How food speaks to you: A new brain-gut axis for lifelong health.

What we eat has a major impact on our lifelong health. Being overweight causes multiple diseases, the severity of which is exacerbated by age. This makes understanding how diet impacts the ageing process, and finding ways to manipulate it, an important priority for research and public health policy. Nutrition is a known modulator of longevity. It is possible to increase lifespan and improve age-related health by modulating food intake eg. dietary restriction or intermittent fasting, or even by simply smelling changes in nutrient levels. This project investigates what connects the sensing of nutrition by the brain with changes to other metabolic tissues like the gut (henceforth referred to as the brain-gut axis), and links this to eating behaviours, metabolic health, and ageing. Identifying new molecular targets implicated in the nutrition-brain-gut response provides tangible methods to treat age-associated pathologies and improve health. Recently the Taylor and Tullet labs independently identified and published two compelling candidate pathways that connect nutrient perception to age-related health. These are the NF-E2 related transcription factor (Nrf) and the Unfolded Protein Response (UPR) of the endoplasmic reticulum (ER). This collaborative grant brings together our past work and new preliminary data to complete the picture. We hypothesise that Nrf acts in neurons to communicate information about diet and regulate UPR activation in the gut. This sequence of events will then control nutrient regulated feeding behaviours, metabolism and age-related health.

The work proposed here will use the nematode worm Caenorhabditis elegans to investigate the brain-gut relationship between these two pathways. The worm is perfect for this as it comes with a ready-made genetic toolkit, including: mutants that allow us to study the function of specific genes/molecules; fluorescent reporters allowing us to see where and when molecules are switched on or off; and a fully mapped nervous system so that we know exactly which neurons signal to each other. This useful and cost-effective model will allow us to establish the molecular sequence of events from the sensing of food, to neuronal Nrf signalling, to UPR activation. In addition, these tiny animals are excellent models for eating behaviour, age-related health, and lifespan, allowing us to probe the impact of molecular change on these processes.

Identifying the molecular mechanisms that connect nutrient information with effects on metabolic health and ageing would enable the development of therapies that harness these mechanisms or target their specific molecular functions in order to therapeutically manipulate ageing and health, providing avenues to delay and treat both diet-induced and other non-communicable diseases associated with age.

Diet and nutrition are known modulators of age-related health, and many diseases of ageing are exacerbated by poor diet and obesity. Identifying new molecular targets implicated in nutritional responses can therefore provide new routes to treat age-associated pathology. Two compelling candidates for connecting nutrient perception to age-related health are the NF-E2 related transcription factor (Nrf) and the Unfolded Protein Response (UPR). Both pathways influence metabolism and ageing in response to diet, have key roles in the nervous system, and regulate organism-wide responses. Based on published and preliminary data from our labs, we hypothesise that Nrf acts in neurons to communicate information about nutrition and regulate UPR activation in distal tissues. These events would connect the nutritional environment to metabolic tissues via a novel brain-gut axis. In turn this will control eating behaviour, metabolism and age-related health.

The proposed work will establish the relationship between these pathways and determine how they allow neurons to communicate nutrient status to peripheral tissues. This will be achieved using the nematode C. elegans, a tractable model system with established toolkits. We will use classical genetics, transgenic reporters, RNAseq, RNAi/CRISPR screening, and behavioural, metabolic and longevity assays to address 3 objectives: 1) Define the role of neuronal Nrf in nutrient regulated UPR activation; 2) Identify the neuronal circuit underlying the Nrf-UPR interaction; and 3) Determine the role that Nrf-UPR signalling plays in determining feeding behaviour, metabolic state and lifespan. This will identify new, fundamental mechanisms by which nutrient perception is connected to organism-wide effects, and relate this to diet-induced disease as well as age-related health. Evolutionary conservation of these pathways means that this will ultimately provide significant, translatable potential for the development of novel therapeutics.