Metagenomic and Metabolomic Reconstitution of Gut Microbiota After Broad Spectrum Antibiotic Therapy

Study Overview
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Brief Summary
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In the United States, healthcare providers prescribe over 270 million antibiotic prescriptions each year. While antibiotics have transformed medicine and methods of treating life-threatening bacterial infection, broad spectrum antibiotics also induce disruption of resident gut microbial communities by altering both composition and function. This disruption of microbial community dynamics has been demonstrated at the taxonomic level, yet the extent of functional disruptions to microbial metabolic output and host cells remains understudied in humans. This study explores the impact of a broad spectrum antibiotic cocktail on microbial communities throughout the gastrointestinal tract, and the impact of a defined, multi-strain consortia of probiotic organisms following antibiotic exposure.

Official Title
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A Randomized, Double-blind, Placebo-controlled Study to Determine the Efficacy of a Multi-strain Synbiotic (SH-DS01) to Restore Gut Barrier Integrity and Gut Microbiota Composition After Antibiotic Administration.

Conditions
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Antibiotic Side Effect, Antibiotic-associated Diarrhea, Antibiotic-induced Dysbiosis, Antibiotic-induced Epithelial Barrier Disintegrity

Intervention / Treatment
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* Other: Ciprofloxacin + Metronidazole
* Other: SH-DS01
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males & Females 18-55 years of age, inclusive BMI of 18.5 - 29.9 kg/m2, inclusive Waist circumference < 102 cm in males or < 88 cm in females Female participant is not of child-bearing potential, defined as females who have undergone a sterilization procedure (e.g. hysterectomy, bilateral oophorectomy, bilateral tubal ligation, total endometrial ablation) Or, Females of child-bearing potential must have a negative baseline urine pregnancy test and agree to use a medically approved method of birth control for the duration of the study. All hormonal birth control must have been in use for a minimum of three months. Healthy as determined by laboratory results, medical history, and physical exam by QI Agrees to abstain from use of fermented foods or beverages with live bacteria or products containing active cultures for the duration of the study Agrees to avoid alcoholic beverages and drugs containing alcohol during antibiotic treatment period and for at least one day after (days 0-8) Agrees to avoid high caffeine intake (no more than 1 cup of coffee or 300 mg of caffeine/day) during antibiotic treatment period of the study (days 0-7) Agrees to refrain from intake of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) during antibiotic treatment period of the study (days 0-7) and 72 hours prior to prior to lactulose and mannitol test Agrees to refrain from using drugs and supplements containing aluminum, magnesium, sorbitol and/or mannitol 72 hours prior to lactulose and mannitol test. Agrees to comply with all study procedures Agrees to maintain current level of physical activity throughout the study Exclusion Criteria: Women who are pregnant, breast feeding, or planning to become pregnant during the trial Allergy or sensitivity to antibiotics (Ciprofloxacin, Metronidazole), Lactulose or Mannitol, or investigational product's active or inactive ingredients Use of antibiotics or antifungals within three months prior to enrollment, including topical antibiotics or antifungals. Clinically significant abnormal laboratory results at screening as assessed by the QI Use of PPIs and H2-antagonists Use of tobacco products Type I or type II diabetes mellitus or treatment with anti-diabetic medication Unstable metabolic diseases or chronic diseases as assessed by the QI Self-reported current or pre-existing thyroid condition. Unstable hypertension. Treatment on a stable dose of medication for at least 3 months will be considered by the QI Current or history of any significant diseases of the gastrointestinal tract that may impact study outcomes as assessed by the QI Significant cardiovascular event in the past 6 months. If the event occurred greater that 6 months ago and if on stable medication may be included after assessment by the QI on a case by case basis Major surgery in the past 3 months or individuals who have planned surgery during the course of the trial. Participants with minor surgery will be considered on a case-by-case basis by the QI Self-reported an autoimmune disease or an immune-compromised state Self-reported HIV-, Hepatitis B- and/or C-positive diagnosis History of or current diagnosis with kidney and/or liver diseases as assessed by the QI on a case-by-case basis, with the exception of history of kidney stones symptom free for 6 months Self-reported medical or neuropsychological condition and/or cognitive impairment that, in the QI's opinion, could interfere with study participation Self-reported blood/bleeding disorder. To be confirmed by the QI on a case by case basis Cancer in the five years prior to enrollment, except skin cancers completely excised with no chemotherapy or radiation with a follow up that is negative. Volunteers with cancer in full remission for more than five years after diagnosis are acceptable following case by case assessment by QI. Clinically significant illness in the four weeks prior to randomization Current use of prescribed medications listed in Section 7.3.1 Current use of over-the-counter medications, supplements, foods and/or drinks listed in Section 7.3.2 Current use of any probiotic, prebiotic and symbiotic product unless willing to undergo a 4-week washout and abstain from consuming such products during the study. Medical use of cannabinoid products Use of any cannabinoid products (including synthetics) within one month of study entry Alcohol or drug abuse within the last 12 months High alcohol intake (>2 per day or a total of >10 standard drinks per week) Blood donation 30 days prior to screening, during the study, or a planned donation within 30-days of the last study visit Participation in other clinical research trials 30 days prior to screening Any other active or unstable medical condition, that, in the opinion of the QI, may adversely affect the participant's ability to complete the study or its measures or pose significant risk to the participant

