**5. Overview of gastrointestinal innervation and immunity**

The gastrointestinal (GI) tract has several vital functions, acting as not only a digestive organ but also as an important endocrine and immune organ. The GI tract handles the breakdown and acquisition of nutrients as well as influences peripheral nutrient handling. The GI tract is home to vital neurological networks, including both the autonomic nervous system (with sympathetic and parasympathetic fibers that communicate with the spinal cord and central nervous system (CNS) through the dorsal root ganglia) and the unique enteric nervous system (ENS) [37]. The ENS, unlike the autonomic nervous system, is autonomous from the CNS and is comprised of over 108 sensory, motor, and interneurons that release acetylcholine and neuropeptides [38]. In response to ingested nutrients and bulk, GRP triggers enteroendocrine cell hormone release that regulate intestinal motility, digestive enzyme release from the pancreas, bile acid and bicarbonate release, stimulation of splanchnic blood flow, and electrolyte balances, each of which shape the stability and composition of the gut microbial ecology [39].

Approximately, 70 and 80% of all active immune cells in the body are innervated by ENS fibers connected to the epithelial and immune cells that make up the gut's huge surface area of over 400 m<sup>2</sup> [40]. This immune function is the vital barrier between the host and its environment. The gut and other mucosal surfaces are tasked with defending against dietary, microbial, and environmental products through innate barriers, adaptive immunity, and stable microbial colonizers. Barriers include ranging from simple cellular layers, complex secreted products such as antimicrobial peptides and glycoproteins, specific and non-specific immunoglobulins (IgA), and maintenance of the gut microbiome [38]. During periods of both feeding and fasting, the defenses provided by ENS-innervated immune cells facilitate digestion, maintenance of immune response, and the prevention of pathogens from entering systemic circulation.
