Based on a synthesis of recent findings, we argue that the gut and its microbiome are likely candidates to fulfill this role, and that this could account for interpersonal differences in susceptibility. We first review the physiological system of motion sickness and the pathways in which sensory or symptom-related information travels between body and brain. We then present recent insights on the role of gut microbiome in body-to-brain signaling in scenarios of conflicting motion. Finally, we argue how the gut or its microbiome could form the 'missing link' between our current understanding of motion sickness etiology and empirical observations.
A schematic version of the brain-body relation in perception of motion and motion sickness is presented in Fig. 1. Its components are explained in the following section.
The first component is the vestibular system (Fig. 1, I). Without a functioning vestibular system, motion sickness does not occur and sickness can occur in response to isolated vestibular stimulation. The vestibular system consists of two sub-systems: The otolith organs, which respond to translational (i.e., gravitational) acceleration, and the semicircular canals, which respond to angular accelerations. Sensory signals are communicated through neural pathways and synaptic connections through the vestibular nuclei in the brainstem, where they are processed.
The visual system (Fig. 1, II) is likely to be a modulating factor in motion sickness. Visual inputs could either exacerbate or alleviate motion sickness symptoms, depending on their alignment with vestibular signals. Visually impaired people (e.g., blind) can experience motion sickness. Light-sensitive cells in the retina translate optical motion stimuli into neural signals, which travel via the optic nerve to the visual cortex, where heading direction and velocity are inferred. These signals are also integrated with vestibular signals in the vestibular nuclei.
Somatosensory inputs, such as proprioceptive or haptic cues (Fig. 1, III) constitute a third component system involved in motion sickness. Its influence, reinforcing or contradicting vestibular signals, is thought to be a secondary contributor or anticipatory factor to the vestibular and visual systems. Proprioceptive cues are primarily signaled through the nerves in the spinal cord (Fig. 1, 1.2), up to the brainstem.
After integration of these inputs, the vestibular nuclei feed into five distinct networks in the brain, which are actively involved in mediation of motion sickness. Increased neuronal activation (indicated by Fos protein expression) in two of these networks, correlates with severity of motion sickness symptoms and drives autonomic and gastrointestinal physiological responses (e.g., nausea, pallor and vomiting). The three other networks mediate psychological aspects (e.g., apathy, anxiety, agitation, and abulia). For details on these processing networks, see Yates et al..
Many evident and less evident symptoms (Fig. 1, red) accompany motion sickness, further elaborated in Table 1. While, for example, the motor act of vomiting is generally well-understood, the manifestation of several other symptoms such as subjective nausea, is a complex and poorly understood interplay of nervous systems, brain regions and pathways. Symptom manifestation from mild to severe can be clustered in three categories: Cognitive response, autonomic response and visceral response. While cognitive and emotional factors such as anxiety or expectation influence the perception of motion sickness symptoms, these are beyond the scope of this work.
Classical models of motion sickness primarily emphasize brain-to-body signaling, focusing on symptom expression rather than input mechanisms. However, a clear cause-and-effect has yet to be established. Recent research highlights four bidirectional communication routes between the body and brain, that may contribute to conditions like hearing loss, tinnitus, and potentially also motion sickness. These (1) anatomical, (2) hormonal, (3) immune, and (4) extracellular pathways are visualized in Fig. 1. Supporting information is provided in Table 2. Our review of the evidence supports the hypothesis that peripheral (body-to-brain) signaling may play a role in the pathophysiology of motion sickness. In the following sections, we examine each pathway's evidence for afferent contributions.
The Vagus nerve (Fig. 1, 1.1) is one of the significant anatomical pathways linking the brain and the body up to parts of the ear and vestibular system. It predominantly regulates parasympathetic autonomic functions like heart rate, digestion, respiration, and inflammation by transmitting signals, for example as a result of conflicting motion.
Contrary to its reputation as a modulating pathway with mainly efferent (brain-to-body) fibers, signals can travel bidirectionally along the nerve. The roughly 80% afferent (sensory) and 20% efferent (motor) fibers coexist within the same anatomical structure. During the act of vomiting, both directions are simultaneously activated. Specifically, vestibular signals and gastrointestinal signals simultaneously converge on this shared pathway, causing reciprocal influences between sensations of motion sensed by the vestibular, and gastrointestinal states such as gastric dysrhytmias. Not only do both signals share the same communication pathway, the afferent Vagus signals from the gut also appear to be relayed to and processed by the same central brain region (the nucleus tractus solitarius (NTS)), which integrates vestibular information and coordinates nausea and vomiting, during, for example, conditions of sensory conflict. Both inputs are then integrated and influence the brain's nausea-processing, even suggestively altering susceptibility to (motion-induced) nausea and vomiting. Hereafter, the efferent Vagus (and spinal nerves) carry signals back to the body (e.g., stomach) for symptom manifestation.
