Genetic and transcriptomic landscape of colonic diverticulosis.

OBJECTIVE: Colonic diverticulosis is a prevalent condition among older adults, marked by the presence of thin-walled pockets in the colon wall that can become inflamed, infected, haemorrhage or rupture. We present a case-control genetic and transcriptomic study aimed at identifying the genetic and cellular determinants underlying this condition and the relationship with other gastrointestinal disorders. DESIGN: We conducted DNA and RNA sequencing on colonic tissue from 404 patients with (N=172) and without (N=232) diverticulosis. We investigated variation in the transcriptome associated with diverticulosis and further integrated this variation with single-cell RNA-seq data from the human intestine. We also integrated our expression quantitative trait loci with genome-wide association study using Mendelian randomisation (MR). Furthermore, a Polygenic Risk Score analysis gauged associations between diverticulosis severity and other gastrointestinal disorders. RESULTS: We discerned 38 genes with differential expression and 17 with varied transcript usage linked to diverticulosis, indicating tissue remodelling as a primary diverticula formation mechanism. Diverticula formation was primarily linked to stromal and epithelial cells in the colon including endothelial cells, myofibroblasts, fibroblasts, goblet, tuft, enterocytes, neurons and glia. MR highlighted five genes including CCN3, CRISPLD2, ENTPD7, PHGR1 and TNFSF13, with potential causal effects on diverticulosis. Notably, ENTPD7 upregulation was confirmed in diverticulosis cases. Additionally, diverticulosis severity was positively correlated with genetic predisposition to diverticulitis. CONCLUSION: Our results suggest that tissue remodelling is a primary mechanism for diverticula formation. Individuals with an increased genetic proclivity to diverticulitis exhibit a larger numbers of diverticula on colonoscopy.

AGA Clinical Practice Guideline on Fecal Microbiota-Based Therapies for Select Gastrointestinal Diseases.

BACKGROUND & AIMS: Fecal microbiota-based therapies include conventional fecal microbiota transplant and US Food and Drug Administration-approved therapies, fecal microbiota live-jslm and fecal microbiota spores live-brpk. The American Gastroenterological Association (AGA) developed this guideline to provide recommendations on the use of fecal microbiota-based therapies in adults with recurrent Clostridioides difficile infection; severe to fulminant C difficile infection; inflammatory bowel diseases, including pouchitis; and irritable bowel syndrome. METHODS: The guideline was developed using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) framework to prioritize clinical questions, identify patient-centered outcomes, and conduct an evidence synthesis. The guideline panel used the Evidence-to-Decision framework to develop recommendations for the use of fecal microbiota-based therapies in the specified gastrointestinal conditions and provided implementation considerations for clinical practice. RESULTS: The guideline panel made 7 recommendations. In immunocompetent adults with recurrent C difficile infection, the AGA suggests select use of fecal microbiota-based therapies on completion of standard of care antibiotics to prevent recurrence. In mildly or moderately immunocompromised adults with recurrent C difficile infection, the AGA suggests select use of conventional fecal microbiota transplant. In severely immunocompromised adults, the AGA suggests against the use of any fecal microbiota-based therapies to prevent recurrent C difficile. In adults hospitalized with severe or fulminant C difficile not responding to standard of care antibiotics, the AGA suggests select use of conventional fecal microbiota transplant. The AGA suggests against the use of conventional fecal microbiota transplant as treatment for inflammatory bowel diseases or irritable bowel syndrome, except in the context of clinical trials. CONCLUSIONS: Fecal microbiota-based therapies are effective therapy to prevent recurrent C difficile in select patients. Conventional fecal microbiota transplant is an adjuvant treatment for select adults hospitalized with severe or fulminant C difficile infection not responding to standard of care antibiotics. Fecal microbiota transplant cannot yet be recommended in other gastrointestinal conditions.

Dietary Calcium and Risk of Microscopic Colitis.

