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

NCT04171466 | Completed

• 1 other identifier: 19SAHS
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Antibiotic Side Effect; Antibiotic-associated Diarrhea; Antibiotic-induced Dysbiosis; Antibiotic-induced Epithelial Barrier Disintegrity

Keywords

Gut microbiome; Dysbiosis; Antibiotic therapy; Rationally-defined consortia; Short-chain fatty acids; Gut metabolome; Metagenomic sequencing; Ciproflozacin; Metronidazole; Probiotic Therapy

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• Difference in serum LPS-binding protein (LBP) at Day 7.

  Baseline- Days 91

• Difference in the Intestinal Permeability Assessment (IPA) at Day 7 as measured by Lactulose/mannitol testing.

  Baseline- Days 91

• Metabolomic profile of stool samples.

  Baseline- Days 91

• Number of participants with improved Antibiotic-Associated Gastrointestinal Function

  Baseline- Days 91

Study Arms (4)

Broad Spectrum Antibiotic Therapy + Microbial Consortia

ACTIVE COMPARATOR

Other: Ciprofloxacin + Metronidazole; Other: SH-DS01

Broad Spectrum Antibiotic Therapy + Placebo

PLACEBO COMPARATOR

Other: Ciprofloxacin + Metronidazole; Other: Placebo

No Antibiotic Therapy + Microbial Consortia

ACTIVE COMPARATOR

Other: SH-DS01

No Antibiotic Therapy + Placebo

PLACEBO COMPARATOR

Other: Placebo

Interventions

Ciprofloxacin + Metronidazole OTHER

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.

Broad Spectrum Antibiotic Therapy + Microbial Consortia; Broad Spectrum Antibiotic Therapy + Placebo

SH-DS01 OTHER

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.

Broad Spectrum Antibiotic Therapy + Microbial Consortia; No Antibiotic Therapy + Microbial Consortia

Placebo OTHER

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.

Broad Spectrum Antibiotic Therapy + Placebo; No Antibiotic Therapy + Placebo

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Seed Health: lead

Study Sites (1)

KGK Science

London, Ontario, N6A 5R8, Canada

Location

Related Publications (13)

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• Nagpal R, Wang S, Ahmadi S, Hayes J, Gagliano J, Subashchandrabose S, Kitzman DW, Becton T, Read R, Yadav H. Human-origin probiotic cocktail increases short-chain fatty acid production via modulation of mice and human gut microbiome. Sci Rep. 2018 Aug 23;8(1):12649. doi: 10.1038/s41598-018-30114-4.

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• Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly-Y M, Glickman JN, Garrett WS. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science. 2013 Aug 2;341(6145):569-73. doi: 10.1126/science.1241165. Epub 2013 Jul 4.

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• Ho L, Ono K, Tsuji M, Mazzola P, Singh R, Pasinetti GM. Protective roles of intestinal microbiota derived short chain fatty acids in Alzheimer's disease-type beta-amyloid neuropathological mechanisms. Expert Rev Neurother. 2018 Jan;18(1):83-90. doi: 10.1080/14737175.2018.1400909. Epub 2017 Nov 14.

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• Suez J, Zmora N, Zilberman-Schapira G, Mor U, Dori-Bachash M, Bashiardes S, Zur M, Regev-Lehavi D, Ben-Zeev Brik R, Federici S, Horn M, Cohen Y, Moor AE, Zeevi D, Korem T, Kotler E, Harmelin A, Itzkovitz S, Maharshak N, Shibolet O, Pevsner-Fischer M, Shapiro H, Sharon I, Halpern Z, Segal E, Elinav E. Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT. Cell. 2018 Sep 6;174(6):1406-1423.e16. doi: 10.1016/j.cell.2018.08.047.

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MeSH Terms

Conditions

Dysbiosis

Interventions

Ciprofloxacin; Metronidazole

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nitroimidazoles; Nitro Compounds; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring

Study Officials

• Gregor Reid, PhD

  Lawson Health Research Institute, St. Joseph's Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 19, 2019
• First Posted: November 21, 2019
• Study Start: August 12, 2020
• Primary Completion: September 7, 2022
• Study Completion: September 7, 2022
• Last Updated: October 25, 2022

Record last verified: 2022-10

Locations

CA (1)