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.

Large caliber empiric esophageal dilation results in sustained improvement for selected patients with non-obstructive dysphagia.

INTRODUCTION: Empiric esophageal dilation (EED) remains a controversial practice for managing non-obstructive dysphagia (NOD) secondary to concerns about safety and efficacy. Here, we examine symptom response, presence of tissue disruption, and adverse events (AEs) after EED. METHODS: We examined large caliber bougie EED for NOD at two tertiary referral centers: retrospectively evaluating for AEs. Esophageal manometry diagnoses were also reviewed. We then prospectively assessed EED's efficacy using the NIH Patient-Reported Outcomes Measurement Information System (PROMIS) disrupted swallowing questionnaire to assess dysphagia at baseline, 1-, 3-, and 6-months after EED. Treatment success was defined by improvement in patient reported outcome score. RESULTS: AE rate for large caliber dilation in the retrospective cohort of 180 patients undergoing EED for NOD was low (0.5% perforations, managed conservatively). Visible tissue disruption occurred in 18% of patients, with 47% occurring in the proximal esophagus. Obstructive motility disorders were found more frequently in patients with tissue disruption compared to those without (44% vs 14%, p=0.05).The primary outcome, the mean disrupted swallowing T-score was 60.1 ± 9.1 at baseline, 56.1 ± 9.5 at 1-month (p=0.03), 57 ± 9.6 at 3-months (p=0.10), and 56 ± 10, 6-months (p=0.02), (higher scores note more symptoms). EED resulted in a significant and durable improvement in dysphagia, and specifically solid food dysphagia among patients with tissue disruption. DISCUSSION: EED is safe in solid food NOD and particularly effective when tissue disruption occurs. EED tissue disruption in NOD does not preclude esophageal dysmotility.

Gastrointestinal diagnoses in patients with eating disorders: A retrospective cohort study 2010-2020.

BACKGROUND AND AIMS: Gastrointestinal (GI) disorders are common in patients with eating disorders. However, the temporal relationship between GI and eating disorder symptoms has not been explored. We aimed to evaluate GI disorders among patients with eating disorders, their relative timing, and the relationship between GI diagnoses and eating disorder remission. METHODS: We conducted a retrospective analysis of patients with an eating disorder diagnosis who had a GI encounter from 2010 to 2020. GI diagnoses and timing of eating disorder onset were abstracted from chart review. Coders applied DSM-5 criteria for eating disorders at the time of GI consult to determine eating disorder remission status. RESULTS: Of 344 patients with an eating disorder diagnosis and GI consult, the majority (255/344, 74.2%) were diagnosed with an eating disorder prior to GI consult (preexisting eating disorder). GI diagnoses categorized as functional/motility disorders were most common among the cohort (57.3%), particularly in those with preexisting eating disorders (62.5%). 113 (44.3%) patients with preexisting eating disorders were not in remission at GI consult, which was associated with being underweight (OR 0.13, 95% CI 0.04-0.46, p < 0.001) and increasing number of GI diagnoses (OR 0.47 per diagnosis, 95% CI 0.26-0.85, p = 0.01). CONCLUSIONS: Eating disorder symptoms precede GI consult for most patients, particularly in functional/motility disorders. As almost half of eating disorder patients are not in remission at GI consult. GI providers have an important role in screening for eating disorders. Further prospective research is needed to understand the complex relationship between eating disorders and GI symptoms.

Latent profile analysis reveals the central role of psychological symptoms in driving disease severity in chronic constipation.