Several experimental studies illustrate the critical role of Vagal afferents in motion sickness. In human studies, it is shown that targeted Vagal nerve stimulation reduces motion sickness symptoms, as the artificial stimulation is said to stabilize the gut barrier function. Essentially, stimulating some Vagal afferents appears to send a "calm down" signal, counteracting the aberrant firing that would induce nausea. In non-human studies, using musk shrews, it is shown that surgical disruption of Vagal signaling (vagotomy) reduced gastric rhythmic stability and abolished the normal gastric dysrhythmias induced by motion stimuli. Vagotomy did not entirely eliminate vomiting, suggesting that alternative independent pathways exist. Similarly, in a study in which rats were rotated to induce motion sickness, vagotomy prevented conditioned taste aversion, which is an index of motion sickness. Disruptions in Vagal sensory function can also exacerbate emotional responses, such as increased fear reactions in mice exposed to auditory (i.e., vestibular) stimuli. These findings combined suggest that sensory conflicts involving vestibular (i.e., brain) and gastrointestinal (i.e., body) systems might mutually modulate stress, nausea, and vomiting responses, positioning the nerve as an integrative mediator in motion sickness.
Additionally, Vagal afferents may convey gravitational sensory information from visceral organs such as the kidneys or large blood vessels to the brain. This hypothesis, by Mittelstaedt, arises from observations that gravity perception persists in individuals with impaired vestibular function; inertial reflexes still occurr after otolith membrane removal; and as a result of biological evidence for two distinct afferent channels signaling gravitational information. More generally, the bidirectional flow of signals between the brainstem and the body's organs over the Vagus, suggestively facilitates the integration of autonomic responses for equilibrium, one of the key principles during sensory conflict causing motion sickness. Studies addressing conditions of altered (micro)gravity, mention visceral dynamics to significantly change as a result of the absence of gravitational forces, thereby eliminating the typical gravitational feedback of fluids in the body normally conveyed via Vagal afferents.
Whereas efferent Vagal fibers promote parasympathetic regulation as a physiological response carrier to motion-induced conflicts, aforementioned studies also indicate the role of the Vagus afferent fibres as a potential gut-derived perception carrier. While speculative, visceral organs or nearby vessels may act as additional graviceptors to the vestibular system, responding to unfamiliar altered force distributions (e.g., fluid shifts) over Vagal afferents. Such input could contribute to sensory conflict and amplify sensations of motion or imbalance.
Other anatomical connections related to motion sickness and vomiting are wired through the spinal cord (Fig. 1, 1.2) as part of the Central Nervous System (CNS). Vomiting is a coordinated reflex that recruits parasympathetic efferents, primarily via the Vagus nerve, alongside somatic motor output through spinal nerves, such as the phrenic nerve (to the diaphragm) and intercostal nerves (to abdominal muscles). Other (autonomic) motion sickness symptoms such as pallor (skin blood vessel constriction), cold sweating (activation of sweat glands) and changes in heart rate or blood pressure, involve sympathetic efferents from the spinal cord.
Spinal afferent signals contribute to motion perception and motion sickness by relaying proprioceptive and somatosensory information about body position directly to the cerebellum and vestibular nuclei. Their integration with visual and vestibular inputs is essential for accurate self-motion perception and postural control, although their role in triggering motion sickness through conflicting motion, is likely secondary.
Studies in paraplegic patients suggest that somatic graviception relies on two anatomically distinct inputs entering the spinal cord, at thoracic and cervical levels. Removal of kidneys was found to eliminate the effect of the thoracic input, implicating the kidneys in sensing gravitational forces. For the cervical input, evidence indicates that spinal nerves convey gravitational information by detecting the inertia of internal body masses. While for example quadriplegics, paralyzed individuals whose proprioceptive cues cannot be communicated to the brain, do experience motion sickness, individuals with cervical or upper thoracic spinal cord injury often present symptoms of autonomic dysfunction similar to astronauts.
