This is a 3D reconstruction of a neuropod cell utilizing a serial block face scanning electron microscopy (SBEM) data set in Imaris software.^[1] On the left side of the cell has microvilli extending into the gut lumen and the right side has a neuropod extending into the basal lamina propria.^[1]

A neuropod cell is a specialized enteroendocrine cell (i.e., sensory epithelial cell) within the gut that is capable of synapsing with afferent nerves.^[2][3] Previously, transmission of sensory signals from enteroendocrine cells were thought to only occur in a paracrine fashion, in which secreted peptide hormones diffused through the lamina propria and contacted either intrinsic or extrinsic neurons, entered the circulation, and/or acted on specific target tissues.^[4][5] However, neuropod cells, discovered by Dr. Diego V. Bohórquez in 2015 and later coined in 2018, were observed forming synaptic connections with nerves in the mucosa of the small and large intestine of rodents.^[3][6] These synapses were revealed to involve neurons originating from the dorsal root ganglia and the vagal nodose ganglia of the spinal cord, which suggested that sensory information from the gut lumen could be conveyed to the brain within milliseconds of activation.^[6] Also, it was found that these neuropod cells contained both pre- and postsynaptic proteins, suggesting that information could not only be conveyed to, but also received by neurons.^[3][6][7] This newly found transmission mechanism of luminal senses from the gut to the brain may spark a new area of exploration within the gut-brain axis and sensory neurobiology.

Nutrient sensing and behavior

Although it has been understood for some time that there is a relationship between consumed food, cravings, and bodily health, it is only of recent that the mechanisms underlying gut sensation of food have been discovered. Integral to this sensation of nutrients and the regulation of postprandial physiology are enteroendocrine cells.^[8] These cells are not only able to assess nutrient content of ingested food by sensing glucose, fatty acids, amino acids, monoacylglycerols, and oligopeptides, but they may also drive appetitive decisions.^[8][9] Although sugar and artificial sweeteners generate a sweet taste, natural sugar is preferred and can even be distinguished from artificial sweeteners by mice lacking taste receptors.^[10][11][12] This suggests that the gut is important for not only discerning between the two sugars, but also guiding the animal's preference for the natural sugar over the artificial sweetener. Upon infusion of natural sugar or artificial sweetener into the small intestine, duodenal neuropod cells transduced luminal information onto distinct vagal nodose neuron populations either through glutamatergic neurotransmission (sucrose) or purinergic neurotransmission (sucralose).^[9] Moreover, the animal's preference for sucrose over sucralose was abolished (90.8% to 58.9% sucrose preference) after utilizing a flexible fiberoptic cable (optogenetics) to selectively silence duodenal neuropod cells.^[9] These data suggest that duodenal neuropod cells are not only capable of distinguishing natural sugar from artificial sweetener by utilizing different neurotransmitters and through activation of different neuronal populations, but they also capable of driving appetitive preferences for the natural sugar.

Microbial interactions

Gut microbiota have been known to prime the immune system and to aid in the preservation of a healthy central nervous system, which has been extensively documented in germ-free and gnotobiotic mice that present with overzealous immune systems and an abundance of neurological deficits.^[13][14] Interestingly, within these germ-free mice the general abundance of chromogranin A-positive enteroendocrine cells decreased in the ileum and increased in the colon, suggesting a potential connection between the microbiota and the normal distribution of gut sensory cells.^[15] Furthermore, human and murine enteroendocrine cells possess receptors for microbe-associated molecular patterns (MAMPS) like bacterial lipopolysaccharide (LPS) and receptors for a range of bacterial metabolites like short chain fatty acids (SCFAs).^[16][17] The presence of these receptors suggest that the synaptically connected neuropod cells may be responsible for detecting microbial signals and metabolites within the gut lumen and then conveying said information to the brain. Finally, specific pathogenic bacteria (e.g., Chlamydia trachomatis) have been implicated in the pathogenesis of irritable bowel syndrome by directly infecting enteroendocrine cells and upregulating distinct neurotransmitter transporters like glutamate.^[18][19] Also, helminth infections with Trichinella spiralis can lead to a significant reduction in food consumption, which is dependent on enteroendocrine cell presence and abundance.^[20] These findings suggest that not only can pathogenic bacteria gain access to neuropod cells and possibly the associated central nervous system, but they may also be able to direct behavior of the host.

References