The effect of early-life prebiotic feeding on adult hippocampal function, central and peripheral metabonomics and microbial metagenomics

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

The influence of the intestinal microbiota on adult brain function has been convincingly demonstrated in rodents and humans. Nurturing the growth of the beneficial gut bacteria with probiotics and prebiotics alters brain chemistry, and improves cognitive performance in the healthy host. There are also some suggestions that the early-life establishment of gut microbial communities influences brain development. Therefore, supporting the proliferation of the commensal microbiota in early-life, may ensure healthy brain development and reduced susceptibility to the age-related, progressive decline in executive brain functions.
In pilot studies, we have observed that the administration of the prebiotic BGOS (Bimuno, galacto-oligosaccharides) to neonatal rats from post-natal day (PD) 3-21, increases the levels of hippocampal glutamate NMDAR receptor, NR2A subunits, Brain Derived Neurotrophic Factor (BDNF), and the synaptic protein, synaptophysin, at PD22, 56 and 112, relative to controls. These proteins are crucial for normal brain development and function, and our data suggest that early-life BGOS feeding may improve adult brain performance. Early-life dietary supplementation with prebiotics may also influence the microbiota-dependent metabolic processes in later-life.
Our proposed research will: 1) test if feeding neonatal rats with BGOS alters glutamate receptor dependent excitatory post-synaptic potentials in the hippocampus at PD22, 56, 112 and 196; 2) evaluate hippocampus-dependent spatial memory in adult rats at the aforementioned ages following neonatal BGOS supplementation; 3) examine the metabolic profile of rats at all ages after early-life BGOS feeding, using metabonomic technology; and 4) apply metagenomic technology to monitor gut microbial communities in the aging rat following neonatal BGOS intake. Overall, the current proposal will provide new insights into how early-life gut microbiota influences adult microbial colonization and host physiology.

Who will benefit and how? In addition to the immediate beneficiaries from academia, our proposed project, if successful, is likely to benefit the commercial private sector with a particular interest in prebiotics. We believe that manufacturers of such products would be attracted to such research as it offers the potential to develop a new market strategy for prebiotics as agents capable of maintaining brain and metabolic health from an early age, in addition to their more widely accepted role on digestive and immune well-being. Thus, if we show in our study that neonatal prebiotic administration prevents an age-related decline in cognitive behaviour, then it may be commercialised as an active ingredient which may be incorporated into other foods, including infant milk formulations.
Understanding more about how the gut bacteria may modulate normal brain function in early-life and through the life-course, will help agencies (Food Standards Agency, Department of Health, Department for Environment, Food and Rural Affairs) inform the public and encourage them to make more sensible healthy food choices. For example, many natural foods including, asparagus, oatmeal and legumes, contain high amounts of prebiotics. It is conceivable that the whole population within a 10 to 15 year period may experience the benefits of healthy diet with children, and succeeding generations, gaining most from an improved quality of health and life expectancy.
The individual consumer may also directly benefit from our work shows that prebiotics improve working memory. In this regard, the active compound we will test (the prebiotic BGOS) is a commercially available product. Therefore once disseminated through public engagement channels listed below - one could encourage the uptake of such products and their related benefits. Thus, the potential of our research to impact on the health of the UK could be realized in a short time. Since the proposal is highly translational, and the compounds tested are greatly tolerated, human studies could proceed very soon after our data in animals are analysed. This would immediately preclude the use of rodents for this type of research, and result in their direct 'replacement' (cf the 3Rs) with human subjects.
Staff engaged in the project will be trained and expected to acquire proficiency in several research skills including microbiology, metagenomic and metabonomic technologies electrophysiology, behavioural neuroscience and animal welfare. Moreover, the post-doctoral researcher will develop an aptitude in management and organization so that the several components of the study between two institutions can be efficiently co-ordinated. Importantly, the appointed staff will experience research within both an academic and Industrial environment, and thus allow them to make a founded decision about their scientific career that suits them best. All these attributes will provide the researcher with a multiple of scientific as well as interpersonal skills, which would be appreciated in several employment sectors.

Exploitation plans: To ensure that the identified groups will benefit, the results of the proposed investigation would be disseminated through publication in peer-reviewed journals and presented at national and international scientific meetings. In addition, the results would be communicated more widely to the general public via the channels of public meetings (e.g. at schools and charitable organizations), and the general print and broadcast media in which the applicants are active. Our Industrial partner has an additional duty to distribute potentially beneficial information via their established channels and policies, thereby extending dissemination coverage. We will actively pursue companies interested in prebiotics in order to fund additional work in this area, in particular human intervention studies which are costly to implement but which will directly benefit all parties involved.