This is a randomized, double-blind, placebo-controlled study in sickle cell disease participants with a history of Vaso-occlusive Crises (VOCs). Approximately 60 participants with sickle cell disease will be enrolled and randomized: 12 participants in each of four active novel formulation rifaximin groups and 6 participants in each of 2 placebo groups.

Inclusion Criteria:

1. ability and willingness to sign a written informed consent form.

2. between the ages of 18 to 70 years old (inclusive) at the time of consent.

3. SCD of any genotype (HbSS, HbSC, HbS β-thalassemia). If the subject's genotype has not been previously documented, genotyping will be performed during Screening using high-performance liquid chromatography (HPLC)/electrophoresis.

4. least 2 VOCs within the 12 months prior to Screening.

5. if receiving hydroxyurea (HU)/hydroxycarbamide (HC), subject must have been receiving the treatment for at least 6 months prior to Screening and must agree to maintain the same dose and schedule for the duration of the study.

6. must have laboratory values at Screening as follows:

   1. Absolute Neutrophil Count ≥1.0 x 109/L
   2. Platelets ≥ 75 x 109/L
   3. Hemoglobin (Hgb) ≥ 6.0 g/dL
   4. Glomerular filtration rate (GFR) ≥ 45 mL/min/1.73 m2 using the CKD-EPI formula
   5. Total bilirubin ≤ 15 mg/dL
   6. Alanine transaminase (ALT) ≤ 3.0 x ULN
   7. International Normalized Ratio (INR) ≤ 2.0

7. Eastern Cooperate Oncology Group (ECOG) performance status ≤ 2

8. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must have a negative serum pregnancy test at Screening and agree to use standard prevention methods for the duration of the study.

Exclusion Criteria:

1. receiving concomitant treatment with voxelotor, crizanlizumab, or L-glutamine.
2. any history of stem cell transplant, is planning to begin or has received in past 30 days.
3. acute VOC, requiring a visit to a medical facility and/or healthcare professional, ending within 7 days prior to Day 1 dosing.
4. has received any blood products within 30 days prior to Day 1 dosing.
5. uncontrolled liver disease or renal impairment, ulcerative colitis, Crohn's disease, or other chronic GI disorder.
6. has received active treatment in another investigational trial within 30 days or 5 half-lives of the last dose of the investigational agent, whichever is greater, prior to Screening.
7. has received penicillin prophylaxis or antibiotics for treatment of infection within 30 days or 5 half-lives of the treatment, whichever is greater, prior to Screening.
8. significant medical condition that required hospitalization (other than for a VOC) within 2 months prior to Screening.
9. planning on undergoing an exchange transfusion during the duration of the study or has completed one within 4 weeks prior to Day 1 dosing.
10. hypersensitivity to rifaximin, rifampin, rifamycin antimicrobial agents, or any components of rifaximin ER and DER.
11. pregnant or a nursing woman.
12. history of illicit drug use or abuse, either documented or in the opinion of the Investigator.
13. using any medication that is known to inhibit or induce CYP3A4, or P-gp and OATP1B1/B3 within 30 days or 5 half-lives, whichever is longer, prior to Day 1 dosing, or in the opinion of the Investigator, may affect the evaluation of the study product or place the subject at undue risk.
14. has had any prior gastrointestinal surgery which has altered the anatomy of the esophagus, stomach, or small/large intestine (with the exception of appendectomy, cholecystectomy, and fundoplication).
15. has had a colonoscopy or sigmoidoscopy within 30 days prior to Day 1 or plans to undergo such a procedure during the duration of the study.
16. has used bowel prep, laxative, or enema within 30 days prior to Day 1.
17. bleeding disorder including, but not limited to, acquired or congenital platelet function defects, disseminated intravascular coagulation (DIC), bleeding factor deficiencies, hemophilia, idiopathic thrombocytopenia purpura (ITP), or von Willebrand's disease.
18. planning to undergo a major surgical procedure during the duration of the study.
19. positive test for human immunodeficiency virus (HIV)1 or HIV2.
20. active Hepatitis B infection (HBsAg positive). Prior infection that is not active (i.e., HBsAg negative, HBcAb positive, and HBsAb positive) is permitted.
21. positive test for Hepatitis C (HCV RNA). Prior infection with spontaneous resolution or sustained resolution for ≥ 24 weeks after cessation of antivirals is permitted.
22. active COVID-19 infection or complication(s) related to COVID 19 infection that are unresolved or, in the opinion of the Investigator, may affect evaluation of the study drug or place the subject at undue risk.
23. received a vaccine (including COVID-19 vaccine) within 2 weeks prior to Screening. If subject has received their first of two COVID-19 vaccination doses, as applicable, they must wait for at least 2 weeks after receiving the second dose, and be symptom-free, prior to beginning Screening. Subject must not be planning for COVID-19 or other vaccinations while on study.
24. malignant disease. Exceptions include malignancies that were treated curatively and have not recurred within 2 years prior to study treatment, completely resected basal cell and squamous cell skin cancers, and any completely resected carcinoma in situ.
25. prolonged QT interval as assessed by ECG history within the past 3 months. For subjects with no historical ECG information, subject has a resting QTcF ≥ 460 msec for males and ≥ 470 msec for females at Screening.
26. any unstable cardiac condition that, in the opinion of the Investigator, may worsen during the study or interfere with successful evaluation of the study treatment.
27. serious mental or physical illness which, in the opinion of the Investigator, would compromise participation in the study.
28. any condition which, in the opinion of the Investigator, is likely to interfere with the successful collection of the measurements required for the study.
29. unable to understand or comply with study instructions and requirements.