The goal of this study is to test the efficacy and feasibility of Colesevelam administration (50% of the recommended dose) to reduce serum PFAS concentration in the Veteran population who have serum PFAS levels that exceed the National Academies Science criteria (PFASsix > 20 ng/ml) using a double blind-placebo controlled study. Based on PFAS prevalence in serum samples, we anticipate recruiting up to n=500 Veterans to meet the goal of n=50 study participants to receive intervention or placebo. The primary outcome will be initial and final PFAS content in serum (total and 7 individual PFAS). The secondary outcome will be initial and final serum biomarkers related to lipid metabolism. As an exploratory aspect to the proposal, we will also measure fecal PFAS, bile acids, and microbial diversity to examine associations between PFAS content and bile acid levels and microbiome. Fecal PFAS, bile acid content, and microbiome may also be measured.

This double-blind randomized controlled trial has a extended open phase to test the use of oral Colesevelam (3 x 625 mg tablets qd) for 12 weeks to lower total serum PFAS levels in individuals with >20 ng/ml PFAS. After 12 weeks, participants assigned to placebo will have an opportunity to participate in the intervention of 12 weeks. Participants on the intervention will remain on the intervention for another 24 weeks.

Inclusion:

• Male or female Veterans aged 25- 65 who have serum PFAS >20 ng/ml exceeding National Academy of Science guidance.
• Written informed consent will be obtained.
• Outpatient.
• Agreeable to participate in sharable data and biorepository.

Exclusion:

• Under the age of 25 years
• Unable or unwilling to sign the informed consent statement and HIPAA Authorization form
• Females who are pregnant (confirmed by urine pregnancy test), nursing or planned pregnancy within study period.
• Patients with hypertriglyceridemia, vitamin deficient patients, hyperthyroidism and diabetic, pancreatitis and intestinal and bowel obstruction
• Be receiving any investigational drug other than Colesevelam or participating in any other investigational study.
• Significant medical illnesses that may limit the subject's ability to complete follow-up visits, in the opinion of the investigator.
• Be receiving any non-standard immunosuppression protocol or other non-standard treatment that could affect interpretation of the study results.
• Those with significant cardiovascular disease including treatment with inotropes.
• Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.
• Active substance abuse if this, in the opinion of the investigator, will interfere with the subject's ability to adhere to the study protocol.

All parties involved in treatment administration, data collection, and outcome assessment are blinded during the first 12-week phase. Randomization is performed in REDCap using block randomization.