Inflammatory bowel disease (IBD) is a complex genetic disease that is instigated and amplified by the confluence of multiple genetic and environmental variables that perturb the immune-microbiome ...axis. The challenge of dissecting pathological mechanisms underlying IBD has led to the development of transformative approaches in human genetics and functional genomics. Here we describe IBD as a model disease in the context of leveraging human genetics to dissect interactions in cellular and molecular pathways that regulate homeostasis of the mucosal immune system. Finally, we synthesize emerging insights from multiple experimental approaches into pathway paradigms and discuss future prospects for disease-subtype classification and therapeutic intervention.
The inflammatory bowel diseases (IBDs) are among the most closely studied chronic inflammatory disorders that involve environmental, host genetic, and commensal microbial factors. This combination of ...features has made IBD both an appropriate and a high-priority platform for translatable research in host-microbiome interactions. Decades of epidemiology have identified environmental risk factors, although most mechanisms of action remain unexplained. The genetic architecture of IBD has been carefully dissected in multiple large populations, identifying several responsible host epithelial and immune pathways but without yet a complete systems-level explanation. Most recently, the commensal gut microbiota have been found to be both ecologically and functionally perturbed during the disease, but with as-yet-unexplained heterogeneity among IBD subtypes and individual patients. IBD thus represents perhaps the most comprehensive current model for understanding the human microbiome’s role in complex inflammatory disease. Here, we review the influences of the microbiota on IBD and its potential for translational medicine.
Inflammatory bowel diseases (IBDs) involve environmental, host genetic, and commensal microbial factors, thereby allowing interrogation of interactions between the microbiome and immune system. Here Huttenhower et al. review the role of microbiota in IBD and its potential for translational medicine.
Perturbations in the intestinal microbiome are implicated in inflammatory bowel disease (IBD). Studies of treatment-naive patients have identified microbial taxa associated with disease course and ...treatment efficacy. To gain a mechanistic understanding of how the microbiome affects gastrointestinal health, we need to move from census to function. Bacteria, including those that adhere to epithelial cells as well as several Clostridium species, can alter differentiation of T helper 17 cells and regulatory T cells. Similarly, microbial products such as short-chain fatty acids and sphingolipids also influence immune responses. Metagenomics and culturomics have identified strains of Ruminococcus gnavus and adherent invasive Escherichia coli that are linked to IBD and gut inflammation. Integrated analysis of multiomics data, including metagenomics, metatranscriptomics and metabolomics, with measurements of host response and culturomics, have great potential in understanding the role of the microbiome in IBD. In this Review, we highlight current knowledge of gut microbial factors linked to IBD pathogenesis and discuss how multiomics data from large-scale population studies in health and disease have been used to identify specific microbial strains, transcriptional changes and metabolic alterations associated with IBD.
The intestinal microbiota, which is composed of bacteria, viruses, and micro-eukaryotes, acts as an accessory organ system with distinct functions along the intestinal tract that are critical for ...health. This review focuses on how the microbiota drives intestinal disease through alterations in microbial community architecture, disruption of the mucosal barrier, modulation of innate and adaptive immunity, and dysfunction of the enteric nervous system. Inflammatory bowel disease is used as a model system to understand these microbial-driven pathologies, but the knowledge gained in this space is extended to less-well-studied intestinal diseases that may also have an important microbial component, including environmental enteropathy and chronic colitis-associated colorectal cancer.
The human gut microbiota plays an important role in maintaining a healthy gastrointestinal tract. In this review, Wlodarska et al. discuss the current knowledge of host-microbiota interactions in gut health, and how microbial dysbiosis contributes to the development and pathology of inflammatory diseases of the intestine, including inflammatory bowel disease.
Taxonomic and functional changes to the composition of the gut microbiome have been implicated in multiple human diseases. Recent microbiome genome-wide association studies reveal that variants in ...many human genes involved in immunity and gut architecture are associated with an altered composition of the gut microbiome. Although many factors can affect the microbial organisms residing in the gut, a number of recent findings support the hypothesis that certain host genetic variants predispose an individual towards microbiome dysbiosis. This condition, in which the normal microbiome population structure is disturbed, is a key feature in disorders of metabolism and immunity.
Recent advances have provided substantial insight into the maintenance of mucosal immunity and the pathogenesis of inflammatory bowel disease. Cellular programs responsible for intestinal homeostasis ...use diverse intracellular and intercellular networks to promote immune tolerance, inflammation or epithelial restitution. Complex interfaces integrate local host and microbial signals to activate appropriate effector programs selectively and even drive plasticity between these programs. In addition, genetic studies and mouse models have emphasized the role of genetic predispositions and how they affect interactions with microbial and environmental factors, leading to pro-colitogenic perturbations of the host-commensal relationship.
