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Principal Investigator: ROBERT S. SANDLER
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $585,867
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY
Microscopic colitis is the most common cause of chronic watery diarrhea in older adults. The symptoms of this
disease are debilitating. Patients describe isolation and withdrawal from social life and activities. Treatment is
limited to expensive therapies that are sometimes ineffective. Disease relapse is common after medications
are stopped. Although the incidence is comparable to inflammatory bowel disease, the disease has received
much less research attention. A number of medications (PPIs, NSAIDs, statins, SSRIs) have been linked with
microscopic colitis. Although guidelines suggest discontinuing these medications as the initial step in
treatment, the evidence supporting this recommendation is weak. The first phase of this study enrolled patients
with microscopic colitis and diarrhea controls. Contrary to existing beliefs, there was no association with
medications previously linked to microscopic colitis. There was a strong inverse association with obesity and
exogenous hormones. Amplicon sequencing by 16S rRNA demonstrated that microbiome alpha-diversity was
significantly lower in microscopic colitis cases compared to controls. Several taxa were enriched in cases. The
present study is designed to extend and expand on the initial findings. The aims of the proposed case-control
study are: 1) To investigate medications, oral contraceptives, postmenopausal hormones and obesity by
comparing microscopic colitis cases to two comparison groups – patients referred for colonoscopy for diarrhea
and colonoscopy for colorectal cancer screening. 2) To use shotgun metagenomic sequencing to gain insight
into biodiversity and function. 3) To use RNA sequencing of mucosal samples from microscopic colitis patients,
diarrhea controls and screening controls to reveal genetic signatures associated with microscopic colitis and
discover potential druggable disease targets. The study will enroll 150 microscopic colitis cases, 300 diarrhea
controls and 300 screening colonoscopy controls. Biopsies from the colon will be used to evaluate adherent
bacterial organisms and to conduct RNAseq experiments in 100 microscopic colitis cases, 100 diarrhea
controls and 100 screening colonoscopy controls. Structured telephone interviews will obtain detailed dietary,
medication and lifestyle information on study subjects. The prospective data collection corrects important
limitations of prior research by others. The addition of a second control group could provide more definitive
evidence to avoid unnecessarily stopping therapeutically important medications (PPIs, NSAIDs, statins,
SSRIs). Shotgun metagenomics could provide information on microbial etiology or functional genes potentially
leading to strategies to prevent or treat the disease. The study will improve our understanding of risk factors,
set the stage for more scientifically grounded future research, and potentially suggest new interventions for a
disease that is currently poorly understood.
Terms: <16S gene sequencing><16S rRNA amplicon sequencing><16S rRNA gene amplicon sequencing><16S rRNA gene sequencing><16S rRNA genomic profiling><16S rRNA sequencing><16S ribosomal RNA gene sequencing><16S ribosomal RNA sequencing><16S sequencing><Address><Adrenergic beta-Antagonists><Adrenergic beta-Blockers><Anal Incontinence><Attention><BMI><BMI percentile><BMI z-score><Belief><Biodiversity><Biological Diversity><Biopsy><Body mass index><Bowel incontinence><CRC screening><Case-Base Studies><Case-Comparison Studies><Case-Compeer Studies><Case-Referent Studies><Case-Referrent Studies><Case/Control Studies><Causality><Cell Communication and Signaling><Cell Signaling><Chronic><Clinical><Colon><Colonoscopy><Control Groups><Data><Data Collection><Development><Diarrhea><Disease><Disorder><Drugs><Dysfunction><Economic Burden><Endocrine Gland Secretion><Enrollment><Etiology><Exposure to><Fecal Incontinence><Female><Functional Metagenomics><Functional disorder><Funding><Genes><Guidelines><Health behavior><Hormonal><Hormones><Incidence><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Intervention><Intervention Strategies><Interview><Intracellular Communication and Signaling><Life><Life Style><Lifestyle><Link><Lipids><Medical History><Medication><Metagenomics><Microscopic Colitis><Mucosa><Mucosal Tissue><Mucous Membrane><NIH><NSAIDs><National Institutes of Health><Non-Steroidal Anti-Inflammatory Agents><Obesity><Oral Contraceptives><Organism><Patients><Personal Medical History><Personal Medical History Epidemiology><Pharmaceutical Preparations><Phase><Physicians><Physiopathology><Play><Post-Menopause><Post-menopausal Period><Postmenopausal Period><Postmenopause><Proteobacteria><Purple Bacteria><Quetelet index><RNA Seq><RNA sequencing><RNAseq><Recommendation><Recurrent disease><Relapsed Disease><Reporter><Research><Risk><Risk Factors><Role><SSRI><SSRIs><Sampling><Selective Serotonin Reuptake Inhibitor><Selective serotonin re-uptake inhibitor><Shotguns><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Study Subject><Symptom Burden><Symptoms><Telephone Interviews><Therapeutic><Therapeutic Hormone><United States National Institutes of Health><Withdrawal><Woman><adiposity><after menopause><anti-depressant agent><anti-depressant drugs><anti-depressants><anti-depressive agents><beta blocker><beta-Adrenergic Blocking Agents><beta-Adrenergic Receptor Blockaders><biological signal transduction><birth control pill><case-controlled studies><causation><colorectal cancer detection><colorectal cancer early detection><colorectal cancer screening><comparator group><compare to control><comparison control><comparison group><corpulence><design><designing><detect colorectal cancer><developmental><dietary><differential expression><differentially expressed><disease causation><drug/agent><enroll><experiment><experimental research><experimental study><experiments><following menopause><gene signatures><genetic signature><gut dysbiosis><health related behavior><improved><inflammatory disease of the intestine><inflammatory disorder of the intestine><insight><interventional strategy><intestinal autoinflammation><life-style factor><lifestyle factors><living system><metagenome sequencing><metagenomic sequencing><microbial><microbiome><non-steroidal anti-inflammatory drugs><older adult><older adulthood><participant enrollment><past menopause><pathophysiology><patient enrollment><post-menopausal><postmenopausal><postmenopausal status><prevent><preventing><prospective><screening><screenings><serotonin reuptake inhibitor><shot gun><social><social role><socio-demographics><sociodemographics><transcriptional differences><transcriptome sequencing><transcriptomic sequencing>