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

Summary

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.

Conditions

• Quorum Sensing
• Prebiotics
• Probiotics
• Sepsis

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

Sponsors & Collaborators

• University of Nottingham

  lead OTHER

Principal Investigators

• Abeed Chowdhury, MB ChB BSc MRCS · University of Nottingham

• Dileep Lobo, MBBS DM FRCS · University of Nottingham

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

DOUBLE

Model

FACTORIAL

Eligibility

Min Age

18 Years

Max Age

75 Years

Sex

MALE

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2009-10-31

Primary Completion

2011-05-31

Completion

2011-05-31

Countries

• United Kingdom

Study Locations