Functional characterisation of the molecular mechanisms that control bacterial community structure and dynamics in the human gut microbiome
Lead Research Organisation:
QUADRAM INSTITUTE BIOSCIENCE
Department Name: UNLISTED
Abstract
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Technical Summary
Objective 1: Determine what molecules are produced by bacteria to impact community composition and dynamics.
Importance: Understanding what mechanisms shape a healthy community will lead to the identification of drug candidates and probiotic strains that promote health and protect from invading pathogens.
Approaches: Our in silico analysis of the healthy human gut microbiota has identified several BGCs predicted to impact community composition. We will experimentally characterise the molecular products from the most abundant BGC families using bacterial molecular genetics and biochemistry approaches, supported by a transcriptomics analysis. Next, we will verify the impact of these molecules on assembled communities in vitro in the colon model and in vivo in mice that have received their microbiota from a human stool sample.
Milestones:
year 2: characterise at least 5 small molecules with community modulating properties
year 3: in vitro colon model and year 4: in vivo mouse model for community modulation
Objective 2: Investigate how do the microbiota protect themselves in an inflamed gut environment.
Importance: Understanding how bacteria manage oxidative stress will help identification of strategies to stimulate the healthy community members or interfere with the defence mechanisms in pathogens.
Approaches: We identified a widespread family of bacterial antioxidants and will use a combination of bacterial molecular genetics and biochemical techniques to elucidate their biosynthetic pathway to identify potential drug targets. We will use 16S community analysis of endoscopy samples from healthy and chronically inflamed patients to identify the impact of inflammation and oxidative stress on the individual community members. This will allow us to set up an in vitro colon model for the inflamed gut, seeded with representative stool samples.
Milestones:
year 1: biosynthesis pathway elucidated
year 3: community analysis of elderly patients
year 4: in vitro community model
Importance: Understanding what mechanisms shape a healthy community will lead to the identification of drug candidates and probiotic strains that promote health and protect from invading pathogens.
Approaches: Our in silico analysis of the healthy human gut microbiota has identified several BGCs predicted to impact community composition. We will experimentally characterise the molecular products from the most abundant BGC families using bacterial molecular genetics and biochemistry approaches, supported by a transcriptomics analysis. Next, we will verify the impact of these molecules on assembled communities in vitro in the colon model and in vivo in mice that have received their microbiota from a human stool sample.
Milestones:
year 2: characterise at least 5 small molecules with community modulating properties
year 3: in vitro colon model and year 4: in vivo mouse model for community modulation
Objective 2: Investigate how do the microbiota protect themselves in an inflamed gut environment.
Importance: Understanding how bacteria manage oxidative stress will help identification of strategies to stimulate the healthy community members or interfere with the defence mechanisms in pathogens.
Approaches: We identified a widespread family of bacterial antioxidants and will use a combination of bacterial molecular genetics and biochemical techniques to elucidate their biosynthetic pathway to identify potential drug targets. We will use 16S community analysis of endoscopy samples from healthy and chronically inflamed patients to identify the impact of inflammation and oxidative stress on the individual community members. This will allow us to set up an in vitro colon model for the inflamed gut, seeded with representative stool samples.
Milestones:
year 1: biosynthesis pathway elucidated
year 3: community analysis of elderly patients
year 4: in vitro community model
Planned Impact
unavailable
People |
ORCID iD |
| Jan Claesen (Principal Investigator) |