Although many people will develop recurrent pouchitis (inflammation of the ileal pouch-anal anastomosis or J-pouch after colectomy for ulcerative colitis) after an initial episode of pouchitis, there are currently no effective treatments to prevent recurrent pouchitis. The goal of this study is to evaluate the potential for rifaximin, an antibiotic, to prevent recurrent pouchitis after treatment for an initial episode of pouchitis. In this study, all patients will be given daily rifaximin for one year after being treated for an initial episode of pouchitis. This study will examine whether people are willing to take rifaximin for one year with the goal of preventing recurrent pouchitis. Additionally, this study will examine whether patients experience any unexpected side effects of rifaximin therapy. The information gained through this study will potentially be helpful in improving the ability to prevent recurrent pouchitis in patients who have a colectomy for ulcerative colitis.

Inclusion Criteria:

• Informed consent will be obtained before any study-related procedures
• Age > 18 and <75 years
• Participants with a proven history of ulcerative colitis and history of 1,2, modified -2 or 3 stage Ileal pouch anal anastomosis (IPAA) and ileostomy takedown
• Diagnosis of initial episode of pouchitis within the first 12 months after ileostomy takedown/final stage of IPAA surgery

Exclusion Criteria:

• Known hypersensitivity to rifaximin or its metabolites
• Known Crohn's disease
• History of perianal fistula
• Known incontinence due to anal sphincter dysfunction
• Known irritable pouch syndrome
• Active ongoing pelvic infection/sepsis at baseline visit
• New onset of high bowel frequency in the setting of acute pouchitis in the first 4 weeks after IPAA
• Known Clostridoides difficile infection
• Need for antibiotic long-term therapy (e.g. doxycycline for acne)
• Known active Hepatitis B, C, HIV
• Clinically significant liver disease (Primary Sclerosing Cholangitis with LFT's <1.5 upper limit of normal can be included)
• Severe hepatic impairment, defined as Child-Pugh Class C
• Concomitant use of p-glycoprotein (P-gp) inhibitors (e.g. cyclosporine)
• Known decreased kidney function with a glomerular filtration rate <60 ml/min/1.732
• Fecal microbiota transplantation within 16 weeks before ileostomy takedown
• History of malignancy, except for basal cell carcinoma, non-metastatic squamous cell carcinoma of the skin, or prior malignancy with curative therapy completed at least 5 years prior to Screening and no recurrence.
• Clinically significant laboratory results at screening or baseline, as judged by the Investigator from local testing.
• Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using a highly effective contraceptive method. Women of child-bearing potential must have a negative urine pregnancy test prior to drug being dispensed.
• Participation in any clinical trial of an approved or non-approved investigational medicinal product within 30 days before screening.
• Any disorder, which in the investigator's opinion might jeopardize participant's safety or compliance with the protocol.

Deidentified individual data that supports the results will be shared beginning 9 to 12 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with UNC.

beginning 9 and continuing for 12 months following publication

Investigator has approved IRB, IEC, or REB and an executed data use/sharing agreement with UNC.