Genome-wide association studies (GWAS) have revealed risk alleles for ulcerative colitis (UC). To understand their cell type specificities and pathways of action, we generate an atlas of 366,650 ...cells from the colon mucosa of 18 UC patients and 12 healthy individuals, revealing 51 epithelial, stromal, and immune cell subsets, including BEST4+ enterocytes, microfold-like cells, and IL13RA2+IL11+ inflammatory fibroblasts, which we associate with resistance to anti-TNF treatment. Inflammatory fibroblasts, inflammatory monocytes, microfold-like cells, and T cells that co-express CD8 and IL-17 expand with disease, forming intercellular interaction hubs. Many UC risk genes are cell type specific and co-regulated within relatively few gene modules, suggesting convergence onto limited sets of cell types and pathways. Using this observation, we nominate and infer functions for specific risk genes across GWAS loci. Our work provides a framework for interrogating complex human diseases and mapping risk variants to cell types and pathways.
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•51 cell subsets in colon mucosa of 18 ulcerative colitis and 12 healthy individuals•M-like cells, inflammatory monocytes and fibroblasts, and CD8+IL-17+ T cells expand in disease•Oncostatin M circuit in inflammatory monocytes and fibroblasts may affect drug response•Co-expression of genes within cells allows inference of causal genes across risk loci
Single-cell analyses of colon biopsy specimens from patients with ulcerative colitis delineate how expression patterns and shifting cell populations may shape disease and drug resistance, and provide a framework for linking GWAS risk loci with specific cell types and functional pathways.
The gut microbiome plays a central role in inflammatory bowel diseases (IBDs) pathogenesis and propagation. To determine whether the gut microbiome may predict responses to IBD therapy, we conducted ...a prospective study with Crohn’s disease (CD) or ulcerative colitis (UC) patients initiating anti-integrin therapy (vedolizumab). Disease activity and stool metagenomes at baseline, and weeks 14, 30, and 54 after therapy initiation were assessed. Community α-diversity was significantly higher, and Roseburia inulinivorans and a Burkholderiales species were more abundant at baseline among CD patients achieving week 14 remission. Several significant associations were identified with microbial function; 13 pathways including branched chain amino acid synthesis were significantly enriched in baseline samples from CD patients achieving remission. A neural network algorithm, vedoNet, incorporating microbiome and clinical data, provided highest classifying power for clinical remission. We hypothesize that the trajectory of early microbiome changes may be a marker of response to IBD treatment.
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•Stool metagenomes of IBD patients starting biologic therapy were prospectively assessed•Higher abundance of butyrate producers at baseline in therapy-responsive CD patients•Baseline enrichment of 13 microbial pathways in therapy-responsive CD patients•Early microbial changes at week 14 persist up to 1 year in responders
Gut microbiome may predict responses to clinical therapy. Ananthakrishnan et al. conducted a prospective study with IBD patients initiating anti-integrin therapy. Higher abundance of butyrate producers and enrichment of 13 microbial pathways at baseline in therapy-responsive CD patients was observed. Early microbial changes persist up to 1 year in responders.
Alcohol-related liver disease (ALD) accounts for the majority of cirrhosis and liver-related deaths worldwide. Activation of IFN-regulatory factor (IRF3) initiates alcohol-induced hepatocyte ...apoptosis, which fuels a robust secondary inflammatory response that drives ALD. The dominant molecular mechanism by which alcohol activates IRF3 and the pathways that amplify inflammatory signals in ALD remains unknown. Here we show that cytoplasmic sensor cyclic guanosine monophosphate-adenosine monophosphate (AMP) synthase (cGAS) drives IRF3 activation in both alcoholinjured hepatocytes and the neighboring parenchyma via a gap junction intercellular communication pathway. Hepatic RNA-seq analysis of patients with a wide spectrum of ALD revealed that expression of the cGAS-IRF3 pathway correlated positively with disease severity. Alcohol-fed mice demonstrated increased hepatic expression of the cGAS-IRF3 pathway. Mice genetically deficient in cGAS and IRF3 were protected against ALD. Ablation of cGAS in hepatocytes only phenocopied this hepatoprotection, highlighting the critical role of hepatocytes in fueling the cGAS-IRF3 response to alcohol. We identified connexin 32 (Cx32), the predominant hepatic gap junction, as a critical regulator of spreading cGAS-driven IRF3 activation through the liver parenchyma. Disruption of Cx32 in ALD impaired IRF3-stimulated gene expression, resulting in decreased hepatic injury despite an increase in hepatic steatosis. Taken together, these results identify cGAS and Cx32 as key factors in ALD pathogenesis and as potential therapeutic targets for hepatoprotection.
