An esophagus cell atlas reveals dynamic rewiring during active eosinophilic esophagitis and remission.

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 TH17 cells. Ligand-receptor expression uncovers eosinophil recruitment programs, increased fibroblast interactions in disease, and IL-9+IL-4+IL-13+ TH2 and endothelial cells as potential mast cell interactors. Resolution of inflammation-associated signatures includes mast and CD4+ TRM 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.

Eosinophilic esophagitis is associated with increased risk of later inflammatory bowel disease in a nationwide Swedish population cohort.

BACKGROUND: Earlier studies on the possible association between eosinophilic esophagitis (EoE) and inflammatory bowel disease (IBD) have been contradictory. METHODS: Patients with biopsy-verified EoE diagnosed between 1990 and 2017 in Sweden (n = 1587) were age- and sex-matched with up to five general population reference individuals (n = 7808). EoE was defined using pathology reports from all 28 pathology centers in Sweden (the ESPRESSO study). Multivariate Cox regression then estimated hazard ratios for future IBD. IBD was defined based on the international classification of disease codes and histopathology codes. In secondary analyses, sibling comparators were used to further reduce potential familial confounding. Additionally, we performed logistic regression examining earlier IBD in EoE. RESULTS: During follow-up until 2020, 16 (0.01%) EoE patients and 21 (0.003%) general population reference individuals diagnosed with IBD, corresponding to a 3.5-fold increased risk of future IBD (aHR = 3.56; 95% CI 1.79-7.11). EoE was linked to Crohn's disease (aHR = 3.39 [95% CI 1.02-9.60]) but not to ulcerative colitis (aHR = 1.37; 95% CI 0.38-4.86). Compared to their siblings, patients with EoE were at a 2.48-fold increased risk of IBD (aHR = 2.48; 95% CI 0.92-6.70). Earlier IBD was 15 times more likely in EoE patients than in matched reference individuals (odds ratio, 15.39; 95% CI 7.68-33.59). CONCLUSION: In this nationwide cohort study, EoE was associated with a 3.5-fold increased risk of later IBD diagnosis. This risk increase may be due to shared genetic or early environmental risk factors, but also surveillance bias could play a role.

Pregnancy Outcomes in Females with Eosinophilic Esophagitis: A Nationwide Population-Based Study.

Introduction: Eosinophilic esophagitis (EoE) is a chronic, allergic inflammatory disease of the esophagus. It has a peak incidence in the 2nd and 3rd decades of life. Despite this, little is known about pregnancy outcomes in patients with EoE. Methods: Using a validated histopathologic and nationwide population-based cohort for the diagnosis of EoE, we examined maternal and fetal outcomes, with preterm birth as the primary outcome, in females with EoE compared to matched controls. Odds ratios (ORs) were calculated using logistic regression. Results: Between 1992 and 2016, we identified 19 females with EoE who gave birth to 23 children (reference births: n = 115). There was 1 (4.3%) preterm birth in the EoE cohort versus 8 (7.0%) in the reference cohort (OR = 0.60; 95% CI = 0.07-5.14). Secondary fetal outcomes included stillbirth, neonatal death, small for gestational age, low birth weight (LBW), and low Apgar score. Of these, LBW (<2,500 g) in patients with EoE compared to controls correlated to an OR of 12.42 (95% CI = 1.26-122.42); however, this finding was based on very low numbers. The remaining fetal outcomes were not significantly different between females with EoE and controls. Secondary pregnancy and maternal outcomes including induction of labor, instrumental delivery, gestational diabetes, or pre-eclampsia were not significantly different between patients with EoE and controls. Discussion/Conclusion: Overall in this nationwide cohort study, we did not find increased association of preterm birth in patients with EoE.

Prior hospital-based infection and risk of eosinophilic esophagitis in a Swedish nationwide case-control study.