BACKGROUND: Microscopic colitis (MC) is an increasingly common cause of watery diarrhea particularly in older individuals. The role of diet in MC has received little study. METHODS: We conducted a case-control study at a single institution enrolling patients referred for elective outpatient colonoscopy for diarrhea. Patients were classified as cases with MC or non-MC controls after a review of colon biopsies by 1 research pathologist. Study subjects were interviewed by a trained telephone interviewer using a validated food frequency questionnaire. Adherent microbes were evaluated from colonic biopsies using 16s rRNA sequencing. RESULTS: The study population included 106 cases with MC and 215 controls. Compared with controls, the cases were older, better educated, and more likely to be female. Cases with MC had lower body mass index and were more likely to have lost weight. Subjects in the highest quartile of dietary calcium intake had a lower risk of MC compared with those in the lowest quartile (adjusted odds ratio 0.22, 95% confidence interval 0.07-0.76). The findings were not explained by dairy intake, body mass index, or weight loss. We found that dietary calcium intake had significant associations with the abundance of Actinobacteria and Coriobacteriales in the microbial community of colonic biopsies. DISCUSSION: Compared with patients with diarrhea, cases with MC had a lower intake of dietary calcium. Diet can be associated with alterations in the gut microbiota and with luminal factors that could affect the risk of MC.

Gastrointestinal outcomes among older women with endometrial cancer.

OBJECTIVE: Treatment for endometrial cancer may contribute to bowel dysfunction and other gastrointestinal outcomes. We investigated the risk of several gastrointestinal diagnoses among older women with endometrial cancer and matched women without a history of cancer. METHODS: Women aged 66 years and older diagnosed with endometrial cancer during 2004-2017 (N = 44,386) and matched women without a known cancer history (N = 221,219) were identified in the SEER-Medicare linked data. An index date was defined as the endometrial cancer diagnosis date in that matched set. ICD-9 and -10 diagnosis codes were used to define gastrointestinal outcomes, including constipation, abdominal pain, IBS, fecal incontinence, bowel obstruction, ileus, radiation enteritis or proctitis, colonic stricture, and vascular insufficiency of the bowel in the Medicare claims. Hazard ratios (HRs) for incident gastrointestinal diagnoses were estimated using multivariable Cox proportional hazards regression models. RESULTS: Compared to women without cancer, women with endometrial cancer had an increased risk of gastrointestinal symptoms after the index date, including constipation (HR = 2.27; 95% CI: 2.22-2.32), abdominal pain (HR = 2.94; 95% CI: 2.89-2.99), and fecal incontinence (HR = 1.96; 95% CI: 1.83-2.10). The risk of other gastrointestinal diagnoses was also higher among women with endometrial cancer (e.g., bowel obstruction: HR = 5.72; 95% CI: 5.47-5.98; ileus: HR = 7.22; 95% CI: 6.89-7.57). These associations were also apparent in sensitivity analyses limited to 1+ and 5+ years after the index date. CONCLUSIONS: Older women with endometrial cancer experience an excess risk of gastrointestinal diagnoses that may persist long after cancer diagnosis. Surveillance for these conditions may be a critical part of survivorship care.

Alpha-Gal Sensitization in a US Screening Population Is Not Associated With a Decreased Meat Intake or Gastrointestinal Symptoms.

INTRODUCTION: Patients with alpha-gal syndrome, a delayed reaction to mammalian meat, can present with isolated gastrointestinal (GI) symptoms. We aimed to estimate the frequency of alpha-gal sensitization in a Southeastern US population and determine the association between sensitization and mammalian product dietary intake or GI symptoms. METHODS: We performed a cross-sectional study of participants who underwent a screening colonoscopy at our center between 2013 and 2015. We quantified serum alpha-gal immunoglobulin E antibodies in participants who were prospectively enrolled at screening colonoscopy and compared diet intake and lower GI symptoms reported in standardized questionnaires among those with elevated versus no alpha-gal IgE antibodies. RESULTS: Alpha-gal IgE antibodies were common-31.4% of screening colonoscopy participants (127 of 404) had elevated serum alpha-gal IgE >0.1 kU/L. Alpha-gal-sensitized participants endorsed similar rates of abdominal pain compared with those without alpha-gal antibodies (33% vs 38%, adjusted odds ratio 0.9, 95% confidence interval 0.7-1.3). Mammalian meat consumption did not differ based on alpha-gal sensitization status (average 1.43 servings/d in sensitized subjects vs 1.50 in alpha-gal IgE-negative subjects, P = 0.9). Alpha-gal-sensitized participants with levels ≥10 (n = 21) were overrepresented in the lowest quartiles of mammalian meat consumption, but not among those with GI symptoms in general. Participants with high alpha-gal antibody levels >2 kU/L (n = 45) or ≥10 U/L (n = 21) did not have a reduced mean daily mammalian meat intake compared with seronegative people. DISCUSSION: Elevated alpha-gal IgE antibodies were common and not associated with a reduced mammalian meat intake, abdominal pain, or diarrhea. Seropositivity did not predict symptomatic alpha-gal sensitization in this general screening population. Other host factors likely contribute to the phenotypic expression of alpha-gal syndrome.

