Document text
Principal Investigator: Hamed Khalili
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2024
Award: $531,975
Funding agency: National Institute on Aging
PROJECT SUMMARY/ABSTRACT
Microscopic colitis (MC) is a chronic inflammatory disorder of the large intestine with a rising global incidence.
MC primarily affects older adults, in whom it accounts for a significant proportion of cases of chronic diarrhea
and fecal incontinence. The growing burden of the disease is primarily thought to be related to its increased
recognition, an aging population and polypharmacy. Yet, the exact etiology remains largely unknown. This
proposal will expand upon emerging evidence from our group and others that medications such as proton pump
inhibitors (PPIs), non-steroidal anti-inflammatory drugs (NSAIDs) and exogenous hormone use are associated
with increased risk of MC and that among patients with chronic diarrhea, the gut microbiota in active MC is
characterized by dysbiosis and unique compositional and functional changes. Our central hypothesis is that the
pathogenesis of MC is, at least in part, related to pharmacologic-induced perturbations in the aging gut
microbiota. To test this hypothesis, we have assembled the first nationwide gastrointestinal histopathology
cohort, with a validated definition for MC (n = 14,000) and over 20 years of follow up as well as a highly-
phenotyped colonoscopy-based cohort (n = 1600) with detailed questionnaires and biobanking of blood and stool
samples. Our specific aims include: 1) identification of key pharmacologic determinants of MC (Aim 1); 2)
identifying novel microbial signatures of MC in older adults with chronic diarrhea (Aim 2); 3) characterizing the
structure and function of the gut microbiota according to MC disease activity (Aim 2); 4) identifying microbial
communities and metabolites that mediate the relationship between medication-related risk factors and MC (Aim
3). The proposed work will have significant clinical and mechanistic implications. First, current guidelines
recommend discontinuing “potential” pharmacologic triggers as an adjunct therapy, particularly in recurrent or
refractory disease. However, as this approach may lead to unnecessary discontinuation of important medications
such as antihypertensive and lipid-lowering drugs, that have been linked to MC in some studies, findings from
our high quality pharmacoepidemiologic studies could directly inform clinical guidelines. Second, the results of
our microbiome studies could provide valuable data on use of gut microbiota signatures as a non-invasive
biomarker for diagnosing MC in older adults with chronic diarrhea. Lastly, the proposed work is significant as it
enhances our fundamental understanding of the relationship between commonly prescribed medications, the
aging gut microbiota, and gut inflammation in older adults. The proposal is innovative in its assembly of high-
level multidisciplinary team with complementary set of expertise and use of start-of-the-art computational
methods to characterize the relationship between medications and the gut microbiota in MC. Given the aging
U.S. population, the growing incidence of MC and the lack of FDA-approved medical treatments for patients with
established disease, this proposal addresses an area of great unmet need in aging research and is a topic of
high priority for the current grant announcement (PA-18-738).
Terms: <Active Follow-up><Address><Affect><Aging><Anaerobic Bacteria><Anal Incontinence><Anti-Hypertensive Agents><Anti-Hypertensive Drugs><Anti-Hypertensives><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Area><Bacteria><Biological Markers><Blood><Blood Reticuloendothelial System><Blood Sample><Blood specimen><Bowel incontinence><Butyrates><Causality><Chronic><Chronic diarrhea><Clinical><Colitis><Colonoscopy><Communities><Computational Biology><Computing Methodologies><Data><Development><Diagnosis><Digestive Diseases><Digestive System Diseases><Digestive System Disorders><Disease><Disease remission><Disorder><Drug Prescribing><Drug Prescriptions><Drugs><Dysfunction><E coli><E. coli><Endocrine Therapy><Environmental Exposure><Environmental Factor><Environmental Risk Factor><Epidemiology><Escherichia coli><Etiology><Evaluation><Exogenous Hormone Therapy><Exogenous Hormone Use><FDA approved><Fatty Acids><Fecal Incontinence><Feces><Foundations><Functional disorder><GI microbiome><GI microbiota><GI tract disorder><Gastrointestinal Diseases><Gastrointestinal microbiota><Genetic><Goals><Grant><Guidelines><Health Benefit><Histopathology><Hormonal Therapy><Hypotensive Agent><Hypotensive Drugs><Immune response><Immunological response><Incidence><Individual><Inflammatory><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Large Intestine><Link><Lipids><Mediating><Mediation><Medical><Medication><Microbe><Microbiomics><Microscopic><Microscopic Colitis><NSAIDs><Negotiating><Negotiation><Non-Steroidal Anti-Inflammatory Agents><Oral><Oxidative Stress><Oxidative Stress Induced Gene Expression Via Nrf2><Oxidative Stress Pathway><Pathogenesis><Pathology><Patients><Pharmaceutical Epidemiology><Pharmaceutical Preparations><Pharmacoepidemiology><Phase><Phenotype><Physiopathology><Polypharmacy><Population><Production><Proton Pump Inhibitors><Public Health><Publications><Pump><QOL><Quality of life><Questionnaires><Recommendation><Recurrent disease><Refractory Disease><Relapsed Disease><Remission><Research><Research Design><Risk><Risk Factors><Role><Ruminococcus><Scientific Publication><Short-Chain Fatty Acids><Streptococcus><Structure><Study Type><Sweden><Testing><Volatile Fatty Acids><Work><active followup><aged group><aged groups><aged individual><aged individuals><aged people><aged person><aged persons><aged population><aged populations><aging population><anaerobe><anti-hypertension><bile salts><bio-markers><biobank><biologic marker><biomarker><biorepository><bowel inflammation><burden of disease><burden of illness><causation><cohort><community microbes><computational methodology><computational methods><computer based method><computer biology><computer methods><computing method><developmental><digestive disorder><digestive tract disease><digestive tract microbiome><disease burden><disease causation><drug epidemiology><drug/agent><dysbacteriosis><dysbiosis><dysbiotic><enteric microbial community><enteric microbiome><enteric microbiota><environmental risk><epidemiologic><epidemiological><fecal sample><follow up><follow-up><followed up><followup><gastrointestinal><gastrointestinal disorder><gastrointestinal microbial flora><gastrointestinal microbiome><gastrointestinal tract disease><gastrointestinal tract disorder><gut commensal><gut community><gut flora><gut inflammation><gut microbe community><gut microbial community><gut microbial composition><gut microbial consortia><gut microbiome><gut microbiota><gut microbiotic><gut microflora><gut-associated microbiome><hormone therapy><host response><immune system response><immunoresponse><inflamed bowel><inflamed gut><inflamed intestine><inflammatory disease of the intestine><inflammatory disorder of the intestine><inhibitor><innovate><innovation><innovative><insight><intestinal autoinflammation><intestinal biome><intestinal flora><intestinal inflammation><intestinal microbiome><intestinal microbiota><intestinal microflora><intestinal tract microflora><large bowel><medication prescription><metagenome sequencing><metagenomic sequencing><microbial community><microbial consortia><microbial flora><microbial imbalance><microbial signature><microbiome><microbiome research><microbiome science><microbiome signature><microbiome studies><microbiota><microbiota patterns><microbiota profiles><microbiota signature><microflora><mortality><multidisciplinary><multispecies consortia><non-steroidal anti-inflammatory drugs><novel><older adult><older adulthood><pathophysiology><pharmacoepidemiologic><pharmacoepidemiological><pharmacologic><polymicrobial community><population aging><prescribed medication><social role><stool><stool sample><stool specimen><study design>