BACKGROUND AND AIMS: Eosinophilic esophagitis (EoE) is an increasingly common, largely food allergen-driven disease characterized by dysphagia. Prior infections are known to associate with other loss of tolerance diseases such as autoimmunity. We aimed to determine if antecedent infection was associated with later EoE development. METHODS: We performed a case-control study of all patients with biopsy-verified EoE diagnosed between 2000 and 2017 in Sweden (n = 1587) and matched to 5 general population controls (n = 7660). Cases were identified using histopathology codes from the Epidemiology Strengthened by histopathology Reports in Sweden study, a validated cohort of gastrointestinal pathology reports from all 28 pathology centers in Sweden. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals for antecedent infections from patients seen at hospital-based outpatient clinics or inpatients. In secondary analyses, we compared EoE patients with their full siblings to further reduce residual confounding. RESULTS: 564 (35.7%) EoE patients and 1793 (23.4%) matched controls had an earlier record of infection. This corresponded to a 2-fold increased risk of infections in EoE patients (OR 2.01; 95%CI: 1.78-2.27). ORs for earlier gastrointestinal or respiratory infection were 2.73 (n = 128 EoE, 268 control; 95%CI: 2.17-3.41) and 1.89 (n = 305 EoE, 960 control; 95%CI: 1.63-2.20), respectively. Having an EoE diagnosis was linked to a 3.39-fold increased odds of sepsis (n = 14 EoE, 21 control; 95%CI: 1.68-6.65). Individuals with EoE were also more likely to have had an infection compared to their non-EoE siblings (n = 427 EoE, 593 control; OR = 1.57; 95%CI = 1.30-1.89). CONCLUSION: In this nationwide cohort study, prior infection, was associated with subsequent EoE. Risks were particularly high after sepsis, and gastrointestinal or respiratory infections.

Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation.

Environmental enteropathy (EE) is a subclinical condition of the small intestine that is highly prevalent in low- and middle-income countries. It is thought to be a key contributing factor to childhood malnutrition, growth stunting, and diminished oral vaccine responses. Although EE has been shown to be the by-product of a recurrent enteric infection, its full pathophysiology remains unclear. Here, we mapped the cellular and molecular correlates of EE by performing high-throughput, single-cell RNA-sequencing on 33 small intestinal biopsies from 11 adults with EE in Lusaka, Zambia (eight HIV-negative and three HIV-positive), six adults without EE in Boston, United States, and two adults in Durban, South Africa, which we complemented with published data from three additional individuals from the same clinical site. We analyzed previously defined bulk-transcriptomic signatures of reduced villus height and decreased microbial translocation in EE and showed that these signatures may be driven by an increased abundance of surface mucosal cells-a gastric-like subset previously implicated in epithelial repair in the gastrointestinal tract. In addition, we determined cell subsets whose fractional abundances associate with EE severity, small intestinal region, and HIV infection. Furthermore, by comparing duodenal EE samples with those from three control cohorts, we identified dysregulated WNT and MAPK signaling in the EE epithelium and increased proinflammatory cytokine gene expression in a T cell subset highly expressing a transcriptional signature of tissue-resident memory cells in the EE cohort. Together, our work elucidates epithelial and immune correlates of EE and nominates cellular and molecular targets for intervention.

Models and Tools for Investigating Eosinophilic Esophagitis at the Bench.

Eosinophilic esophagitis (EoE) is an increasingly common food allergy disease of the esophagus that received its medical designation code in 2008. Despite this recency, great strides have been made in the understanding of EoE pathophysiology and type 2 immunity through basic and translational scientific investigations conducted at the bench. These advances have been critical to our understanding of disease mechanisms and generating new hypotheses, however, there currently is only one very recently approved FDA-approved therapy for EoE, leaving a great deal to be uncovered for patients with this disease. Here we review some of the innovative methods, models and tools that have contributed to the advances in EoE discovery and suggest future directions of investigation to expand upon this foundation.

Mortality and cancer in eosinophilic gastrointestinal disorders distal to the esophagus: nationwide cohort study 1990-2017.

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.

Risk of fractures in individuals with eosinophilic esophagitis: nationwide population-based cohort study.