BACKGROUND: Chronic constipation (CC) is defined by symptom criteria reflecting heterogenous physiology. However, many patients with CC have significant psychological comorbidities-an alternative definition using a biopsychosocial classification model could be warranted to inform future treatments. We sought to: (1) empirically derive psychological symptom profiles of patients with CC using latent profile analysis and (2) validate these profiles by comparing them on symptom severity, GI-specific anxiety, body mass index (BMI), and anorectal manometry findings. METHODS: Participants included adults presenting for anorectal manometry for CC (N = 468, 82% female, Mage = 47). Depression/anxiety symptoms and eating disorder (ED) symptoms (EAT-26) were used as indicators (i.e., variables used to derive profiles) representing unique psychological constructs. Constipation symptoms, GI-specific anxiety, BMI, and anorectal manometry results were used as validators (i.e., variables used to examine the clinical utility of the resulting profiles). KEY RESULTS: A 5-profile solution provided the best statistical fit, comprising the following latent profiles (LPs): LP1 termed "high dieting, low bulimia;" LP2 termed "high ED symptoms;" LP3 termed "moderate ED symptoms;" LP4 termed "high anxiety and depression, low ED symptoms;" and LP5 termed "low psychological symptoms." The low psychological symptom profile (61% of the sample) had lower abdominal and overall constipation severity and lower GI-specific anxiety compared to the four profiles characterized by higher psychological symptoms (of any type). Profiles did not significantly differ on BMI or anorectal manometry results. CONCLUSIONS AND INFERENCES: Profiles with high psychological symptoms had increased constipation symptom severity and GI-specific anxiety in adults with CC. Future research should test whether these profiles predict differential treatment outcomes.

Association Between Celiac Disease and Irritable Bowel Syndrome: A Nationwide Cohort Study.

BACKGROUND & AIMS: The aim of this study was to determine the risk of irritable bowel syndrome (IBS) diagnosis in patients with celiac disease (CD) compared with general population comparators. METHODS: Using Swedish histopathology and register-based data, we identified 27,262 patients with CD diagnosed in 2002-2017 and 132,922 age- and sex-matched general population comparators. Diagnoses of IBS were obtained from nationwide inpatient and non-primary outpatient records. Cox regression estimated hazard ratios (aHRs) for IBS adjusted for education level and Charlson Comorbidity Index. To reduce potential surveillance bias our analyses considered incident IBS diagnosis ≥1 year after CD diagnosis. Using conditional logistic regression, secondary analyses were calculated to estimate odds ratios (ORs) for IBS diagnosis ≥1 year before CD diagnosis. RESULTS: During an average of 11.1 years of follow-up, 732 celiac patients (2.7%) were diagnosed with IBS vs 1131 matched general population comparators (0.9%). Overall (≥1-year of follow-up), the aHR for IBS was 3.11 (95% confidence interval [CI], 2.83-3.42), with aHR of 2.00 (95% CI, 1.63-2.45) after ≥10 years of follow-up. Compared with siblings (n = 32,010), celiac patients (n = 19,211) had ≥2-fold risk of later IBS (aHR, 2.42; 95% CI, 2.08-2.82). Compared with celiac patients with mucosal healing, those with persistent villus atrophy on follow-up biopsy were less likely to be diagnosed with IBS (aHR, 0.66; 95% CI, 0.46-0.95). CD was also associated with having an earlier IBS diagnosis (OR, 3.62; 95% CI, 3.03-4.34). CONCLUSIONS: In patients with CD, the risk of IBS is increased long before and after diagnosis. Clinicians should be aware of these long-term associations and their implications on patient management.

High Comorbidity of Gastrointestinal Disorders Among Those Seeking Care for Dyspareunia.

Dyspareunia, defined as genital pain that occurs before, during, or after sexual intercourse, is the most commonly diagnosed form of female sexual dysfunction. As high as 43% of women experience some form of sexual dysfunction, but the etiology of these conditions is not well understood.1 Prior research on sexual dysfunction in gastrointestinal (GI) patients has focused primarily on inflammatory bowel disease (IBD) alone. 2,3 More than 49% of females with IBD have been reported to experience sexual dysfunction.4 Not yet understood is the prevalence of comorbid GI conditions among those seeking care for dyspareunia.5 Thus, we sought to characterize GI disorders within a dyspareunia patient population.

