Metagenomics analysis reveals unique gut microbiota signature of slow-transit constipation.

INTRODUCTION: Altered gut microbiota may play a role in slow-transit constipation (STC). We conducted a study of gut microbiota composition and functionality in STC using metagenomic analyses. METHODS: We assembled a clinical cohort of 24 patients with STC physiology age- and sex-matched to 24 controls. We performed shotgun metagenomic sequencing followed by prediction of metabolite composition from functional profiles. RESULTS: In a middle-aged (mean 55.3 years), predominantly female cohort, there were no significant differences in α diversity indices, but permutational multivariate analysis of variance analysis showed significant between-group differences (R2=0.050, p<0.001) between STC patients and controls. Gordonibacter pamelaeae, Bifidobacterium longum, Firmicutes bacterium CAG 94, and Anaerotruncus colihominis were more abundant in STC, while Coprococcus comes and Roseburia intestinalis were more abundant in controls. Gut-derived metabolites varying in STC relative to controls were related to bile acid and cholesterol metabolism. DISCUSSION: We found a unique metagenomic and metabolomic signature of STC.

Gut microbiome structure and function in asymptomatic diverticulosis.

BACKGROUND: Colonic diverticulosis, the most common lesion found in routine colonoscopy, affects more than 50% of individuals aged ≥ 60 years. Emerging evidence suggest that dysbiosis of gut microbiota may play an important role in the pathophysiology of diverticular disease. However, specific changes in microbial species and metabolic functions in asymptomatic diverticulosis remain unknown. METHODS: In a cohort of US adults undergoing screening colonoscopy, we analyzed the gut microbiota using shotgun metagenomic sequencing. Demographic factors, lifestyle, and medication use were assessed using a baseline questionnaire administered prior to colonoscopy. Taxonomic structures and metabolic pathway abundances were determined using MetaPhlAn3 and HUMAnN3. We used multivariate association with linear models to identify microbial species and metabolic pathways that were significantly different between asymptomatic diverticulosis and controls, while adjusting for confounders selected a priori including age at colonoscopy, sex, body mass index (BMI), and dietary pattern. RESULTS: Among 684 individuals undergoing a screening colonoscopy, 284 (42%) had diverticulosis. Gut microbiome composition explained 1.9% variation in the disease status of asymptomatic diverticulosis. We observed no significant differences in the overall diversity of gut microbiome between asymptomatic diverticulosis and controls. However, microbial species Bifidobacterium pseudocatenulatum and Prevotella copri were significantly enriched in controls (q value = 0.19 and 0.14, respectively), whereas Roseburia intestinalis, Dorea sp. CAG:317, and Clostridium sp. CAG: 299 were more abundant in those with diverticulosis (q values = 0.17, 0.24, and 0.10, respectively). We observed that the relationship between BMI and diverticulosis appeared to be limited to carriers of Bifidobacterium pseudocatenulatum and Roseburia intestinalis (Pinteraction = 0.09). CONCLUSIONS: Our study provides the first large-scale evidence supporting taxonomic and functional shifts of the gut microbiome in individuals with asymptomatic diverticulosis. The suggestive interaction between gut microbiota and BMI on prevalent diverticulosis deserves future investigations.

Maladaptive weight control and eating behaviours in female adolescents/young adults are associated with increased risk of irritable bowel syndrome in adulthood: Results from the Growing Up Today Study (GUTS).

BACKGROUND: Irritable bowel syndrome (IBS) is common among individuals with eating disorders. The relationship between these conditions is likely bidirectional. However, data on the risk of IBS among those with prior eating disorders is largely limited to cross-sectional studies. AIM: To prospectively evaluate the association between maladaptive weight control/eating behaviours in females during adolescence/young adulthood with subsequent IBS using the Growing Up Today Study (GUTS). METHODS: Starting in 1996 (age: 9-14) and during follow-up, participants reported frequency of maladaptive eating/weight control behaviours during the past year to lose weight: self-induced vomiting (n = 5740), laxative use (n = 5438), and fasting (n = 5522) in addition to reporting binge eating (n = 4459). Starting in 2001 and during follow-up, participants reported if they had ever been diagnosed with an eating disorder (n = 5316). Incident IBS cases were identified from four questionnaire cycles (2013, 2014, 2016, 2019), with participants specifying the year of diagnosis if occurring before the questionnaire date. Multivariable logistic regressions adjusting for age, body mass index, and depressive symptoms estimated the associations of interest. RESULTS: Maladaptive weight control/eating behaviours were associated with increased IBS risk [ORs (95% CIs) for laxatives to lose weight = 3.67 (2.52-5.35), vomiting to lose weight = 1.83 (1.29-2.60), fasting to lose weight = 2.62 (1.86-3.70), and bingeing = 2.25 (1.54-3.28)] as was history of eating disorder diagnosis [OR (95% CI) = 3.42 (2.38-4.90)]. The magnitude of IBS risk increased with the frequency of maladaptive behaviours. CONCLUSIONS: There is evidence for the potential role of early maladaptive weight control/eating behaviours in the development of adult IBS among females.