BACKGROUND AND AIMS: Eosinophilic esophagitis (EoE) is an emerging, chronic immune-mediated disease for which swallowed topical steroids and proton pump inhibitors (PPIs) represent first-line treatments. Immune-mediated diseases, steroids, and PPI use have been linked to osteoporosis. We assessed the risk of fractures in patients with EoE and determined whether the most commonly used treatments for EoE were associated with increased fracture risk. METHODS: We followed a nationwide cohort of 1263 individuals in Sweden with biopsy-verified EoE diagnosed between 2005 and 2016 for first-time fracture of any type. Age- and sex-matched reference individuals were retrieved from the Total Population Register (n = 5164). We estimated hazard ratios (HRs) for fracture in relation to EoE diagnosis, steroid exposure, and PPI use. In a separate analysis, we compared fracture risk among individuals with EoE to their siblings (n = 1394). RESULTS: During 4521 person-years of follow-up, 69 individuals with EoE experienced a first-time fracture (15.3/1000 person-years) compared with 234 reference individuals (12.6/1000 person-years). After adjusting for age, sex, birth year, and county of residence, EoE was not associated with a statistically significantly increased risk of fractures (HR = 1.2, 95% CI = 0.9-1.6). Among EoE individuals, exposure to PPIs and swallowed steroids did not modify the risk of fracture (p for heterogeneity 0.20 and 0.07 respectively). There was no increased risk of fractures in EoE compared to EoE-free siblings. CONCLUSION: The risk of fracture in EoE was not statistically significantly elevated compared to non-EoE reference individuals. Fracture risk in EoE was not modified by PPIs or steroid use.

Increasing incidence of eosinophilic esophagitis in Sweden: a nationwide population study.

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.

Individuals With Eosinophilic Esophagitis Are at Greater Risk of Later Psychiatric Disorder.

INTRODUCTION: Several gastrointestinal and allergic diseases have been linked to psychiatric disease, but there are limited data on psychiatric disease in eosinophilic esophagitis (EoE). Our aim was to study the association between EoE and later psychiatric disorders. METHODS: This was a population-based nationwide cohort study. Individuals with EoE diagnosed during 1989-2017 in Sweden (n = 1,458) were identified through the ESPRESSO histopathology cohort that represents all gastrointestinal biopsy reports in Sweden's 28 pathology departments. Individuals with EoE were matched with up to 5 reference individuals on sex, age, county, and calendar year (n = 6,436). Cox proportional hazard modeling estimated adjusted hazard ratios (HRs). In a secondary analysis, we compared individuals with EoE with their siblings to adjust for intrafamilial confounding. RESULTS: The median age at EoE diagnosis was 39 years, and 76% of the enrolled individuals with EoE were male. During a median follow-up of 4 years, 106 individuals with EoE (15.96/1,000 person-years) developed a psychiatric disorder compared with 331 reference individuals (10.93/1,000 person-years), corresponding to an HR of 1.50 (95% confidence interval = 1.20-1.87). The increased risk was seen in the first 5 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% confidence interval = 1.14-2.31). EoE was linked to mood disorders, anxiety disorder, and attention-deficit hyperactivity disorder. DISCUSSION: 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.

Mortality in Eosinophilic Esophagitis - a nationwide, population-based matched cohort study from 2005 to 2017.

BACKGROUND: There is a lack of knowledge about mortality in eosinophilic esophagitis (EoE). Therefore, this study aimed to examine the mortality in EoE. METHODS: A nationwide, population-based matched cohort study was conducted of all EoE patients in Sweden diagnosed between July 2005 and December 2017. Individuals with EoE (n = 1,625) were identified through prospectively recorded histopathology codes from all gastrointestinal pathology reports in Sweden, representing 28 pathology departments (the ESPRESSO study). Each individual with EoE was then matched with up to five reference individuals from the general population (n = 8,003) for age, sex, year of birth, and place of residence. We used the Cox proportional hazard modeling to estimate the adjusted hazard ratio (aHR) and 95% confidence interval (95% CI) while adjusting for other potential confounders. In sensitivity analyses, mortality in EoE patients was compared with mortality in their siblings. RESULTS: Through December 2017, 34 deaths were confirmed in EoE patients (4.60 per 1,000 person-years) compared with 165 in reference individuals (4.57 per 1,000 person-years). This rate corresponds to an aHR of 0.97 (95% CI = 0.67-1.40). HRs were similar in males (aHR = 1.00 [0.66-1.51]) and females (aHR = 0.92 [0.38-2.18]). We observed no increased risk in mortality due to esophageal or other gastrointestinal cancers in patients with EoE (aHR = 1.02 [0.51-2.02]).Mortality was similar in EoE patients and their siblings (aHR = 0.91 [0.44-1.85]). CONCLUSION: In this nationwide, population-based matched cohort study in Sweden, there was no increased risk of death in patients with EoE compared with their siblings and the general population.