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Broad Spectrum Antibiotic Therapy + Microbial Consortia<br> | Other: Ciprofloxacin + Metronidazole<br>* Participants will be instructed to take 1 capsule of Ciprofloxacin (500mg) twice daily for 7 days and 1 capsule of Metronidazole (500mg) thrice daily for 7 days. Antibiotics should be taken at least 2 hours before or 6 hours after mineral supplements containing magnesium or aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc.<br>Other: SH-DS01<br>* SH-DS01 is a rationally defined microbial consortia consisting of 24 strains across 12 species, with polyphenolic and phenolic prebiotic bioactive compounds. Participants will be instructed to take 2 capsules daily for the duration of the trial.<br>|
| Placebo Comparator: Broad Spectrum Antibiotic Therapy + Placebo<br> | Other: Ciprofloxacin + Metronidazole<br>* Participants will be instructed to take 1 capsule of Ciprofloxacin (500mg) twice daily for 7 days and 1 capsule of Metronidazole (500mg) thrice daily for 7 days. Antibiotics should be taken at least 2 hours before or 6 hours after mineral supplements containing magnesium or aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc.<br>Other: Placebo<br>* Placebo capsules for SH-DS01 will contain rice flour matched for color and texture in an identical outer capsule shell. Participants will be instructed to take 2 capsules daily for the duration of the trial.<br>|
| Active Comparator: No Antibiotic Therapy + Microbial Consortia<br> | Other: SH-DS01<br>* SH-DS01 is a rationally defined microbial consortia consisting of 24 strains across 12 species, with polyphenolic and phenolic prebiotic bioactive compounds. Participants will be instructed to take 2 capsules daily for the duration of the trial.<br>|
| Placebo Comparator: No Antibiotic Therapy + Placebo<br> | Other: Placebo<br>* Placebo capsules for SH-DS01 will contain rice flour matched for color and texture in an identical outer capsule shell. Participants will be instructed to take 2 capsules daily for the duration of the trial.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in microbiota composition at 3 months as assessed by whole genome shotgun sequencing. | Microbiota composition will be identified through fecal samples for total genomic DNA extraction in participants supplemented with SH-DS01 and with or without antibiotics. | Baseline- Days 91 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in serum LPS-binding protein (LBP) at Day 7. | As a measure of intestinal barrier integrity in response to antibiotic therapy. | Baseline- Days 91 | 
| Difference in the Intestinal Permeability Assessment (IPA) at Day 7 as measured by Lactulose/mannitol testing. | As a measure of intestinal barrier integrity in response to antibiotic therapy. | Baseline- Days 91 | 
| Metabolomic profile of stool samples. | As assessed by untargeted metabolomics on whole stool samples. | Baseline- Days 91 | 
| Number of participants with improved Antibiotic-Associated Gastrointestinal Function | As assessed by daily symptom tracking software of stool quality, regularity, ease of expulsion, bloating, flatulence, and intestinal transit time. | Baseline- Days 91 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gut microbiome, Dysbiosis, Antibiotic therapy, Rationally-defined consortia, Short-chain fatty acids, Gut metabolome, Metagenomic sequencing, Ciproflozacin, Metronidazole, Probiotic Therapy