A single weight based dose of alcohol will be given to approximate an alcohol binge (aiming to achieve a blood alcohol concentration of approximately 0.08%) to investigate downstream effects on intestinal permeability and changes in hepatic steatosis. Several studies have been performed in humans under similar conditions and looking at similar things. The PI, Dr. Garth Swanson, conducted one of these studies previously. Here, participants will be given a weight-based dose (2mL vodka per kg body weight) of alcohol, with assessment of intestinal permeability via urine collection over the 24 hours directly following alcohol consumption, assessment of changes in hepatic steatosis by evaluation with fibroscan before and after alcohol consumption, and blood markers of endotoxemia and related inflammatory markers after. The weight-based dosing of alcohol was chosen to reflect previous studies looking at the effects of a single episode of alcohol binge use, with the goal of achieving a blood alcohol concentration of approximately 0.08%, the lower limit of what is needed to be considered an acute alcohol binge.

The goal of the DDRCC Biorepository is to collect human samples and health information to store for future research. Samples to be collected are blood, tissue (intestinal, liver, pancreas and/or lymph nodes), stool, and cheek swabs. Participants may be eligible to enroll if scheduled for a clinical visit or surgical procedure during which these samples could be collected.

The long-term objective of this proposed R24 program is to enhance our understanding of how circadian rhythm disruption contributes to vulnerability to alcohol-induced organ damage, and to explore the underlying mechanisms (e.g. microbiota) that could lead to the identification of novel therapeutic targets. This knowledge aims to inform the development of innovative strategies to prevent and to treat alcohol-related pathologies.

5-aminosalicylic acid (5-ASA) medications are first line treatment for mild to moderate Ulcerative Colitis (UC), comprise 81% of all UC prescriptions, and have a market share of 1.5 billion. However, despite 5-ASA frequency and optimization, 35% of patients fail induction therapy and 52% of patients fail to maintain remission at 12 months, requiring step up therapy to immunomodulators or biologics which have increased side effects and cost. This highlights a key challenge in UC which is to address the large inter- and intrapatient variabilities in both disease progression and variability in response to treatment. Chronotherapy is the timing of medical interventions according to the host circadian rhythms in order to optimize drug response and minimize toxicity, and is one explanation for the large variability in response to medications. The long-term objective of our research is to establish the hypothesis that is that appropriate time of day of administration of oral, once daily 5-ASA therapy in alignment with the host circadian rhythms will improve subclinical inflammation and microbial structure/function and increase mucosal 5-ASA levels. To test this hypothesis, In
response to the small R01 for pilot and feasibility clinical trials (PAS-20-160) and to test our hypothesis, we propose to conduct a six month, single center, randomized crossover pilot trial involving 60 subjects with inactive UC [Mayo score ≤2, endoscopic score 0-1] but subclinical inflammation [stool calprotectin > 50 mcg/g] on a stable dose of once daily 5-ASA medication. All subjects will be randomized to once daily 5-ASA medications two different times of the day: either between 06:00 – 10:00 h or 18:00 – 22:00 h. Three disease assessments will performed at: 1) enrollment just before randomization; 2) month 3, at the completion of first arm (condition 1), and 3) month 6, after completion of the second arm (condition 2). We will assess time impact of our chronotherapy protocol on: 1) subclinical inflammation (Aim 1): a) stool calprotectin; b) intestinal barrier integrity; and c) endoscopic/histology scores; 2) Microbiota: mucosal and stool microbiota structure and function (Aim 2); and 3) 5-ASA metabolism: a) increase mucosal levels of 5-ASA and b) mucosal NAT activity (Aim 3). In addition, optimal 5-ASA treatment (i.e., Aims 1-3) will depend upon host chronotype which will be monitored by validated questionnaires, rest-wake actigraphy, and urinary melatonin. The results of this innovative proposal will establish a key role for chronotherapy in the treatment of UC and provide pilot data for the future larger multicenter clinical trials. Chronotherapy will allow for a personalized medicine approach that incorporates circadian biology to improve efficacy and minimize intolerance in treatment of UC.