Differences in provider recommendations for Black/African American and White patients with irritable bowel syndrome.

BACKGROUND: Health disparities and barriers to equitable care for patients from racial and ethnic minority backgrounds are common. We sought to evaluate disparities in management recommendations among Black/African American (AA) patients seeking care for IBS. METHODS: We assembled a retrospective cohort of patients at two tertiary care centers who were self-identifying as Black/AA and attended a first gastroenterology consult for IBS. These patients were age- and sex-matched to White controls with IBS also attending an initial gastroenterology consult. Retrospective chart review determined patient demographics, income, comorbidities, as well as provider management recommendations including pharmacologic therapies and non-pharmacologic interventions. KEY RESULTS: Among 602 IBS patients ages 14-88 (M ± SD = 43.6 ± 18.6 years) with IBS, those who identified as Black/AA (n = 301) had a lower estimated mean income and were significantly more likely to have a number of specific chronic medical conditions. Black/AA patients were significantly less likely to have implemented dietary changes for symptoms prior to receiving a diagnosis of IBS from a gastroenterologist. Black/AA patients were also less likely to receive a referral to a dietician within 1 year following their diagnosis of IBS (p = 0.01). Black/AA patients were prescribed pharmacologic therapy more often for constipation (41.9% vs. 34.6%, p = 0.01). It was more common for White patients to present at the initial encounter having already initiated a neuromodulator (41.9% vs. 27.9%, p < 0.001). CONCLUSION & INFERENCES: Management recommendations for IBS appear to vary by race, specifically for dietary advice and referrals.

Optimizing the Management Algorithm for Adults With Functional Constipation Failing a Fiber/Laxative Trial in General Gastroenterology: Cost-Effectiveness and Cost-Minimization Analysis.

INTRODUCTION: Anorectal function testing is traditionally relegated to subspecialty centers. Yet, it is an office-based procedure that appears capable of triaging care for the many patients with Rome IV functional constipation that fail empiric over-the-counter therapy in general gastroenterology, as an alternative to empirical prescription drugs. We aimed to evaluate cost-effectiveness of routine anorectal function testing in this specific population. METHODS: We performed a cost-effectiveness analysis from the patient perspective and a cost-minimization analysis from the insurer perspective to compare 3 strategies: (i) empiric prescription drugs followed by pelvic floor physical therapy (PFPT) for drug failure, (ii) empiric PFPT followed by prescription drugs for PFPT failure, or (iii) care directed by up-front anorectal function testing. Model inputs were derived from systematic reviews of prospective clinical trials, national cost data sets, and observational cohort studies of the impact of chronic constipation on health outcomes, healthcare costs, and work productivity. RESULTS: The most cost-effective strategy was upfront anorectal function testing to triage patients to appropriate therapy, in which the subset of patients without anal hypocontractility on anorectal manometry and with a balloon expulsion time of at least 6.5 seconds would be referred to PFPT. In sensitivity analysis, empiric PFPT was more cost effective than empiric prescription drugs except for situations in which the primary goal of treatment was to increase bowel movement frequency. If adopted, gastroenterologists would refer ∼17 patients per year to PFPT, supporting feasibility. DISCUSSION: Anorectal function testing seems to be an emergent technology to optimize cost-effective outcomes, overcoming testing costs by phenotyping care.

Relationship Between Psychological Trauma and Irritable Bowel Syndrome and Functional Dyspepsia in a Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome Patient Population.

