the intertwined relationship between chemosensing and the microbiome

The detection of chemical cues from the outside world is fundamental to animal survival. In mammals, sensing of the external chemical environment governs diverse behaviours including selection of food, social interactions, and avoidance of predators. Decoding the complex chemical milieu of odorants in the environment into functionally relevant responses requires similarly complex detection systems and, in many animals, this is achieved through two principal chemosensory systems: the main olfactory epithelium (MOE) and the vomeronasal organ (VNO) in the nose. These evolutionary conserved olfactory organs contain millions of olfactory sensory neurons and vomeronasal sensory neurons that express arrays of chemosensory receptors each activated by a specific chemical signal. Sensory neurons of the MOE and VNO are the only neurons in mammals that are in direct contact with the external environment, which includes the specialised microbial communities of the nasal tissues. Given this direct contact, these sensory neurones are permanently exposed to oxidative stress, pathogens, or xenobiotics and, consequently, have a limited lifespan, compensated by continuous neurogenesis throughout adulthood. Increasingly, it is appreciated that development and maintenance of host tissues is influenced by the microbial communities that live in and on our skin, gut, mouth, and nose. This can be due to direct contact, as in the gut, or via the production of microbial metabolites that have an indirect influence on development of organs such as the brain. Recent evidence from humans and mouse suggests that the microbiome can also impact smell, and chemosensing. For example, a number of viral and bacterial infections can lead to loss of the sense of smell. Anosmia is an early sign of COVID-19, with ACE2, critical for SARS-CoV2 entry into cells, being expressed in the olfactory support populations. Disturbed nasal microbiome and metabolites have additionally been discovered in patients with olfactory dysfunction. The gut microbiome metabolites can also impact the olfactory system, such that mice with low gut microbial TMA production have altered olfactory perception. Importantly, germ-free (GF) mice have an impaired olfactory function when compared to conventionally reared specific-pathogen free (SPF) mice, taking longer to find hidden food pellets, and showing reduced expression of olfactory receptors. In this application we will investigate the role of the host and maternal microbiota in the development and maintenance of chemosensing using mouse models. Three aims will be addressed: Aim 1. To map the distribution of microbiota in the nose over time and correlate to gene expression patterns: mapping the host and microbiome together. Aim 2. To understand when and how the microbiota impact chemosensation. Aim 3: To assess whether chemosensation can be rescued or reduced by timed introduction/loss of microbiota and/or metabolites. The results will highlight the under-explored impact of the microbiome on chemosensation, teasing apart metabolite versus direct effects, and developmental changes versus maintenance. Of particular importance, the findings will open potential avenues to manipulate and rescue chemosensation through control of the microbial environment or provision of metabolites. This could lead to new therapeutics and recovery of chemosensation in affected patients. The research falls within the remit of Research committee C "Genes, development and STEM approaches" and the overall BBSRC strategy of supporting bioscience discovery and understanding the rules of life. Knowledge of microbiome interactions has the potential to catalyse the creation of novel therapeutics, but it is first important to understand the underlying mechanisms.