Clinical studies indicate that alterations in spinal afferent signaling can modify motion sickness susceptibility. For instance, patients who have impaired spinal-cerebellar connectivity, exhibit reduced susceptibility to motion sickness. Conversely, abnormal cervical proprioceptive inputs, for example, as a result of chronic neck tension, are associated with increased motion sickness symptoms, suggesting that distorted spinal afferents exacerbate sensory mismatch. Moreover, spinal nociceptive pathways of mice may indirectly modulate susceptibility by afferently influencing central processing of motion-related nausea.
Concluding, even though the spinal nerves contribute to accurate motion perception and equilibrium through afferents, and the response of symptoms such as vomiting occurs mainly through its efferents, it is questionable if this pathway is a primary determinant of individual susceptibility to motion sickness.
The hormonal pathway (Fig. 1, 2) involves endocrine signals transmitted through the bloodstream between the brain and the body.
Motion sickness activates neuroendocrine stress responses primarily via the hypothalamic-pituitary-adrenal (HPA) axis, resulting in the release of for example corticotropin from the hypothalamus, adrenocorticotropic hormones (ACTH) from the pituitary gland, and cortisol from the adrenal glands. Increased cortisol levels, reflecting stress-induced adrenal activation, have also been observed during motion sickness episodes. Further supporting this link, individuals with primary adrenal insufficiency (i.e., impaired cortisol production) show increased motion sickness susceptibility. Motion stimuli can additionally release arginine vasopressin (AVP), which is a reliable biomarker of nausea and correlates strongly with symptom severity. Experimental infusion of AVP independently elicits subjective nausea, but temporal synchronization of AVP (and ACTH) fluctuations with nausea symptoms is inconsistent, suggesting that their release represents the result of a general stress response rather than a direct nausea trigger. Motion stimuli have also been demonstrated to raise epinephrine and norepinephrine hormone levels, both of which contribute to some of the known symptoms and feed back to the brain's vestibular and autonomic centers. Neuroendocrine cells in the intestinal lining additionally respond to microbial cues by secreting hormones into circulation, thereby influencing brain functions through the gut-brain axis, further explained in the next section. Ghrelin, a stomach-derived hormone influencing appetite and motility, was shown to correlate with autonomic symptoms and rose during seasickness. As ghrelin can cross the blood-brain barrier or act on Vagal afferents, this finding suggests an afferent signaling to and influencing of the brain regions (also implicated in vomiting reflexes) in turn affecting symptom manifestation as a result of motion. Increased levels of estrogen and progesterone during menstruation and pregnancy are associated with greater motion sickness susceptibility, likely due to their effects on neural processing and modulation of vasopressin and cortisol release.
Neurotransmitter pathways involving acetylcholine (ACh), serotonin, histamine, and substance P/neurokinin, are furthermore implicated in the mediation of motion sickness symptoms. Cholinergic (ACh) overactivity, for example, contributes significantly to motion sickness symptoms, aligning with the therapeutic effectiveness of anticholinergic medications like scopolamine. Also aforementioned studies speculate on the involvement of a cholineric component in motion sickness modulation, which will be elaborated on in the next section. Medications effective against vestibular-induced nausea, such as scopolamine, differ in effectiveness compared to those targeting other nausea forms (e.g., serotonin antagonists), implying unique or distinct neurochemical pathways for vestibular-induced sickness. The existence of two effective drug categories, one blocking ACh and one activating central sympathetic areas, especially when combined, suggests competitive neural systems involved in motion sickness.
The role of the hormonal pathways in motion sickness can thus be represented by a systemic stress response, possibly interacting with neural circuits to modulate symptoms via the afferent (gut-to-brain) direction, particularly through the HPA axis and several peripheral hormones.
The immune pathway (Fig. 1, 3) between the body and the brain encompasses signals carried by immune cells and inflammatory mediators such as cytokines and histamine. This communication is used in for example sickness during infection, but the pathway appears to play a role in motion sickness as well.