BACKGROUND: There is frequent overlap between and the connective tissue diseases Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome (JHS/EDS) and disorders of the gut-brain interaction (DGBIs). AIMS: Because not all JHS/EDS patients develop DGBIs, we sought to determine whether secondary environmental triggers may lead to development of irritable bowel syndrome (IBS) and functional dyspepsia (FD) in patients with JHS/EDS. METHODS: We sent electronic surveys to 253 patients from a JHS/EDS support group, with responses collected over one year. IBS and FD were diagnosed by the Rome IV criteria, with additional validated assessments of adverse childhood experiences (ACEs) and traumatic stressors according to DSM-V criteria. We compared clinical and psychological characteristics of JHS/EDS patients with and without DGBIs using univariable and multivariable analyses. RESULTS: We enrolled 193 JHS/EDS patients, of whom 67.9% met Rome IV criteria for IBS. The IBS and JHS/EDS overlap group reported significantly more traumatic exposures (P < 0.001) and were more likely to have experienced greater than 3 ACEs (P < 0.001) than JHS/EDS patients without IBS. FD was found in 35.2% of patients and was associated with significantly more traumatic exposures (P < 0.001) and were more likely to have experienced greater than 3 ACEs (P < 0.001) than JHS/EDS patients without FD. CONCLUSIONS: We found that JHS/EDS patients with IBS and FD overlap reported significantly more traumatic exposures and ACEs compared to JHS/EDS patients without overlapping IBS or FD. JHS/EDS patients may have increased susceptibility to DGBIs, with traumatic life experiences and/or ACEs acting a secondary environmental trigger driving the subsequent development of DGBIs.

Safety of Pneumatic Dilation in Older Adults with Achalasia: An International Multicenter Cross-Sectional Study.

BACKGROUND: Pneumatic dilation (PD) is an effective first line treatment option for many patients with achalasia. PD use may be limited in adults with achalasia who are older than 65 because of concern for adverse events (AE), and less efficacious therapies are often utilized. We explored the periprocedural safety profile of PD in older adults. METHODS: An international real world cross-sectional study of patients undergoing PD between 2006-2020 in two tertiary centers. Thirty-day AEs were compared between older adults (65 and older) with achalasia and younger patients. RESULTS: A total of 252 patients underwent 319 PDs. In 319 PDs, 18 (5.7%) complications occurred: 6 (1.9%) perforations and 12 (3.8%) emergency department referrals with benign (non-perforation) chest pain, of which 9 (2.8%) were hospitalized. No bleeding or death occurred within 30 days. Perforation rates were similar in both age groups and across achalasia subtypes. Advanced age was protective of benign chest pain complications in univariate analysis, and the limited number of AEs precluded multivariable analysis. CONCLUSIONS: The safety of PD in older adults is at least comparable to that of younger patients and should be offered as an option for definitive therapy for older patients with achalasia. Our results may affect informed consent discussions.

Diet and gut microbial associations in irritable bowel syndrome according to disease subtype.

The role of diet and the gut microbiome in the etiopathogenesis of irritable bowel syndrome (IBS) is not fully understood. Therefore, we investigated the interplay between dietary risk factors and gut microbiota in IBS subtypes using a food frequency questionnaire and stool metagenome data from 969 participants aged 18-65 years in the ZOE PREDICT 1 study, an intervention study designed to predict postprandial metabolic responses. We identified individuals with IBS subtype according to the Rome III criteria based on predominant bowel habits during symptom onset: diarrhea (i.e. looser), constipation (i.e. harder), and mixed. Participants with IBS-D (n = 59) consumed more healthy plant-based foods (e.g. whole grains, leafy vegetables) and fiber, while those with IBS-C (n = 49) tended to consume more unhealthy plant-based foods (e.g. refined grains, fruit juice) than participants without IBS (n = 797). Microbial diversity was nominally lower in patients with IBS-D than in participants without IBS or with IBS-C. Using multivariable-adjusted linear regression, we identified specific microbiota variations in IBS subtypes, including slight increases in pro-inflammatory taxa in IBS-C (e.g. Escherichia coli) and loss of strict anaerobes in IBS-D (e.g. Faecalibacterium prausnitzii). Our analysis also revealed intriguing evidence of interactions between diet and Faecalibacterium prausnitzii. The positive associations between fiber and iron intake and IBS-diarrhea were stronger among individuals with a higher relative abundance of Faecalibacterium prausnitzii, potentially driven by carbohydrate metabolic pathways, including the superpathway of ß-D-glucuronide and D-glucuronate degradation. In conclusion, our findings suggest subtype-specific variations in dietary habits, gut microbial composition and function, and diet-microbiota interactions in IBS, providing insights into potential microbiome-informed dietary interventions.