Background
Eosinophilic gastrointestinal disorders (EGIDs) include inflammatory conditions with enteric infiltration of eosinophils and resulting symptoms. This study aims to examine a ...population-based sample of patients for prevalence, mortality, and cancer risk in EGIDs distal to the esophagus.
Methods
Nationwide, population-based cohort study. EGID was identified through relevant biopsy codes from Sweden’s all 28 pathology departments through the ESPRESSO cohort. Individuals with EGID were then matched to general population reference individuals with similar age and sex. Study participants were linked to Swedish healthcare registers. Through Cox regression, we calculated adjusted hazard ratios (aHRs) adjusting for sex, age, county, calendar period, and education.
Results
In total, 2429 patients (56% female) were found to have EGID distal to the esophagus, representing a prevalence of about 1/4800 in the Swedish population. Mean age was 44 years with 11% children at the time of diagnosis. Mortality was increased 17% in patients with EGIDs compared to reference individuals (aHR = 1.17; 95%CI = 1.04–1.33). Excess mortality was seen in gastric and small bowel eosinophilic disease, but not colonic disease (aHR = 1.81; 95%CI = 1.32–2.48, aHR = 1.50; 95%CI = 1.18–1.89, and aHR = 0.99; 95%CI = 0.85–1.16, respectively). Cause specific mortality was driven by cancer-related death (aHR = 1.33; 95%CI = 1.05–1.69). However, this study failed to show an increase in incident cancers (aHR = 1.14; 95%CI = 0.96–1.35). Comparison of EGID individuals with their siblings yielded similar aHRs.
Conclusions
This study found an increased risk of death in patients with EGIDs distal to the esophagus, with cancer death driving the increase. Proximal gut disease seems to confer the greatest risk. There was no increase in incident cancers.
Background
Eosinophilic esophagitis (EoE) is a chronic inflammatory condition of the esophagus associated with dysphagia and esophageal fibrosis. The incidence of EoE is not precisely known, and ...significant heterogeneity in study design and disease definition have led to widely variable estimates. Through the ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden) study we performed a nationwide population-based study to estimate the incidence and temporal patterns of biopsy-verified EoE.
Methods
Between October 2015 and April 2017, we contacted all pathology departments in Sweden (
n
= 28) to obtain biopsy report data on EoE. To assure a high degree of completeness, we restricted the study to 2004–2015. We then calculated age-specific and age-standardized incidence rates.
Results
We identified 1412 incident EoE cases between 2004–2015. The overall age-standardized incidence rates of EoE in Sweden was 1.22 per 100,000 person-years. During the study period, there was a significant increase of 33% 95%CI = 31–36% (
P
< 0.001) per year in EoE incidence, and in the last 3 years of follow-up (2013–2015) the incidence was 2.79 per 100,000 person-years. This corresponds to a lifetime risk of biopsy-verified EoE for men of 0.33% (1 in 295 men) and for women 0.12% (1 in 813 women). We observed an early peak of EoE disgnosed at age 15–19 years for both males and females, and a second peak in the late 30 s for males, and early 40 s for females. We noted a 3:1 male-to-female predominance, which did not significantly vary over time.
Conclusions
EoE seems to be increasing in Sweden, with an overall age-standardized incidence of EoE of 1.22 per 100,000 person-years in the last decade.
Several gastrointestinal and allergic diseases have been linked to psychiatric disease, but there is limited data on psychiatric disease in eosinophilic esophagitis (EoE). Our aim is to study the ...association between EoE and later psychiatric disorders.
Population-based nationwide cohort study. Individuals with EoE diagnosed 1989-2017 in Sweden (n=1458) were identified through the ESPRESSO histopathology cohort that represents all gastrointestinal biopsy reports in Sweden's 28 pathology departments. EoE individuals were matched with up to five reference individuals on sex, age, county, and calendar year (n=6436). Cox proportional hazard modeling estimated adjusted hazard ratios (HRs). In a secondary analysis we compared EoE individuals with their siblings to adjust for intrafamilial confounding.