The Development of Persistent Gastrointestinal Symptoms in Patients With Melanoma Who Have Had an Immune Checkpoint Inhibitor-Related Gastrointestinal Toxicity.

INTRODUCTION: Immune-related adverse events (irAE) secondary to immune checkpoint inhibitors (ICI) have gastrointestinal (GI) manifestations, including gastritis, enteritis, and/or colitis. The long-term sequelae of ICI-associated GI toxicities (GI-irAE), particularly the development of disorders of gut-brain interaction, are not well known. We characterized the incidence of persistent GI symptoms after GI-irAE. METHODS: This is a retrospective study of adults with melanoma treated with ICI and diagnosed with GI-irAE at our institution from 2013 to 2021. All patients had endoscopic and histologic evidence of GI-irAE. The primary outcome was incidence of persistent GI symptoms (diarrhea, abdominal pain, bloating, constipation, fecal incontinence, nausea, vomiting) after resolution of GI-irAE. Hazard ratios evaluated the association between parameters and time to persistent GI symptoms. RESULTS: One hundred four patients with melanoma (90% stage IV disease) and GI-irAE met inclusion criteria. Thirty-four percent received anti-cytotoxic T lymphocyte-associated protein-4 therapy, 33% anti-programmed death-1, and 34% dual therapy. Patients were treated for GI-irAE for an average of 9 ± 6 weeks. Twenty-eight (27%) patients developed persistent GI symptoms 1.6 ± 0.8 years after GI-irAE. The most common symptom was constipation (17%), followed by bloating (8%) and diarrhea (5%). Over 453 person-years, the incident rate was 6.2% per 100 person-years. Use of cytotoxic T lymphocyte-associated protein-4 single or dual therapy was associated with a 3.51× risk of persistent GI symptoms (95% confidence interval 1.20-10.23). DISCUSSION: In this cohort of melanoma patients who experienced GI-irAE, 26% developed persistent GI symptoms, most frequently constipation. Future studies should characterize the GI sequelae after GI-irAE, which may shed light on disorders of gut-brain interaction pathogenesis and improve the lives of cancer survivors.

AGA Clinical Practice Update on Diagnosis and Management of Cyclic Vomiting Syndrome: Commentary.

DESCRIPTION: The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update (CPU) is to review the available evidence and provide expert advice regarding the diagnosis and management of cyclic vomiting syndrome. METHODS: This CPU was commissioned and approved by the AGA Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPUC and external peer review through standard procedures of Gastroenterology. This expert commentary incorporates important as well as recently published studies in this field, and it reflects the experiences of the authors who are experts in treating patients with cyclic vomiting syndrome.

Pain is a cardinal symptom cutting across Rome IV anatomical categories in disorders of gut-brain interaction: A network-based approach.

INTRODUCTION: Disorders of gut-brain interaction (DGBI) are symptom-based disorders categorized by anatomic location but have high overlap and heterogeneity. Viewing DGBI symptoms on a spectrum (i.e. dimensionally) rather than categorically may better inform interventions to accommodate complex clinical presentations. We aimed to evaluate symptom networks to identify how DGBI symptoms interact. METHODS: We used the Rome IV Diagnostic Questionnaire continuously/ordinally scored items collected from the Rome Foundation Global Epidemiology Study. We excluded participants who reported ≥1 organic/structural gastrointestinal disorder(s). We sought to (1) identify core symptoms in the DGBI symptom networks, (2) identify bridge pathways between Rome IV diagnostic categories (esophageal, bowel, gastroduodenal, anorectal), and (3) explore how symptoms group together into communities. RESULTS: Of 54,127 adults, 20,229 met criteria for at least one DGBI (age mean = 42.2 ± 15.5; 57% female). General abdominal pain and epigastric pain were the core symptoms in the DGBI symptom network (i.e., had the strongest connections to other symptoms). Pain symptoms emerged as bridge pathways across existing DGBI diagnostic anatomic location (i.e., abdominal pain connected to chest pain, epigastric pain, rectal pain). Without a priori category definitions, exploratory network community analysis showed that symptoms grouped together into "pain," "gastroduodenal," and "constipation," rather than into groups by anatomic location. CONCLUSION: Our findings suggest pain symptoms are central and serve as a key connection to other symptoms, crosscutting anatomic location. Future longitudinal research is needed to test symptom network relations longitudinally and investigate whether targeting pain symptoms (rather than anatomic- or disorder-specific symptoms) has clinical impact.

