PROTECT: Priming for healthy eating via the diet-microbiota -gut-brain axis


Early-life diet significantly affects neonatal brain development and metabolic programming. Poor diet can drive unhealthy eating patterns and increase the risk for obesity and type 2 diabetes later in life. Maturation of the intestinal microbiota in infancy is also critically determined by diet, and alterations in microbiota composition and diversity have been linked to the development of metabolic syndrome. While gut microbiota functionality rapidly changes in response to changes in diet, it is not known if the gut microbiome in early life is critical for the establishment of healthy eating behaviour in adulthood.

The central neural computations execute decisions on food seeking, food intake and eating behaviour, and the enteric nervous system reciprocally signals the nutritional outcomes following these food choices back to the brain. This bidirectional brain-gut communication allows a dynamic and flexible updating of the intrinsic food value, quality and palatability, which will determine ongoing eating behaviour and direct food selection. A poor diet in early life negatively impacts the neurodevelopment of central appetite, food reward, and energy metabolism and can change the decisions about food and food preference. An increasing number of studies suggest that the gastrointestinal microbiota also influences host appetitive behaviour, including food seeking and food cravings for highly palatable foods. For example, early life exposure to high-fat and high-sugar diets negatively impacts on the maturation of the gut bacterial community and can increase preference for fatty and sugary foods, increasing the overall risk of metabolic syndrome in the offspring.

This points to a potential orchestrating role for the microbiota in diet-gut-brain axis signalling at the interface of metabolism and centrally regulated eating behaviour and food reward. The orexigenic hormone, ghrelin, also called the hunger hormone, uniquely stands out as the only gastrointestinal signal stimulating food intake and adiposity. It plays a key role in the central regulation of appetite and food reward and can modulate fat preference and food choice. Moreover, ghrelin is a major regulator of the development of hypothalamic neuronal feeding pathways early in life. We have recently shown that microbiota-derived short-chain fatty acids (SCFAs) and specific bacterial strains, including strains of the Bifidobacterium genus, can modify ghrelin receptor signalling. In addition, germ free mice and antibiotic treated animals have lower circulating ghrelin levels and both pre- and probiotic supplementations have been shown to normalize ghrelin levels. Nevertheless, more mechanistic studies are needed to understand the full impact of the microbiota-ghrelin interaction on metabolic priming and the establishment of central-regulated homeostatic and non-homeostatic controls of food intake.

We hypothesize that a deficit in microbial maturation following early life high-fat/high-sugar diet (HFHS) critically determines the neurobehavioural outcomes directing eating behaviour in adulthood, which in part may be mediated by ghrelinergic signalling. Given the importance that early life colonization of the gut microbiota has on brain development and metabolic priming, we will (1) assess the role of the gut microbiota following an early life HFHS diet on long-term changes in dietary preferences and central reward signalling in adulthood; (2) we will investigate the effects of early-life HFHS on development and functioning of hypothalamic and extrahypothalamic neuropeptide systems, including ghrelinergic signalling; (3) we will investigate the potential of gut-microbiota-based interventions in remediating such effects. To interrogate the early-life HFHS-microbiota-eating behaviour trajectory, we will use three different approaches.

First, we will compare food intake behaviour, food preference and reward in adult animals following early-life HFHS diet exposure compared to control. Male and female pups will be exposed from birth, via maternal diet, and up to two weeks after weaning, via offspring diet, after which they will receive standard chow. Next, pups exposed to early life HSHF will be co-treated with a metabolically active Bifidobacterium longum strain (APC1472), or with a dietary prebiotic mixture (FOS/GOS), that stimulates the growth of Bifidobacteria, to investigate potential attenuating effects on the long-term negative consequences of eating behaviour associated with early life HFHS.

Throughout, we will investigate changes in peripheral and central neuroendocrine biomarkers, including ghrelinergic signalling, as well as changes in gut microbiota. Identifying early-life microbiota-mediated mechanisms underpinning the neurodevelopment of appetite, food reward pathways and food preference, which drive eating behaviour, has unique potential for the development of nutritional- and microbiota-targeting strategies to improve metabolic health and prime a healthy eating behaviour.

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