Antibiotic use as a risk factor for irritable bowel syndrome: Results from a nationwide, case-control study.

BACKGROUND: The microbiome plays an important role in the pathophysiology of irritable bowel syndrome (IBS). Antibiotic use can fundamentally alter gut microbial ecology. We examined the association of antibiotic use with IBS in a large population-based investigation. METHODS: A case-control study with prospectively collected data on 29,111 adult patients diagnosed with IBS in Sweden between 2007 and 2016 matched with 135,172 controls. Using a comprehensive histopathology cohort, the Swedish Patient Register, and the Prescribed Drug Register, we identified all consecutive cases of IBS in addition to cumulative antibiotic dispensations accrued until 1 year prior to IBS (exclusionary period) for cases and time of matching for up to five general population controls matched on the basis of age, sex, country and calendar year. Conditional logistic regression estimated multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of IBS. RESULTS: Patients with IBS (n = 29,111) were more likely than controls (n = 135,172) to have used antibiotics up to 1 year prior to diagnosis (74.9% vs. 57.8%). After multivariable adjustment, this translated to a more than twofold increased odds of IBS (OR 2.21, 95% CI 2.14-2.28) that did not differ according to age, sex, year of IBS diagnosis or IBS subtype. Compared to none, 1-2 (OR 1.67, 95% CI 1.61-1.73) and ≥3 antibiotics dispensations (OR 3.36, 95% CI 3.24-3.49) were associated with increased odds of IBS (p for trend <0.001) regardless of the antibiotic class. CONCLUSIONS: Prior antibiotics use was associated with an increased odds of IBS with the highest risk among people with multiple antibiotics dispensations.

Assessment of Gastroesophageal Reflux Symptoms and Sleep Quality Among Women in the Nurses' Health Study II.

Importance: Limited data exist on the association of gastroesophageal reflux (GER) symptoms with sleep quality. Objective: To prospectively investigate the association between GER symptoms and sleep quality. Design, Setting, and Participants: This prospective cohort study included data from the Nurses' Health Study II of female nurses in the US. Participants self-reported the frequency and duration of GER symptoms beginning June 2005, with updates every 4 years through June 2015. Follow-up was completed June 2019, and data were analyzed from November 15, 2022, to June 4, 2023. Exposures: Frequency and duration of GER symptoms. Main Outcomes and Measures: Poor sleep quality was assessed in 2017 through a modified Pittsburgh Sleep Quality Index, which included difficulty in falling asleep, restlessness of sleep, daytime sleepiness, sleep disturbance, and sleep duration. Relative risk (RR) for poor sleep quality and individual components of poor sleep quality was estimated according to the frequency and duration of GER symptoms. Results: Among 48 536 women (median age, 59 years [range, 48-69 years]), 7929 (16.3%) developed poor sleep quality during 4 years of follow-up. Compared with those with GER symptoms less than once a month, the multivariable RR for poor sleep quality among women with GER symptoms more than once a week was 1.53 (95% CI, 1.45-1.62). Women who had GER symptoms once or more a week for more than 7 years had an RR of 1.36 (95% CI, 1.30-1.43) compared with women who had not had GER symptoms once or more a week. The frequency and duration of GER symptoms were significantly associated with each individual component of poor sleep quality; for example, the multivariable RRs for GER symptoms 2 or more times per week compared with no GER symptoms were 1.49 (95% CI, 1.39-1.58) for difficulty in falling asleep, 1.47 (95% CI, 1.39-1.56) for excessive daytime sleepiness, and 1.44 (95% CI, 1.36-1.53) for restlessness of sleep. Conclusions and Relevance: In this prospective cohort study of female nurses in the Nurses' Health Study II, the frequency and duration of GER symptoms were associated with subsequent risk of poor sleep quality. The findings suggest that effective treatment of GER disease may be important not only for improvement of symptoms but also for the reduction of comorbidities associated with poor sleep quality.

