Effect of Tenapanor on the Metagenomics and Metabolomics of Patients With Irritable Bowel Syndrome With Constipation

Inclusion Criteria:

1. Ages 18-75 years old
2. BMI >18.5 and <35 kg/m2
3. Rome IV criteria for IBS-C for at least 6 months
4. Compliant with baseline stool submission prior to initiation of medication
5. Ability to follow verbal and written instructions
6. Ability to record daily bowel habits, including frequency, stool consistency (BSFS),and symptom severity
7. Willingness to avoid major dietary changes and use of probiotics during the studyperiod
8. Informed consent form signed by the subjects

Exclusion Criteria:

1. History of loose stools
2. History of irritable bowel syndrome with diarrhea (IBS-D) or mixed irritable bowelsyndrome (IBS-M)
3. Non-compliance with baseline stool submission
4. Previous use of tenapanor
5. GI motility obstruction or GI tract structural abnormality
6. Current use of prescribed or illicit opioids
7. History of pelvic floor dysfunction
8. Need for manual maneuvers in order to achieve a BM
9. History of GI lumen surgery at any time or other GI or abdominal operations within 60days prior to entry into the study
10. History of high-dose stimulative or cathartic laxative abuse as judged by investigatorteam
11. Severe IBS-C as judged by the investigator
12. Neurological disorders, metabolic disorders, or other significant disease that wouldimpair their ability to participate in the study
13. Cardiovascular disease, diabetes, cancer, Crohn's disease, ulcerative colitis
14. BMI of <18.5 or >35 kg/m2
15. Pregnancy (or positive serum or urine pregnancy test(s) in females of childbearingpotential) or lactation
16. Absence of contraception in females of childbearing potential
17. History of allergic reaction to tenapanor
18. Administration of other FDA-approved agents for the treatment of IBS-C within 1 monthprior to Screening Visit:

• Linaclotide
• Lubiprostone
• Plecanatide

19. If treated with any of the following medications, dosing (or approximate frequency of 'as needed' use) must be stable for at least 30 days prior to Screening Visit and thesubject must agree to maintain the same dose (or approximate frequency of 'as needed'use) or a decreased dose of medication throughout the study:

• Probiotics
• Bulk laxatives, fiber, and stool softeners

20. Exclusion of colonic inertia with symptoms of < 1 BM per 2 weeks
21. Subjects anticipating surgical intervention during the study
22. Known history of diabetes (type 1 or 2)
23. Subjects with recent antibiotic use (last 3 months) or anticipated antibiotic useduring the study period
24. History of inflammatory bowel disease
25. Supine SBP > 160 mm Hg and/or supine DBP > 95 mm Hg (mean of two consecutive readings)
26. Angina, coronary bypass, or myocardial infarction within 6 months prior to ScreeningVisit
27. History of swallowing disorders
28. History of gastric bypass or any other gastric surgery
29. History of small bowel resection (except if related to appendectomy)
30. History of gastric or duodenal ulcer
31. History of gastroparesis
32. History of abdominal radiation treatment
33. History of pancreatitis
34. History of intestinal stricture (e.g., Crohn's disease)
35. History of intestinal obstruction or subjects at high risk of intestinal obstructionincluding suspected small bowel adhesions
36. History of malabsorption
37. History of hepatitis B or C
38. History of human immunodeficiency virus
39. History of cancer within the past 5 years (except adequately-treated localized basalcell skin cancer or in situ uterine cervical cancer)
40. Any other clinically significant disease interfering with the assessments oftenapanor, according to the Investigator (e.g., disease requiring correctivetreatment, potentially leading to study discontinuation)
41. HbA1c > 8.5% (> 69 mmol/mol)
42. Any relevant biochemical abnormality interfering with the assessments of tenapanor,according to the Investigator 44. Antidiabetic medications within 1 month prior toScreening Visit (except stable dose of metformin, ≤ 1500 mg/day, for at least 1 month insubjects with type 2 diabetes) 45. Medications requiring mandatory administration twice perday with meals