The Vagus Nerve

The vagus nerve carries sensory and autonomic information from stomach, small intestine and proximal colon to the brainstem and back (Spencer et al. Nat Reviews Gastro & Hep, 2026).

Vagal afferent sensory information from the gut is carried via fibres with cell bodies within two nodose ganglia, one on each side of the neck, just outside the brainstem. These afferents carry information about digestive processes, like stretch and nutrient uptake.

Parasympathetic vagal efferent fibres which project to the gut have their cell bodies within the dorsal motor nucleus of the vagus (DMV) within the medulla. They modulate motility and other digestive functions and are increasingly being reported as having an important immunomodulatory role (Yang et al. Cell Mol Immunol, 2023). The DMV is also the site which Braak & colleagues posited as the ‘central nervous system entry point’ for mis-folded alpha synuclein potentially spreading from the gut at the start of Parkinson’s disease (Braak et al., Neuroscience Letters, 2006).

Classical anterograde labelling studies have consistently suggested that gut vagal innervation omits distal colon and rectum, although three retrograde labelling studies in mouse since 2020 have raised the possibility that this may not be the case. This anatomical point therefore remains an active area of investigation (Spencer et al. Nat Reviews Gastro & Hep, 2026).

Transcriptionally, nodose ganglia are well-characterised in mouse, but unfortunately, we still lack transcriptional data on human nodose ganglia. For mouse, the first single cell RNA-seq dataset appeared in 2019 (Kupari et al. Cell Reports, 2019). Since then, there have been data on developing nodose ganglia (Lowenstein et al. J of Neurosci, 2024), as well as a compilation atlas (Cheng et al. bioRxiv 2025). There is also a retrogradely traced and bar-coded sequencing dataset (Zhao et al. Nature 2022) which suggests that nodose ganglion neurons are transcriptionally distinct depending on their organ of origin (e.g. those from the stomach are transcriptionally different from duodenum and colon nodose neurons). Reports of spatial specialisation are also emerging in the context of nociceptive sensory neurons, which have their cell bodies in the dorsal root ganglia (Wolfson et al. Cell, 2023). However, in the case of nociceptive sensory neurons, specialisation appears to be between gut layers (e.g. myenteric vs. submucosal plexus) rather than along the length of the gut.

The transcriptional landscape of the dorsal motor nucleus of the vagus has also been primarily characterised in rodents (e.g. Hes et al. eLife, 2025, Ludwig et al. Nat Metab, 2021). Of course, human brain atlases do contain nuclei from the medulla, and the Allen Brain Atlas contains sequencing of whole tissue pieces dissected from the DMV region, with an enrichment list available via the Maayan lab Harmonize platform. These datasets can provide an initial idea of how well mouse expression data are likely to translate to human in this region.

Regarding model systems, primary nodose ganglion neuron cultures have been explanted from rodents since the 1980s (Baccaglini & Cooper, J of Physiol, 1982). Just like DRG sensory neurons, adult nodose sensory neurons grow happily in a dish and their function can be interrogated electrophysiologically (Mendelowitz et al., J of Neurophysiol, 1995, Fernández-Fernández et al., protocols.io, 2017). In vivo calcium imaging is also feasible (Huerta et al., Nat Comms, 2025).

To study human vagal neurons, methods are emerging to derive them from stem cells. There are protocols to generate nodose ganglion organoids (Ahn et al., Nat Methods, 2024) and vagal parasympathetic efferents (Thomas et al., bioRxiv, 2025), based on a cranial motor neuron protocol first published by Maury et al., Nat Biotech, 2015. They have yet to be widely adopted, and as with any model system, some features of native cells will be represented, while others will not be.

Text by Franziska Denk, King’s College London