Validation of the diagnosis of eosinophilic esophagitis based on histopathology reports in Sweden.

BACKGROUND: Eosinophilic esophagitis (EoE) is a relatively new diagnosis, where until recently a specific international classification of disease code was missing. One way to identify patients with EoE is to use histopathology codes. We validated the clinicopathological EoE diagnosis based on histopathology reports and patient charts to establish these data sources as the basis for a nationwide EoE patient cohort. METHODS: Through the Epidemiology Strengthened by histoPathology Reports in Sweden (ESPRESSO) study, we randomly selected 165 patients from five Swedish health care regions with a histopathologic diagnosis of EoE. Patients were assigned a histopathology diagnosis of EoE if they had ≥15 eosinophils per high-power field or, in the absence of eosinophil quantification, the pathologist interpreted the biopsy as consistent with EoE. Patient charts were scrutinized to see if the other diagnostic criteria were fulfilled. Of the 131 received patient charts, 111 (85%) had sufficient information to be included in the study. RESULTS: Of the 111 validated patients, 99 had EoE, corresponding to a positive predictive value of 89% (95% confidence interval = 82-94%). Dysphagia was the most common symptom (n = 78, 70%), followed by food impaction (n = 64, 58%) and feeding difficulties (n = 37, 33%). Twelve patients had coexisting asthma (11%) and 16 allergic rhinitis (14%). Seventeen patients underwent esophageal dilatation (15%), of which seven had more than one dilatation. Ninety-seven (87%) patients had a proton-pump inhibitor treatment ≤2 years before or after the diagnosis. Forty-two patients (38%) had been prescribed inhalation steroids and 64 (58%) had undergone esophageal radiology. CONCLUSION: Histopathology reports from the ESPRESSO cohort with esophageal eosinophilic inflammation are suggestive of EoE.

Alterations in Fecal Microbiomes and Serum Metabolomes of Fatigued Patients With Quiescent Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Fatigue is frequent and disabling in patients with inflammatory bowel diseases (IBD) but its mechanisms are poorly understood. We investigated alterations in fecal microbiomes and serum metabolomes and proteomes in patients with quiescent IBD, with vs without fatigue. METHODS: We performed a prospective observational study of patients (44% women; mean age, 39.8 y) with clinically and endoscopically quiescent Crohn's disease (n = 106) or ulcerative colitis (n = 60) at a tertiary hospital, from March 2016 through December 2018. Fatigue was assessed using the functional assessment of chronic illness therapy-fatigue scoring system and defined as a score of 43 or less. We performed metabolomic analysis of serum samples using liquid chromatography-mass spectrometry methods and proteomic analysis using multiplex proximity extension assay (PEA) technology. Stool samples were obtained from 50 patients and analyzed by shotgun metagenomic sequencing on Illumina HiSeq platform. RESULTS: Of the 166 study participants, 91 (55%) were fatigued. Serum samples from patients with fatigue (n = 59) did not have significant increases in levels of inflammatory cytokines compared with serum samples from nonfatigued patients (n = 72). We found a statistically significant difference in a cluster of 18 serum metabolites between patients with fatigue (n = 84) vs without fatigue (n = 72) (P = .033); serum samples from patients with fatigue had significant reductions in levels of methionine (P = .020), tryptophan (P = .042), proline (P = .017), and sarcosine (P = .047). Fecal samples from patients with fatigue had a less diverse gut microbiome, with significant reductions in butyrate-producing bacteria, including Faecalibacterium prausnitzii (P = .0002, q =.007) and Roseburia hominis (P = .0079, q = 0.105). This fatigue-like microbiome was associated with fatigue scales and correlated with progressive depletion of metabolites from serum samples. CONCLUSIONS: In an analysis of fecal and serum samples from 166 patients with IBD, we found alterations in serum metabolites and fecal microbes that were associated with fatigue.

