Biological Modulation of Bacterial QSSMs, Innate and Adaptive Immunity by Antibiotics, Probiotics and Prebiotics in Healthy Individuals

Overview

It has recently been discovered that bacteria are able to communicate using specialised molecules known as Quorum Sensing Signalling Molecules (QSSMs). An accumulation of QSSMs in their surrounding environment allow for the bacteria to quantify the size of colonies. At specific colony sizes the concentration of QSSMs reaches a critical threshold leading to the activation of genes that cause an infection. It is by this mechanism that bacteria within a colony coordinate behaviour to activate infectivity when colony sizes are large enough to withstand defensive measures from the host's immune system. A disruption of quorum sensing may reduce the severity of infection and this has led to the development of inhibitors of quorum sensing as a new strategy in antibacterial therapy. QSSMs are also thought to facilitate infection by other mechanisms and are able to influence the number and function of a specific type of immune cell known as an 'antigen presenting cell'. These cells are pivotal in allowing the immune system to recognise components of bacteria as foreign and thereby mount the appropriate response. It was found that large numbers of these types of cells underwent programmed cell death (cell suicide) in the presence of QSSMs compared to when QSSMs were absent. This mirrors the situation in blood sampled from patients with severe infections where there is a greater proportion of cell deaths among antigen presenting cells than other types of immune cell. This study aims to establish in healthy volunteers, the mechanisms by which QSSMs affect immune cells and facilitate the spread of infection. Antibiotic administration in humans can alter the environment of the intestine and can lead to an overgrowth of harmful bacteria to potentially cause an infection. Probiotics supplements can prevent bacterial overgrowth and potentially reduce infective complications. The mechanism, which we aim to clarify, may involve changes in both the production of QSSMs and the function of immune cells. Hypothesis 1. Antibiotic use alters gut flora, leading to the appearance in the systemic circulation of bacterial QSSMs and changes in immune function of the host. 2. Probiotics and/or prebiotics have beneficial effects by preserving the normal resident gut flora, thereby, modulating bacterial QSSMs and preserving the immune function of the host. Aims The aims of our study are 2 fold: 1. Firstly, to study the effect of orally administered antibiotic on QSSMs (in faeces and blood) and on innate and adaptive immunity in healthy humans. 2. Secondly, to study the effect of orally administered combinations of prebiotic, probiotic and antibiotic on QSSMs (in faeces and blood) and on innate and adaptive immunity in healthy humans.

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Factorial Assignment
    • Primary Purpose: Basic Science
    • Masking: Double (Participant, Investigator)
  • Study Primary Completion Date: May 2011

Interventions

  • Dietary Supplement: Bifidobacterium longum BB536
    • 2 capsules od
  • Dietary Supplement: Active hexose correlated compound (AHCC)
    • One capsule tds
  • Dietary Supplement: Bifidobacterium longum BB536 and Active hexose correlated compound (AHCC)
    • One capsule tds (prebiotic) and two capsules od (probiotic)
  • Dietary Supplement: Corn starch placebo capsule
    • One capsule tds and two capsules od
  • Drug: Azithromycin
    • 250mg od

Arms, Groups and Cohorts

  • Active Comparator: Placebo/Probiotic
  • Active Comparator: Placebo/Prebiotic
  • Active Comparator: Prebiotic/Probiotic
  • Placebo Comparator: Placebo/Placebo

Clinical Trial Outcome Measures

Primary Measures

  • Serum QSSM level
    • Time Frame: 14 days

Secondary Measures

  • T cell Th1/Th2 ratio
    • Time Frame: 14 days

Participating in This Clinical Trial

Inclusion Criteria

  • Male volunteers – Age 18-55 years – Willing to participate and able to give informed consent – Alcohol abstinence during study Exclusion Criteria:

  • Smokers/substance abusers – Individuals with diabetes mellitus – Oral/Intravenous steroids – Allergy to azithromycin – Individuals already taking regular medications/probiotics/nutritional supplements – Individuals with chronic disease or currently under investigation – Individuals with ≤3 bowel movements/week – Individuals with ≥2 bowel movements/day

Gender Eligibility: Male

Minimum Age: 18 Years

Maximum Age: 75 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • University of Nottingham
  • Provider of Information About this Clinical Study
    • Dileep Lobob, University of Nottingham
  • Overall Official(s)
    • Abeed Chowdhury, MB ChB BSc MRCS, Principal Investigator, University of Nottingham
    • Dileep Lobo, MBBS DM FRCS, Study Director, University of Nottingham

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