Studies of the roles of microbial communities in the development of inflammatory bowel disease (IBD) have reached an important milestone. A decade of genome-wide association studies and other genetic ...analyses have linked IBD with loci that implicate an aberrant immune response to the intestinal microbiota. More recently, profiling studies of the intestinal microbiome have associated the pathogenesis of IBD with characteristic shifts in the composition of the intestinal microbiota, reinforcing the view that IBD results from altered interactions between intestinal microbes and the mucosal immune system. Enhanced technologies can increase our understanding of the interactions between the host and its resident microbiota and their respective roles in IBD from both a large-scale pathway view and at the metabolic level. We review important microbiome studies of patients with IBD and describe what we have learned about the mechanisms of intestinal microbiota dysfunction. We describe the recent progress in microbiome research from exploratory 16S-based studies, reporting associations of specific organisms with a disease, to more recent studies that have taken a more nuanced view, addressing the function of the microbiota by metagenomic and metabolomic methods. Finally, we propose study designs and methodologies for future investigations of the microbiome in patients with inflammatory gut and autoimmune diseases in general.
Encounters between immune cells and invading bacteria ultimately determine the course of infection. These interactions are usually measured in populations of cells, masking cell-to-cell variation ...that may be important for infection outcome. To characterize the gene expression variation that underlies distinct infection outcomes and monitor infection phenotypes, we developed an experimental system that combines single-cell RNA-seq with fluorescent markers. Probing the responses of individual macrophages to invading Salmonella, we find that variation between individual infected host cells is determined by the heterogeneous activity of bacterial factors in individual infecting bacteria. We illustrate how variable PhoPQ activity in the population of invading bacteria drives variable host type I IFN responses by modifying LPS in a subset of bacteria. This work demonstrates a causative link between host and bacterial variability, with cell-to-cell variation between different bacteria being sufficient to drive radically different host immune responses. This co-variation has implications for host-pathogen dynamics in vivo.
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•Single-cell RNA-seq reveals heterogeneity of host-pathogen encounters•PhoP-mediated LPS modifications occur in only a subset of bacteria during infection•Intracellular recognition of modified LPS induces heterogeneous type I IFN response•Heterogeneity is a key feature of pathogen population during infection
Functional heterogeneity in the response of host cells to infection is driven by cell-to-cell transcriptional variations in the population of infecting pathogens.
CRISPR-Cas9 is a versatile genome editing technology for studying the functions of genetic elements. To broadly enable the application of Cas9 in vivo, we established a Cre-dependent Cas9 knockin ...mouse. We demonstrated in vivo as well as ex vivo genome editing using adeno-associated virus (AAV)-, lentivirus-, or particle-mediated delivery of guide RNA in neurons, immune cells, and endothelial cells. Using these mice, we simultaneously modeled the dynamics of KRAS, p53, and LKB1, the top three significantly mutated genes in lung adenocarcinoma. Delivery of a single AAV vector in the lung generated loss-of-function mutations in p53 and Lkb1, as well as homology-directed repair-mediated KrasG12D mutations, leading to macroscopic tumors of adenocarcinoma pathology. Together, these results suggest that Cas9 mice empower a wide range of biological and disease modeling applications.
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•Generation of mouse lines with Cre-dependent and constitutive Cas9 expression•Viral/nonviral delivery of sgRNA to the brain, vasculature, immune cells, and lung•Modeling of competition between gain- and loss-of-function mutations in lung cancer•A convenient platform for achieving efficient genome editing in vivo
Viral and nonviral delivery of sgRNAs in CRISPR-Cas9 knockin mice enables diverse genome engineering applications in biology and disease modeling.
Chronic inflammation is often associated with the development of tissue fibrosis, but how mesenchymal cell responses dictate pathological fibrosis versus resolution and healing remains unclear. ...Defining stromal heterogeneity and identifying molecular circuits driving extracellular matrix deposition and remodeling stands to illuminate the relationship between inflammation, fibrosis, and healing. We performed single-cell RNA-sequencing of colon-derived stromal cells and identified distinct classes of fibroblasts with gene signatures that are differentially regulated by chronic inflammation, including IL-11-producing inflammatory fibroblasts. We further identify a transcriptional program associated with trans-differentiation of mucosa-associated fibroblasts and define a functional gene signature associated with matrix deposition and remodeling in the inflamed colon. Our analysis supports a critical role for the metalloprotease Adamdec1 at the interface between tissue remodeling and healing during colitis, demonstrating its requirement for colon epithelial integrity. These findings provide mechanistic insight into how inflammation perturbs stromal cell behaviors to drive fibroblastic responses controlling mucosal matrix remodeling and healing.
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