The brain can influence peripheral immune function through neurohormonal pathways. Stress induced by motion may activate immune cells in the periphery or stimulate histamine release, potentially from mast cells or through modulation by the Vagus nerve. Sympathetic nervous system activation during motion exposure can further affect immune cell trafficking and inflammatory signaling. Histamine, typically associated with allergic responses, also functions as a neurotransmitter. It has been implicated in motion-induced vomiting, with studies demonstrating that increased histamine levels worsen motion sickness symptoms in both humans and animals. Pharmacological interventions blocking histamine receptors or enhancing histamine degradation, effectively reduce motion sickness severity. These findings suggest that mismatched vestibular input during motion may increase histaminergic activity, possibly via immune-mediated vestibular inflammation. As discussed in the previous section, antihistamines are among the most effective treatments for motion sickness.
Less direct but increasingly relevant evidence supports afferent immune signaling in motion sickness. Cytokines produced in for example the gastrointestinal tract, may influence the brain either through circulation or by activating Vagal afferents. One study found increased blood immunoglobulin levels after motion exposure, which correlated with symptom severity. Rodent studies show that vestibular stimulation activates brain microglia and induces c-Fos expression, a marker of neuronal activation associated with vomiting, hinting at a neuroinflammatory response.
Additional evidence comes from clinical overlap between motion sickness and inflammatory conditions. For example, individuals suffering from migraine, which involves sterile neuroinflammation or inner ear inflammation, may show greater susceptibility to motion sickness. While direct causal pathways remain under investigation, these associations suggest that immune-mediated inflammation may lower the threshold for vestibular-induced nausea.
Although specific gut-derived immune hormones directly linked to motion sickness have not yet been identified, gut-resident immune cells can release cytokines or migrate to the CNS, potentially affecting brain function. This supports the idea that the immune pathway is one of several physiological routes contributing to the onset and severity of motion sickness.
The extracellular pathway (Fig. 1, 4) refers to blood-borne chemical communication from the body to the brain, encompassing shifts in pH, electrolyte balance, metabolic byproducts, and microbiome-derived metabolites. These can cross the blood-brain barrier or interact with afferent nerves, influencing brain function. This section also reviews dietary influences, which may interact with the extracellular, immune, and hormonal systems.
Prolonged nausea and reduced intake during motion sickness can cause blood glucose fluctuations. Hyperglycemia has been observed in both humans and animals, suggesting that metabolic state influences visceral symptom severity, with stable glucose levels potentially alleviating symptoms. Altered blood glucose levels can affect the chemosensitivity of the area postrema and the excitability of vagal afferents, modulating nausea intensity. The area postrema, a brain region outside the blood-brain barrier, detects blood-borne signals and plays a role in nausea and vomiting responses. Microbial metabolites, produced by for example gut bacteria, such as short-chain fatty acids, lactate, and neurotransmitter analogues, can enter circulation and impact brain function. The produced metabolites influence the host through a combination of immune, hormonal, and metabolic interactions. Certain gut bacterial metabolites can alter vestibular function or the threshold for nausea by affecting the vagus nerve or blood-brain barrier permeability. For example, gut microbes and their metabolites have been shown to modulate blood-brain barrier integrity and brain function.
Another form of extracellular communication is initiated by dietary intakes. Various dietary factors such as caffeine, alcohol, nicotine, and certain food constituents (e.g., histamine-rich or greasy foods) have been shown to influence susceptibility to and feelings of motion sickness. For instance, individuals prone to motion sickness are advised to avoid heavy meals and ingestion of caffeine, alcohol, and foods high in histamine content before traveling. Also Vitamin C suppresses symptoms of seasickness and ginger root, through mitigating excessive vagal afferent firing associated with nausea, is a classical motion sickness remedy. For a comprehensive overview of nutritional influences to motion sickness, readers are referred to the review by Rahimzadeh et al.. These substances affect the body through blood-borne chemicals, metabolic shifts, and microbiome interactions,
A simulator sickness study found that participants experienced fewer sickness symptoms after alcohol intake. Alcohol, absorbed via the gut and crossing the blood-brain barrier, lowers vestibular fluid density, causing continuous activation of semicircular canal hair cells. This introduces vestibular noise or reduces signal reliability, potentially raising the threshold for detecting sensory mismatch and reduced symptom severity.
Graham et al. conclude that dietary shifts, influencing for example the microbial populations, can impact the central auditory (i.e., vestibular) system by affecting gene expressions that target afferent neurons. Their conclusion, as well as above-mentioned findings, suggest that extracellular signals, including those from dietary intake, may affect sickness by interacting with metabolic, microbial, and neural pathways. Together, this can hint at similar mechanisms for motion-related symptoms.