Inverse Probability Weighting to Estimate Exposure Effects on the Burden of Recurrent Outcomes in the Presence of Competing Events.

Recurrent events-outcomes that an individual can experience repeatedly over the course of follow-up-are common in epidemiologic and health services research. Studies involving recurrent events often focus on time to first occurrence or on event rates, which assume constant hazards over time. In this paper, we contextualize recurrent event parameters of interest using counterfactual theory in a causal inference framework and describe an approach for estimating a target parameter referred to as the mean cumulative count. This approach leverages inverse probability weights to control measured confounding with an existing (and underutilized) nonparametric estimator of recurrent event burden first proposed by Dong et al. in 2015. We use simulations to demonstrate the unbiased estimation of the mean cumulative count using the weighted Dong-Yasui estimator in a variety of scenarios. The weighted Dong-Yasui estimator for the mean cumulative count allows researchers to use observational data to flexibly estimate and contrast the expected number of cumulative events experienced per individual by a given time point under different exposure regimens. We provide code to ease application of this method.

Diverticulosis Is Associated With Internal Hemorrhoids on Colonoscopy: Possible Clues to Etiology.

Hemorrhoids are a common but poorly understood gastrointestinal condition.1 Bowel habits and fiber consumption are frequently cited as risk factors for hemorrhoids, but research has been inconclusive.2 Recent genome-wide association studies (GWAS) have suggested an association between diverticular disease and hemorrhoids.3 We sought to investigate the association between colonic diverticulosis and internal hemorrhoids to validate the prediction from the GWAS.

Microbial Associations With Microscopic Colitis.

INTRODUCTION: Microscopic colitis is a relatively common cause of chronic diarrhea and may be linked to luminal factors. Given the essential role of the microbiome in human gut health, analysis of microbiome changes associated with microscopic colitis could provide insights into the development of the disease. METHODS: We enrolled patients who underwent colonoscopy for diarrhea. An experienced pathologist classified patients as having microscopic colitis (n = 52) or controls (n = 153). Research biopsies were taken from the ascending (ASC) and descending (DES) colon, and the microbiome was characterized with Illumina sequencing. We analyzed the associations between microscopic colitis and microbiome with a series of increasingly complex models adjusted for a range of demographic and health factors. RESULTS: We found that alpha diversity was significantly lower in cases with microscopic colitis compared with that in controls in the DES colon microbiome. In the DES colon, a series of models that adjusted for an increasing number of covariates found taxa significantly associated with microscopic colitis, including Proteobacteria that was enriched in cases and Collinsella that was enriched in controls. While the alpha diversity and taxa were not significantly associated with microscopic colitis in the ASC colon microbiome, the inference P values based on ASC and DES microbiomes were highly correlated. DISCUSSION: Our study demonstrates an altered microbiome in cases with microscopic colitis compared with that in controls. Because both the cases and controls experienced diarrhea, we have identified candidate taxa that could be mechanistically responsible for the development of microscopic colitis independent of changes to the microbial community caused by diarrhea.

Colonic Diverticulosis Is Not Associated With Painful Abdominal Symptoms in a US Population.