Median age at EoE diagnosis was 39 years, and 76% of the enrolled EoE individuals were male. During a median follow-up of 4 years, 106 EoE individuals (15.96/1000 person-years) developed a psychiatric disorder compared with 331 (10.93/1000 person-years) reference individuals, corresponding to HR of 1.50 (95%CI=1.20-1.87). The increased risk was seen in the first five years of follow-up, but not thereafter. The highest relative risks were seen in individuals diagnosed with EoE in childhood. Compared with siblings, individuals with EoE were at an increased risk of psychiatric disease (HR=1.62 (95%CI=1.14-2.31)). EoE was linked to mood disorders, anxiety disorder and attention-deficit hyperactivity disorder.
Individuals with EoE may be at greater risk of psychiatric disease than their siblings and the general population. This risk needs to be considered in clinical care to detect, prevent, and treat comorbidity.
Accurate interpretation of DNA sequence variation is a prerequisite for implementing personalized medicine. Discrepancies in interpretation between testing laboratories impede the effective use of ...genetic test results in clinical medicine. To better understand the underpinnings of these discrepancies, we quantified differences in variant classification internally over time and those between our diagnostic laboratory and other laboratories and resources. We assessed the factors that contribute to these discrepancies and those that facilitate their resolution. Our process resolved 72% of nearly 300 discrepancies between pairs of laboratories to within a one-step classification difference and identified key sources of data that facilitate changes in variant interpretation. The identification and harmonization of variant discrepancies will maximize the clinical use of genetic information; these processes will be fostered by the accumulation of additional population data as well as the sharing of data between diagnostic laboratories.
Despite its increasing prevalence, the economic impact of eosinophilic esophagitis (EoE) is understudied.
We estimated the societal economic burden of EoE by using real-world data from Swedish health ...registers.
EoE patients had 45% higher societal cost ($6,290 vs. $4,349) compared with the general population, primarily driven by increased healthcare costs ($2,414 vs. $1,022) which accounted for 72% of the excess societal cost in EoE.
EoE is associated with a considerable economic burden to society. With the prevalence of EoE still rising, the economic burden of EoE is expected to continue to grow.
Coordinated cell interactions within the esophagus maintain homeostasis, and disruption can lead to eosinophilic esophagitis (EoE), a chronic inflammatory disease with poorly understood pathogenesis. ...We profile 421,312 individual cells from the esophageal mucosa of 7 healthy and 15 EoE participants, revealing 60 cell subsets and functional alterations in cell states, compositions, and interactions that highlight previously unclear features of EoE. Active disease displays enrichment of ALOX15
macrophages, PRDM16
dendritic cells expressing the EoE risk gene ATP10A, and cycling mast cells, with concomitant reduction of T
17 cells. Ligand-receptor expression uncovers eosinophil recruitment programs, increased fibroblast interactions in disease, and IL-9
IL-4
IL-13
T
2 and endothelial cells as potential mast cell interactors. Resolution of inflammation-associated signatures includes mast and CD4
T
cell contraction and cell type-specific downregulation of eosinophil chemoattractant, growth, and survival factors. These cellular alterations in EoE and remission advance our understanding of eosinophilic inflammation and opportunities for therapeutic intervention.
Background & Aims Emerging data suggest that changes in intestinal permeability and increased gut microbial translocation contribute to the inflammatory pathway involved in nonalcoholic ...steatohepatitis (NASH) development. Numerous studies have investigated the association between increased intestinal permeability and NASH. Our meta-analysis of this association investigates the underlying mechanism. Methods A meta-analysis was performed to compare the rates of increased intestinal permeability in patients with NASH and healthy controls. To further address the underlying mechanism of action, we studied changes in intestinal permeability in a diet-induced (methionine-and-choline-deficient; MCD) murine model of NASH. In vitro studies were also performed to investigate the effect of MCD culture medium at the cellular level on hepatocytes, Kupffer cells, and intestinal epithelial cells. Results Nonalcoholic fatty liver disease (NAFLD) patients, and in particular those with NASH, are more likely to have increased intestinal permeability compared with healthy controls. We correlate this clinical observation with in vivo data showing mice fed an MCD diet develop intestinal permeability changes after an initial phase of liver injury and tumor necrosis factor-α (TNFα) induction. In vitro studies reveal that MCD medium induces hepatic injury and TNFα production yet has no direct effect on intestinal epithelial cells. Although these data suggest a role for hepatic TNFα in altering intestinal permeability, we found that mice genetically resistant to TNFα-myosin light chain kinase (MLCK)–induced intestinal permeability changes fed an MCD diet still develop increased permeability and liver injury. Conclusions Our clinical and experimental results strengthen the association between intestinal permeability increases and NASH and also suggest that an early phase of hepatic injury and inflammation contributes to altered intestinal permeability in a fashion independent of TNFα and MLCK.
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