Unrecognized Functional Dyspepsia Among Those With Refractory Chronic Constipation: Analysis of a Tertiary Cohort.

BACKGROUND AND AIMS: Patients with functional constipation (FC) are frequently dissatisfied with current treatment options which may be related to persistent, unaddressed symptoms. We hypothesized that refractory FC may actually represent functional dyspepsia (FD) overlap. Among adults presenting with refractory FC, we sought to (1) identify the prevalence of concurrent FD and (2) identify the symptoms and presentations most frequently associated with concurrent FD and FC. METHODS: We assembled a retrospective cohort of 308 patients sequentially presenting to a tertiary neurogastroenterology clinic for evaluation of refractory FC, defined as having failed first-line therapy. Using Rome IV criteria, trained raters identified the presence and characteristics of concurrent FD in addition to demographics, presenting complaints, and psychological comorbidities. RESULTS: Among 308 patients presenting with refractory FC (average of 3.0 ± 2.3 constipation treatments tried unsuccessfully), 119 (38.6%) had concurrent FD. Aside from meeting FD criteria, the presence of concurrent FD was associated with patient complaints of esophageal symptoms (Odds ratio = 3.1; 95% confidence interval, 1.80-5.42) and bloating and distension (Odds ratio = 2.67; 95% confidence interval, 1.50-4.89). Patients with concurrent FD were more likely to have a history of an eating disorder (21.0% vs 12.7%) and were also more likely to present with current avoidant/restrictive food intake disorder-related symptoms (31.9% vs 21.7%). CONCLUSION: Almost 40% of adult patients referred for refractory FC met criteria for concurrent FD in a tertiary-level cohort. The presence of both FC and FD was associated with greater esophageal symptoms and bloating/distention. Determining presence of concurrent FD may represent an additional therapeutic opportunity in refractory patients who may attribute symptoms to FC alone.

Optimizing the Utility of Anorectal Manometry for Diagnosis and Therapy: A Roundtable Review and Recommendations.

BACKGROUND & AIMS: Anorectal manometry (ARM) is a comprehensive diagnostic tool for evaluating patients with constipation, fecal incontinence, or anorectal pain; however, it is not widely utilized for reasons that remain unclear. The aim of this roundtable discussion was to critically examine the current clinical practices of ARM and biofeedback therapy by physicians and surgeons in both academic and community settings. METHODS: Leaders in medical and surgical gastroenterology and physical therapy with interest in anorectal disorders were surveyed regarding practice patterns and utilization of these technologies. Subsequently, a roundtable was held to discuss survey results, explore current diagnostic and therapeutic challenges with these technologies, review the literature, and generate consensus-based recommendations. RESULTS: ARM identifies key pathophysiological abnormalities such as dyssynergic defecation, anal sphincter weakness, or rectal sensory dysfunction, and is a critical component of biofeedback therapy, an evidence-based treatment for patients with dyssynergic defecation and fecal incontinence. Additionally, ARM has the potential to enhance health-related quality of life and reduce healthcare costs. However, it has significant barriers that include a lack of education and training of healthcare providers regarding the utility and availability of ARM and biofeedback procedures, as well as challenges with condition-specific testing protocols and interpretation. Additional barriers include understanding when to perform, where to refer, and how to use these technologies, and confusion over billing practices. CONCLUSIONS: Overcoming these challenges with appropriate education, training, collaborative research, and evidence-based guidelines for ARM testing and biofeedback therapy could significantly enhance patient care of anorectal disorders.