BACKGROUND AND AIMS: Symptomatic uncomplicated diverticular disease is a controversial diagnosis defined as chronic gastrointestinal symptoms in patients with diverticulosis. We assessed whether individuals with diverticulosis had an increased risk of abdominal pain, irritable bowel syndrome, or altered bowel habits. METHODS: We performed a prospective cohort study of participants who had a first-time screening colonoscopy at the University of North Carolina between 2013 and 2015. The colonoscopy included a detailed assessment for diverticulosis. Participants completed a follow-up interview between 2019 and 2020 to measure bowel habits and gastrointestinal symptoms. Poisson regression was used to estimate relative risk and 95% confidence intervals (CIs). RESULTS: Among the 310 participants, 128 (41%) had diverticulosis at baseline. Follow-up interviews were performed a mean of 6.8 years after the baseline colonoscopy. After adjustment for confounders, there was no association between diverticulosis and abdominal pain lasting >24 hours (relative risk [RR], 0.40; 95% CI, 0.05-3.45) or symptoms of irritable bowel syndrome (RR, 1.30; 95% CI, 0.69-2.42) at the time of follow-up. Compared to those with no diverticulosis, participants with diverticulosis were more likely to have more frequent bowel movements per day (RR, 1.60; 95% CI, 1.05-2.44). The association was stronger in participants with >10 diverticula (RR, 2.03; 95% CI, 1.19-3.48). Diverticulosis was not associated with altered stool consistency. CONCLUSION: These findings suggest that diverticulosis is associated with more frequent bowel movements contrary to the widespread belief that patients with diverticulosis are constipated. Diverticulosis was not associated with abdominal pain or symptoms of irritable bowel syndrome. The diagnosis of symptomatic uncomplicated diverticular disease must be reconsidered.

Diet in Benign Colonic Disorders: A Narrative Review.

PURPOSE: Diet plays an important role in common benign colorectal diseases. This article reviews the evidence for diet and supplemental fiber in patients with chronic constipation, irritable bowel syndrome, inflammatory bowel disease, colonic diverticulitis, and fecal incontinence. METHODS: We performed a narrative review of the evidence for diet and supplemental fiber in patients with 5 common benign colonic diseases and summarized guideline recommendations for each condition. We generated tables of practical dietary advice by disease. FINDINGS: Diet advice must be individualized and depends on underlying conditions, disease severity, symptom burden, and nutrition status. Guidance from a registered dietitian is highly recommended when making any dietary changes. Data from trials suggest that soluble fiber is effective for patients with chronic constipation, irritable bowel syndrome, and fecal incontinence. A diet low in select fermentable, oligo-, di-, and monosaccharides, and polyols may benefit patients with irritable bowel syndrome. Patients with inflammatory bowel disease, especially those with active disease, are at risk for malnutrition. Dietary restrictions may further increase that risk. There is limited evidence to recommend increasing or avoiding select food groups in patients with inflammatory bowel disease. Patients who have recovered from diverticulitis should adopt a prudent dietary pattern high in fruits, vegetables, whole grains, legumes, poultry, and fish. IMPLICATIONS: Clinicians should counsel patients on the contribution of diet to their colorectal condition and the benefits and harms of dietary modification. Dietary advice should be practical and accompanied by realistic expectations for benefit.

Alcohol-Associated Liver Disease Mortality Increased From 2017 to 2020 and Accelerated During the COVID-19 Pandemic.

Alcohol consumption has risen substantially in the United States in the past 2 decades.1,2 Alcohol-associated liver disease (ALD) represents a greater inpatient financial burden than all other etiologies of cirrhosis combined3 and is now the leading indication for liver transplantation.4 A recent study reported that ALD mortality increased between 2006 and 2017.5 Since 2017, alcohol consumption has continued to rise, and more significantly during the COVID-19 pandemic.2 The aim of this research letter is to provide the most updated trends in ALD-related mortality in the United States and to quantify the rate of change of ALD-related mortality over time.

Intraepithelial and Lamina Propria Lymphocytes Do Not Correlate With Symptoms or Exposures in Microscopic Colitis.

INTRODUCTION: Microscopic colitis, a common cause of diarrhea, is characterized by a largely normal appearance of the mucosa but increased numbers of lymphocytes in the epithelium and lamina propria on microscopy. We sought to determine whether T-cell percentage was associated with exposures or symptoms. METHODS: We conducted a case-control study that enrolled patients referred for colonoscopy for diarrhea. Patients were classified as microscopic colitis cases or controls by an experienced pathologist. Participants provided information on symptoms and exposures during a telephone or internet survey. Research biopsies from the ascending colon and descending colon were examined using immunofluorescence stains for CD3, CD8, and FOXP3 to determine percent T cells per total epithelial or lamina propria cells. Digital images were analyzed by regions of interest using Tissue Studio. RESULTS: There were 97 microscopic colitis cases and 165 diarrhea controls. There was no association between demographic factors and percentage of intraepithelial or lamina propria T cells. In cases, the mean percent T cells were similar in the right colon and left colon. There was no association between mean percent T cells and stool frequency or consistency. There was no association with irritable bowel syndrome, abdominal pain, or medications purported to cause microscopic colitis. DISCUSSION: The lack of association between the density of T cells and medications raises further doubts about their role in disease etiology. Loose and frequent stools in patients with microscopic colitis are not correlated with T-cell density.

