Gut microbes and brain function

The gut-brain-microbiota axis comprises an extensive communication network between the brain, the gut, and the microbiota residing there. If the composition or the diversity of the gut microbiota is impaired, this can have negative consequences for host health and has been associated with disorders such as obesity, diabetes, inflammatory diseases, and neuropsychiatric illnesses including anxiety and depression. Therefore, much research effort in recent years has focused on understanding the potential of targeting the intestinal microbiota to prevent and treat such disorders. Preclinical data strongly support the view that microbe manipulation using probiotics and prebiotics to enhance the host-microbe symbiotic relationship has great potential in the future prevention and treatment of such disorders. Therefore, this study aimed to identify novel probiotics by screening gut-derived lactobacilli for bioactive metabolite production, namely GABA and serotonin, identifying one Lactobacillus plantarum GABA producer and two Lactobacillus paracasei serotonin producers which were subsequently characterised and assessed for probiotic characteristics. Enhanced whole genome sequencing identified the trp operon involved in tryptophan and serotonin metabolic pathways, antimicrobial activity including Enterolysin A and Carnocin CP52, as well as genes promoting acid tolerance and adhesion capability such as dlt and fbp. The work described here also explores the influence that environmental factors and diet have on the microbiome and the subsequent effect on anxiety and stress-related behaviour in mouse models and an ecologically relevant model, namely wild caught great tit birds. Chapter 4 explores the effect of environment on the gut microbiota by exposing high anxiety and normal anxiety phenotype mice to an enriched versus standard environment, revealing improved anxiety-like behaviour following environmental enrichment. However, no effect was observed on alpha diversity while differences in beta diversity were based on mouse phenotype and not environment. Chapter 5 investigated the impact of diet on the gut microbiome in wild caught great tit birds, and demonstrates that a diet low in fat, protein and fibre results in lower alpha diversity compared to a high fat, protein and fibre content diet, while several compositional differences were also observed, including a higher abundance of Bacteroidetes and Proteobacteria following administration of an insect diet. Furthermore, the data presented herein outline the potential of harnessing the gut microbiota to improve metabolic and neuropsychological health through probiotic and prebiotic intervention in preclinical and clinical trials, respectively. The data presented in Chapter 6 outline a potential role of metabolic- and neuroactive-microbial metabolite production in the modulation of diet-induced metabolic dysfunction, including abnormal behaviour. Intervention with GABA-producing Lactobacillus brevis strains attenuated several abnormalities associated with metabolic dysfunction, causing a reduction in the accumulation of mesenteric adipose tissue, increased insulin secretion following glucose challenge, improved plasma cholesterol clearance, and reduced despair-like behaviour and basal corticosterone production during the forced swim test. Chapter 7 investigated an alternative method of gut microbiota manipulation, namely prebiotic administration with polydextrose in adults for four weeks which resulted in a modest improvement in cognitive flexibility and an increased ability for sustained attention in this double-blind, randomised, placebo-controlled clinical trial. Although there was no change in microbial diversity, abundance of Ruminiclostridium 5 significantly increased after polydextrose supplementation compared to placebo. Therefore, the results presented herein indicate that probiotic and prebiotic intervention could modulate gut-to-brain communication and benefit metabolic and neuropsychological health