Assessment of Body Weight Changes in Patients with Inflammatory Bowel Diseases Initiating Biologic Therapy: A Prospective Cohort Study.

BACKGROUND: Prior studies have inconsistently suggested that biologic therapy may be associated with weight gain in inflammatory bowel disease patients (IBD). Our aim was to compare weight gain across different biologic therapy classes with distinct mechanisms of action. METHODS: This prospective cohort study recruited patients with moderate to severe IBD initiating outpatient biologic therapy with anti-TNF (infliximab, adalimumab), vedolizumab, or ustekinumab. Weight measurements were performed at weeks 0, 14, 30, and 54. Changes in weight between baseline and each of the follow-up visits were modeled as a continuous variable, and multivariate regression assessed the independent effect of therapeutic class on this outcome. RESULTS: Our study enrolled 269 patients (163 CD, 106 UC) initiating biologic therapy [99 anti-TNF (37%), 122 vedolizumab (45%), 48 ustekinumab (18%)]. From baseline, the weight significantly increased at week 14 with a mean of 0.36 kg (± 3.8 kg, p = 0.004) and continued to increase compared to baseline with 0.96 kg (± 3.9 kg, p < 0.001) and 1.29 kg (± 4.2 kg, p < 0.001) at week 30 and 54, respectively. On univariate and multivariable analysis, no significant differences between any of the biologic therapies for weight gain were seen at any time point (weight gain anti-TNF: 0.31 kg, 1.06 kg, 1.33 kg; VDZ: 0.30 kg, 0.83 kg, 1.10 kg; UST: 0.63 kg, 1.21 kg, 2.31 kg at wk 14, wk 30, and wk 54, respectively). None of the disease activity parameters showed any statistical association with weight gain. CONCLUSION: There was no difference in weight gain among the different biologic therapeutic classes.

Effect of Low-dose and Standard-dose Aspirin on PGE2 Biosynthesis Among Individuals with Colorectal Adenomas: A Randomized Clinical Trial.

Low-dose aspirin is recommended by the U.S. Preventive Services Task Force for primary prevention of colorectal cancer in certain individuals. However, broader implementation will require improved precision prevention approaches to identify those most likely to benefit. The major urinary metabolite of PGE2, 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), is a biomarker for colorectal cancer risk, but it is unknown whether PGE-M is modifiable by aspirin in individuals at risk for colorectal cancer. Adults (N = 180) who recently underwent adenoma resection and did not regularly use aspirin or NSAIDs were recruited to a double-blind, placebo-controlled, randomized trial of aspirin at 81 or 325 mg/day for 8-12 weeks. The primary outcome was postintervention change in urinary PGE-M as measured by LC/MS. A total of 169 participants provided paired urine samples for analysis. Baseline PGE-M excretion was 15.9 ± 14.6 (mean ± S.D, ng/mg creatinine). Aspirin significantly reduced PGE-M excretion (-4.7 ± 14.8) compared with no decrease (0.8 ± 11.8) in the placebo group (P = 0.015; mean duration of treatment = 68.9 days). Aspirin significantly reduced PGE-M levels in participants receiving either 81 (-15%; P = 0.018) or 325 mg/day (-28%; P < 0.0001) compared with placebo. In 40% and 50% of the individuals randomized to 81 or 325 mg/day aspirin, respectively, PGE-M reduction reached a threshold expected to prevent recurrence in 10% of individuals. These results support that aspirin significantly reduces elevated levels of PGE-M in those at increased colorectal cancer risk to levels consistent with lower risk for recurrent neoplasia and underscore the potential utility of PGE-M as a precision chemoprevention biomarker. The ASPIRED trial is registered as NCT02394769.