Obesity is associated with decreased risk of microscopic colitis in women.

BACKGROUND: Microscopic colitis is a leading cause of diarrhea in the older adults. There is limited information about risk factors. We hypothesized that obesity would be associated with microscopic colitis. AIM: To examine the association between obesity and microscopic colitis in men and women undergoing colonoscopy. METHODS: We conducted a case-control study at the University of North Carolina Hospitals. We identified and enrolled men and women referred for elective, outpatient colonoscopy for chronic diarrhea. We excluded patients with a past diagnosis of Crohn's disease or ulcerative colitis. A research pathologist reviewed biopsies on every patient and classified them as microscopic colitis cases or non-microscopic colitis controls. Patients provided information on body weight, height and exposure to medications via structured interviews or Internet based forms. The analysis included 110 patients with microscopic colitis (cases) and 252 non-microscopic colitis controls. Multivariable analyses were performed using logistic regression to estimate odds ratios and 95% confidence intervals. RESULTS: Cases were older and more likely than controls to be white race. Study subjects were well educated, but cases were better educated than controls. Cases with microscopic colitis had lower body mass index than controls and reported more weight loss after the onset of diarrhea. Compared to patients who were normal or under-weight, obese (BMI > 30 kg/m2) patients were substantially less likely to have microscopic colitis after adjusting for age and education, adjusted OR (aOR) 0.35, 95% confidence interval (CI) 0.18-0.66). When stratified by sex, the association was limited to obese women, aOR 0.21, 95%CI: 0.10-0.45. Patients with microscopic colitis were more likely to report weight loss after the onset of diarrhea. After stratifying by weight loss, there remained a strong inverse association between obesity and microscopic colitis, aOR 0.33, 95%CI: 0.10 - 1.11 among the patients who did not lose weight. Ever use of birth control pills was associated with lower risk of microscopic colitis after adjusting for age, education and BMI, aOR 0.38, 95%CI: 0.17-0.84. CONCLUSION: Compared to controls also seen for diarrhea, microscopic colitis cases were less likely to be obese. Mechanisms are unknown but could involve hormonal effects of obesity or the gut microbiome.

Burden and Cost of Gastrointestinal, Liver, and Pancreatic Diseases in the United States: Update 2021.

BACKGROUND & AIMS: Gastrointestinal diseases account for considerable health care use and expenditures. We estimated the annual burden, costs, and research funding associated with gastrointestinal, liver, and pancreatic diseases in the United States. METHODS: We generated estimates using data from the National Ambulatory Medical Care Survey; National Hospital Ambulatory Medical Care Survey; Nationwide Emergency Department Sample; National Inpatient Sample; Kids' Inpatient Database; Nationwide Readmissions Database; Surveillance, Epidemiology, and End Results program; National Vital Statistics System; Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research; MarketScan Commercial Claims and Encounters data; MarketScan Medicare Supplemental data; United Network for Organ Sharing registry; Medical Expenditure Panel Survey; and National Institutes of Health (NIH). RESULTS: Gastrointestinal health care expenditures totaled $119.6 billion in 2018. Annually, there were more than 36.8 million ambulatory visits for gastrointestinal symptoms and 43.4 million ambulatory visits with a primary gastrointestinal diagnosis. Hospitalizations for a principal gastrointestinal diagnosis accounted for more than 3.8 million admissions, with 403,699 readmissions. A total of 22.2 million gastrointestinal endoscopies were performed, and 284,844 new gastrointestinal cancers were diagnosed. Gastrointestinal diseases and cancers caused 255,407 deaths. The NIH supported $3.1 billion (7.5% of the NIH budget) for gastrointestinal research in 2020. CONCLUSIONS: Gastrointestinal diseases are responsible for millions of health care encounters and hundreds of thousands of deaths that annually costs billions of dollars in the United States. To reduce the high burden of gastrointestinal diseases, focused clinical and public health efforts, supported by additional research funding, are warranted.