Clinical Activity and Quality of Life Indices Are Valid Across Ulcerative Colitis But Not Crohn's Disease Phenotypes.
Digestive Diseases and Sciences 61(9):2627 (2016)
Clinical activity and quality of life (QOL) indices assess disease activity in Crohn's disease (CD) and ulcerative colitis (UC). However, a paucity of data exists on the validity of these indices according to disease characteristics.
To examine the correlation between QOL and clinical activity i...
Development of Chemical Probes for Investigation of Salt-Inducible Kinase Function in Vivo.
ACS Chemical Biology 11(8):2105 (2016)
Salt-inducible kinases (SIKs) are promising therapeutic targets for modulating cytokine responses during innate immune activation. The study of SIK inhibition in animal models of disease has been limited by the lack of selective small-molecule probes suitable for modulating SIK function in vivo....
Understanding human immune function using the resources from the Human Functional Genomics Project.
Nature Medicine 22(8):831 (2016)
Inter-individual variability and genetic influences on cytokine responses to bacteria and fungi.
Nature Medicine 22(8):952 (2016)
Little is known about the inter-individual variation of cytokine responses to different pathogens in healthy individuals. To systematically describe cytokine responses elicited by distinct pathogens and to determine the effect of genetic variation on cytokine production, we profiled cytokines pr...
Profiling DNA damage-induced phosphorylation in budding yeast reveals diverse signaling networks.
PNAS 113(26):E3667 (2016)
The DNA damage response (DDR) is regulated by a protein kinase signaling cascade that orchestrates DNA repair and other processes. Identifying the substrate effectors of these kinases is critical for understanding the underlying physiology and mechanism of the response. We have used quantitative...
Genetic Coding Variant in GPR65 Alters Lysosomal pH and Links Lysosomal Dysfunction with Colitis Risk.
Immunity 44(6):1392 (2016)
Although numerous polymorphisms have been associated with inflammatory bowel disease (IBD), identifying the function of these genetic factors has proved challenging. Here we identified a role for nine genes in IBD susceptibility loci in antibacterial autophagy and characterized a role for one of...
Natural history of the infant gut microbiome and impact of antibiotic treatment on bacterial strain diversity and stability.
Science Translational Medicine 8(343):343ra81 (2016)
The gut microbial community is dynamic during the first 3 years of life, before stabilizing to an adult-like state. However, little is known about the impact of environmental factors on the developing human gut microbiome. We report a longitudinal study of the gut microbiome based on DNA sequenc...
CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands.
Nature Medicine 22(6):598 (2016)
Complex interactions between the host and the gut microbiota govern intestinal homeostasis but remain poorly understood. Here we reveal a relationship between gut microbiota and caspase recruitment domain family member 9 (CARD9), a susceptibility gene for inflammatory bowel disease (IBD) that fu...
Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease.
Science 352(6289):1116 (2016)
Inflammatory bowel disease (IBD) is associated with risk variants in the human genome and dysbiosis of the gut microbiome, though unifying principles for these findings remain largely undescribed. The human commensal Bacteroides fragilis delivers immunomodulatory molecules to immune cells via se...
Simultaneous Pathway Activity Inference and Gene Expression Analysis Using RNA Sequencing.
Cell Systems 2(5):323 (2016)
Reporter gene assays are a venerable tool for studying signaling pathways, but they lack the throughput and complexity necessary to contribute to a systems-level understanding of endogenous signaling networks. We present a parallel reporter assay, transcription factor activity sequencing (TF-seq...
Mechanisms of Pediatric Inflammatory Bowel Disease.
Immunology 34:31 (2016)
Inflammatory bowel disease (IBD), including Crohn disease and ulcerative colitis, is characterized by chronic intestinal inflammation due to a complex interaction of genetic determinants, disruption of mucosal barriers, aberrant inflammatory signals, loss of tolerance, and environmental triggers...
Variation in Microbiome LPS Immunogenicity Contributes to Autoimmunity in Humans.
Cell 165(4):842 (2016)
According to the hygiene hypothesis, the increasing incidence of autoimmune diseases in western countries may be explained by changes in early microbial exposure, leading to altered immune maturation. We followed gut microbiome development from birth until age three in 222 infants in Northern Eu...
Our New President-Timothy C. Wang, MD.
Gastroenterology 150(5):1231 (2016)
Proton pump inhibitors affect the gut microbiome.
Gut 65(5):740 (2016)
Proton pump inhibitors (PPIs) are among the top 10 most widely used drugs in the world. PPI use has been associated with an increased risk of enteric infections, most notably Clostridium difficile. The gut microbiome plays an important role in enteric infections, by resisting or promoting coloni...
New Regulatory Roles of Galectin-3 in High-Affinity IgE Receptor Signaling.
Molecular and Cellular Biology 36(9):1366 (2016)
Aggregation of the high-affinity receptor for IgE (FcεRI) in mast cells initiates activation events that lead to degranulation and release of inflammatory mediators. To better understand the signaling pathways and genes involved in mast cell activation, we developed a high-throughput mast cell d...
Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity.
Science 352(6285):565 (2016)
Deep sequencing of the gut microbiomes of 1135 participants from a Dutch population-based cohort shows relations between the microbiome and 126 exogenous and intrinsic host factors, including 31 intrinsic factors, 12 diseases, 19 drug groups, 4 smoking categories, and 60 dietary factors. These f...
Trained immunity: A program of innate immune memory in health and disease.
Science 352(6284):aaf1098 (2016)
The general view that only adaptive immunity can build immunological memory has recently been challenged. In organisms lacking adaptive immunity, as well as in mammals, the innate immune system can mount resistance to reinfection, a phenomenon termed "trained immunity" or "innate immune memory."...
Flow Cytometric Analysis of Mononuclear Phagocytes in Nondiseased Human Lung and Lung-Draining Lymph Nodes.
American Journal of Respiratory and Critical Ca... 193(6):614 (2016)
The pulmonary mononuclear phagocyte system is a critical host defense mechanism composed of macrophages, monocytes, monocyte-derived cells, and dendritic cells. However, our current characterization of these cells is limited because it is derived largely from animal studies and analysis of human...
Sub-clinical detection of gut microbial biomarkers of obesity and type 2 diabetes.
Genome Medicine 8(1):17 (2016)
Obesity and type 2 diabetes (T2D) are linked both with host genetics and with environmental factors, including dysbioses of the gut microbiota. However, it is unclear whether these microbial changes precede disease onset. Twin cohorts present a unique genetically-controlled opportunity to study ...
A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis.
Nature Communications 7:12342 (2016)
Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants as...