Research at the Chair of Intestinal Microbiome

The research focus within the Chair of Intestinal Microbiome involves defining the complex interactions of the intestinal microbiota, particularly during the early life developmental window. The group is focused on how microbial communities and specific microbiota members (e.g. Bifidobacterium) interact with other microbes and the host including: (i) the impact of diet, (ii) how these microbes modulate critical infection (i.e. colonisation) resistance, and (iii) beneficially impact host responses, including immune regulation. Another key goal is to identify bifidobacterial communities and their components that can restore a disturbed early life microbiota back into one able to promote health. We utilise multi-disciplinary approaches to answer these key questions including; microbiology (in vitro model-colon chemostat systems for complex culturing, molecular microbiology), metabolomics (NMR, MS), next generation sequencing (RNASeq, 16S rRNA, WGS, both host and microbe), bioinformatics tools, in vivo models (germ-free and infection models) and human studies (preterm/term infants and adults).

Diet plays a critical role in shaping the early life microbiota, and we have a number of projects seeking to understand the mechanisms underpinning diet-Bifidobacterium interactions.

We are interested in understanding how breast-feeding impacts the early life microbiota. Bifidobacterium species and strains are found at high levels in breast-fed infants; whereas levels are markedly reduced in formula-fed infants. The presence of bifidobacteria at birth (and throughout early life) influences the wider bacterial ecosystem leading to a ‘healthy’ microbiota that can be maintained into adulthood. Using in vitro and in vivo systems, we are seeking to identify the key genetic and metabolic signatures involved in this process, to ultimately develop an enhanced formula that more closely mimics mums’ milk and provide the health benefits children receive when breast-fed.

We are also taking a global genomics approach to bifidobacterial-diet evolutionary processes. We are using wet and dry lab tools to understand how different Bifidobacterium species and strains have evolved the ability to digest different dietary components, including components of breast milk (i.e. human milk oligosaccharides), and plant and bacterial polysaccharides. As part of these studies we are isolating and characterising Bifidobacterium from different hosts, both humans and animals.

The microbiota has been shown to be critical for development of numerous physiological processes including maturation of the gastrointestinal (GI) tract and immune system. However, microbiota disturbances, particularly during early life, have been linked to disease development. Thus, mechanistically understanding how specific bacteria (including Bifidobacterium) influence host responses is key to the development of new therapies.

We have an interest in non-communicable diseases, such as intestinal disorders and cancer, that may be linked to disturbances in the gut microbiota and dysregulated immune responses. We are keen to understand these conditions from the perspective of the microbe(s) and microbial factors that may mediate disease outcomes. For example, we have previously shown that specific molecules (e.g. exopolysaccharide capsules) produced by Bifidobacterium positively impact the gut barrier, which is often ‘leaky’ in inflammatory bowel disease. We are using a range of systems for this research, in vivo models that closely mimic human disease pathology, high throughput in vitro systems, and global bacterial genetic approaches, which will hopefully allow us to identify further molecular and structural components that contribute protective effects. The goal of these projects is to develop novel live biotherapeutics that can reduce disease-associated pathology and positively impact patient outcomes.

Previous work suggests that gut microbiota disturbances in the mother during pregnancy, and in the first 1000 days post birth have a magnified impact on infant health. Therefore, we are working to understand how certain microbes positively (or negatively) influence normal early life immune and metabolic development, including ‘boosting’ responses after e.g. vaccination. These studies involve a combination of clinical samples obtained from ongoing cohorts (PEARL [pregnant mothers and their infants] and BAMBI [preterm infants]), in vivo germ-free models, coupled with innovative sequencing and bioinformatic pipelines. If we can understand the influence of the microbiota on early life host, we may be able to develop new therapies to promote both maternal and infant health. Indeed, with BAMBI we have already been exploring how ‘probiotic’ strategies in premature babies can help ‘restore’ the microbiota, and how this relates to clinical outcomes like necrotising enterocolitis.

One of the fundamental roles the microbiota plays is resisting infection by invading pathogens. However, it is currently unclear how different members of the early life microbiota mediate these beneficial effects, or how pathogens overcome these responses to cause disease.

The gut microbiota represents a complex community of trillions of different microbes, who are in constant ‘competition’ with each other. We are therefore interested in understanding how different beneficial microbiota members (like Bifidobacterium) may outcompete pathogenic microbes via their ability to more efficiently digest dietary components, obtain factors that are normally scarce in the gut (e.g. iron), and produce novel anti-microbial compounds. We also have a focus on pinpointing putative virulence factors of important neonatal-associated pathogens (e.g. Clostridium perfringens), and how these clinically relevant microbes may spread in at-risk populations. We use multi-disciplinary approaches to probe these questions including development of new bioinformatic pipelines which we can apply to sequencing or transcriptional data, in vitro assays, molecular microbiology approaches, proteomics and metabolomics. We hope these projects will allow us to identify key strains able to provide critical colonisation resistance against pathogens including E. coli, Salmonella and Clostridium.

Development of novel anti-infection strategies is particularly important considering the rise in antimicrobial resistance (AMR). Infants often receive many courses of antibiotics, which alongside disturbing the gut microbiota may also contribute to the ‘resistome’ i.e. carriage of antimicrobial resistance and virulence genes within the early life microbial community. To tackle this important issue, we are developing new ‘diagnostic’ approaches, that can profile the gut microbiota and identify potential pathogens and their AMR profile. We are also using different molecular and computational approaches to explore the impact of antibiotics on the early life gut microbiota (using BAMBI and PEARL samples), including understanding how AMR genes may move around within the microbial community, including transfer of resistant genes to pathogenic species.