Medical Comorbidities, Nutritional Markers, and Cardiovascular Risk Markers in Youth With ARFID.

OBJECTIVE: Avoidant/restrictive food intake disorder (ARFID) is common among populations with nutrition-related medical conditions. Less is known about the medical comorbidity/complication frequencies in youth with ARFID. We evaluated the medical comorbidities and metabolic/nutritional markers among female and male youth with full/subthreshold ARFID across the weight spectrum compared with healthy controls (HC). METHOD: In youth with full/subthreshold ARFID (n = 100; 49% female) and HC (n = 58; 78% female), we assessed self-reported medical comorbidities via clinician interview and explored abnormalities in metabolic (lipid panel and high-sensitive C-reactive protein [hs-CRP]) and nutritional (25[OH] vitamin D, vitamin B12, and folate) markers. RESULTS: Youth with ARFID, compared with HC, were over 10 times as likely to have self-reported gastrointestinal conditions (37% vs. 3%; OR = 21.2; 95% CI = 6.2-112.1) and over two times as likely to have self-reported immune-mediated conditions (42% vs. 24%; OR = 2.3; 95% CI = 1.1-4.9). ARFID, compared with HC, had a four to five times higher frequency of elevated triglycerides (28% vs. 12%; OR = 4.0; 95% CI = 1.7-10.5) and hs-CRP (17% vs. 4%; OR = 5.0; 95% CI = 1.4-27.0) levels. DISCUSSION: Self-reported gastrointestinal and certain immune comorbidities were common in ARFID, suggestive of possible bidirectional risk/maintenance factors. Elevated cardiovascular risk markers in ARFID may be a consequence of limited dietary variety marked by high carbohydrate and sugar intake.

Real-world outcomes for a digital prescription mobile application for adults with irritable bowel syndrome.

BACKGROUND: Mahana™ IBS is a Food and Drug Administration-cleared prescription mobile application designed to deliver 3 months of gut-directed cognitive behavioral therapy (CBT) to adults ≥22 years old with irritable bowel syndrome (IBS). We assessed whether gut-directed CBT delivered digitally improved outcomes in IBS management. METHODS: We studied users who had a dispensed physician prescription for Mahana™ IBS between August 2021 and August 2023. The primary outcome was change in IBS symptom severity (IBS-SSS) score. KEY RESULTS: For the 843 patients, 324 (38%) completed half of the program up to session 5, and 162 (19%) of participants completed the full program up to session 10. Median age was 41 years, median IBS-SSS was 270 (moderate severity), IBS-mixed subtype was most common (23%) followed by IBS-C (20%) and IBS-D (19%). The change in IBS-SSS was -81.0 (p = < 0.001) after session 5 and - 104.4 (p = < 0.001) after session 10. In multivariate analyses, a higher baseline IBS-SSS (OR 1.59; 95% CI 1.26-2.01) and high baseline Perceived Stress Scale (PSS) score predicted non-response (OR 0.95; 95% CI 0.91-0.98) while older age (OR 1.10 per decade; 95% CI 1.01-1.20), prescription source from a healthcare provider (as opposed to third party telehealth encounter, OR 1.48; 95% CI 1.07-2.05), and payment for the app (OR 1.93; 95% CI 1.41-2.63) predicted adherence. CONCLUSIONS & INFERENCES: Use of a digital mobile application for gut-directed CBT improved symptoms of IBS. Digital health applications have the potential to democratize CBT and allow integrated care to scale for patients with IBS.

Large-Caliber Empiric Esophageal Dilation Results in Sustained Improvement for Selected Patients With Nonobstructive Dysphagia.

INTRODUCTION: Empiric esophageal dilation (EED) remains a controversial practice for managing nonobstructive dysphagia (NOD) secondary to concerns about safety and efficacy. We examine symptom response, presence of tissue disruption, and adverse events (AEs) after EED. METHODS: We examined large-caliber bougie EED for NOD at 2 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 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 scores. 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 with 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 at 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.

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.

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.

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.

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.

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.