Hepatic gap junctions amplify alcohol liver injury by propagating cGAS-mediated IRF3 activation.

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 alcohol-injured 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.

Longitudinal Trajectory of Fatigue With Initiation of Biologic Therapy in Inflammatory Bowel Diseases: A Prospective Cohort Study.

BACKGROUNDS AND AIMS: Fatigue is prevalent in patients with inflammatory bowel diseases [IBD]. Biologic therapy is effective in achieving symptomatic and endoscopic remission, but its impact on fatigue is less well established. Our aim is to define the longitudinal trajectory of fatigue over 1 year in patients initiating biologic therapy. METHODS: This prospective cohort enrolled patients diagnosed with Crohn's disease [CD] or ulcerative colitis [UC] initiating biologic therapy with infliximab, adalimumab, ustekinumab, or vedolizumab. Fatigue was quantified using the seven-point fatigue question in the Short Inflammatory Bowel Disease Questionnaire [SIBDQ]. A score of ≤4 for this question was used to define fatigue. Multivariable regression models adjusting for relevant confounders examined the independent association between attaining clinical remission and resolution of fatigue. RESULTS: Our study included 326 patients [206 CD, 120 UC] initiating biologic therapy [144 anti-tumour necrosis factor, 129 vedolizumab, 63 ustekinumab]. A total of 61% of the included patients reported significant fatigue at baseline. This was associated with female gender, depressive symptoms, active disease, and disturbed sleep [p < 0.001]. Among the 198 patients who were fatigued at therapy initiation, 86 [70%], 55 [63%], and 44 [61%] remained fatigued at Week 14, 30, and 54, respectively. At each of these time points, achieving clinical remission was associated with lower likelihood of persistent fatigue. However, despite achieving remission, 35%, 30%, and 28% of patients experienced persistent fatigue at Week 14, 30, and 54, respectively. CONCLUSIONS: Fatigue is common in IBD. Though biologic therapy improves fatigue parallel symptomatic improvement, a significant proportion continue to experience persistent fatigue up to 1 year.

Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis.

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.

A miniaturized, tethered, spectrally-encoded confocal endomicroscopy capsule.

BACKGROUND AND OBJECTIVE: The tethered spectrally-encoded confocal endomicroscopy (SECM) capsule is an imaging device that once swallowed by an unsedated patient can visualize cellular morphologic changes associated with gastrointestinal (GI) tract diseases in vivo. Recently, we demonstrated a tethered SECM capsule for counting esophageal eosinophils in patients with eosinophilic esophagitis (EoE) in vivo. Yet, the current tethered SECM capsule is far too long to be widely utilized for imaging pediatric patients, who constitute a major portion of the EoE patient population. In this paper, we present a new tethered SECM capsule that is 33% shorter, has an easier and repeatable fabrication process, and produces images with reduced speckle noise. MATERIALS AND METHODS: The smaller SECM capsule utilized a miniature condenser to increase the fiber numerical aperture and reduce the capsule length. A custom 3D-printed holder was developed to enable easy and repeatable device fabrication. A dual-clad fiber (DCF) was used to reduce speckle noise. RESULTS: The fabricated SECM capsule (length = 20 mm; diameter = 7 mm) had a similar size and shape to a pediatric dietary supplement pill. The new capsule achieved optical sectioning thickness of 13.2 µm with a small performance variation between devices of 1.7 µm. Confocal images of human esophagus obtained in vivo showed the capability of this new device to clearly resolve microstructural epithelial details with reduced speckle noise. CONCLUSIONS: We expect that the smaller size and better image performance of this new SECM capsule will greatly facilitate the clinical adoption of this technology in pediatric patients and will enable more accurate assessment of EoE-suspected tissues. Lasers Surg. Med. 51:452-458, 2019. © 2019 Wiley Periodicals, Inc.