey alterations within IBD patients and their microbiomes during states of remission and relapse. The most comprehensive description of dynamic perturbations in IBD to date, this study identifies factors central to disease activity and paves the way for future research and clinical advances.

Read the study.


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.

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2018

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.

Read the study.


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.

Read the study.


Summary: Antigen Discovery and Specification of Immunodominance Hierarchies for MHCII-restricted Epitopes

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.

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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. Read more in a Broad news story.

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Summary: Compositional and Temporal Changes in the Gut Microbiome of Pediatric Ulcerative Colitis Patients Are Linked to Disease Course

By Katie E. Golden, MD

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.

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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.


2017

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. Read more in a Broad news story.

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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.