A review of the auditory-gut-brain axis

Abstract

Hearing loss places a substantial burden on medical resources across the world and impacts quality of life for those affected. Further, it can occur peripherally and/or centrally. With many possible causes of hearing loss, there is scope for investigating the underlying mechanisms involved. Various signaling pathways connecting gut microbes and the brain (the gut-brain axis) have been identified and well established in a variety of diseases and disorders. However, the role of these pathways in providing links to other parts of the body has not been explored in much depth. Therefore, the aim of this review is to explore potential underlying mechanisms that connect the auditory system to the gut-brain axis. Using select keywords in PubMed, and additional hand-searching in google scholar, relevant studies were identified. In this review we summarize the key players in the auditory-gut-brain axis under four subheadings: anatomical, extracellular, immune and dietary. Firstly, we identify important anatomical structures in the auditory-gut-brain axis, particularly highlighting a direct connection provided by the vagus nerve. Leading on from this we discuss several extracellular signaling pathways which might connect the ear, gut and brain. A link is established between inflammatory responses in the ear and gut microbiome-altering interventions, highlighting a contribution of the immune system. Finally, we discuss the contribution of diet to the auditory-gut-brain axis. Based on the reviewed literature, we propose numerous possible key players connecting the auditory system to the gut-brain axis. In the future, a more thorough investigation of these key players in animal models and human research may provide insight and assist in developing effective interventions for treating hearing loss.

Keywords: auditory system; gut-brain axis; hearing loss; microbiome; noise.

Figure 1

A visual summary of the main components of the peripheral and central auditory systems. Inspired by previous figures of auditory anatomy (Cope et al., 2015; Nipa et al., 2020). A component of the figure used the following online resource which has Creative Commons CC0: https://openclipart.org/detail/281964/ear-anatomy by GDJ; Creative Commons CC0.

Figure 2

Outline of potential anatomical mechanisms that could connect the auditory-gut-brain axis. These include the vagus nerve, the nasal/oral microbiome and the motion sickness pathway. Dotted lines indicate possible pathways of microbe communication. Components of this figure used the following online resources which all have Creative Commons CC0: https://openclipart.org/detail/35791/brain-01 by rejon; https://openclipart.org/detail/269019/ear by CCX; https://www.needpix.com/photo/169098/intestines-bowel-guts-intestinal-gastrointestinal-digestive-system-abdominal-biology-science; https://openclipart.org/detail/184612/nose by Frankes.

Figure 3

Extracellular signaling pathways connecting the ear, gut and brain. These pathways could also play an important role within the auditory-gut-brain axis. Red and green lines indicate feedback inhibition and the pathway through which hormone release is activated in the HPA axis, respectively. Dotted lines show pathways through which evidence suggests the ear, gut and brain communicate with each other. Components of this figure used the following online resources which all have Creative Commons CC0: https://openclipart.org/detail/38533/brain-side-cutaway by rejon; https://openclipart.org/detail/269019/ear by CCX; https://www.needpix.com/photo/169098/intestines-bowel-guts-intestinal-gastrointestinal-digestive-system-abdominal-biology-science.

Figure 4

Potential inflammatory and autoimmune mechanisms which could provide communication pathways within the auditory-gut-brain axis. Gut-to-auditory and auditory-to-gut signaling pathways involving inflammation are shown as blue and orange arrows respectively; inflammatory pathways of the auditory-brain axis are shown as green arrows; yellow arrows represent the contribution of autoimmunity in the auditory-gut-brain axis. Components of this figure used the following online resources which all have Creative Commons CC0: https://openclipart.org/detail/35791/brain-01 by rejon; https://openclipart.org/detail/269019/ear by CCX; https://www.needpix.com/photo/169098/intestines-bowel-guts-intestinal-gastrointestinal-digestive-system-abdominal-biology-science.

Figure 5

Dietary factors which may play a key role in the auditory-gut-brain axis. Components of this figure used the following online resources which all have Creative Commons CC0: https://openclipart.org/detail/35791/brain-01 by rejon; https://openclipart.org/detail/269019/ear by CCX; https://www.needpix.com/photo/169098/intestines-bowel-guts-intestinal-gastrointestinal-digestive-system-abdominal-biology-science.

Figure 6

Proposed auditory-gut-brain axis: Proposed schematic flow of the auditory-gut-brain axis and its implication in gut dysfunction and probiotic intervention: (1) Dysfunctional gut system (e.g., inflammatory bowel disease, IBD) decreases vagal tone (2), increased inflammatory responses and oxidative stress in the middle ear disrupt the central auditory system and could impact the ability to process intricate auditory signals (3), resulting in sensorimotor gating impairment (4). Consequently, dysbiosis-mediated reduction of vagal tone and degraded evoked responses to acoustic stimuli due to altered processing of mis-matches in the ear would cause decreased gut-brain synthesis of neurochemical (e.g., ACh, GABA) (5) and trophic support (6), leading to altered intracellular calcium homeostasis, electro-motility and neurochemical signals between the ear and the brain thereby causing acoustic injury and loss of hair follicles and neuron survival of the inner ear (7). In the process, loss of α-7nAChR subunit or decreased ligand binding (8) induces alterations to GABA and NMDA receptor subunits in the brain (9), accompanied by astrocytic and microglia reactivity (10), increased release of pro-inflammatory cytokines and permeability of blood brain barrier (11) as well as brain region-dependent dysfunction including degeneration of hippocampal pyramidal neurons and loss of glutamatergic and GABAergic receptors of spiral ganglion neurons in the cochlea (12). This can lead to anxiety, reduced prepulse inhibition of the acoustic startle reflex, and cognitive decline (13). However, the hypothetical intervention of hearing loss with probiotics (i) is proposed to normalize hearing (ii), gut-brain-mediated release of neurotransmitters (iii), microglial physiological functions (iv) as well as behavior (v). ACh, Acetylcholine; GABA, Gamma aminobutyric acid; BDNF, Brain derived neurotrophic factor; α-7nAChR, Alpha-7 nicotinic acetylcholine receptor; NMDA, N-methyl-D-aspartate receptor; TNF-α, Tumor necrosis factor-alpha; IL-1β, Interleukin-1beta; IL-4, Interleukin-4; IL-6, Interleukin-6; IL-11, Interleukin-11. Created with BioRender.com.

Figure 7

A summary of potential questions about the auditory-gut-brain axis that could be addressed in the future through (A) in vitro and in silico studies, (B) in vivo animal studies alone, (C) animal studies which can guide human studies and (D) human studies. We make a distinction in animal studies as some investigations with animals cannot be translated into human studies. Components of this figure used the following online resources which all have Creative Commons CC0: https://openclipart.org/detail/35791/brain-01 by rejon; https://openclipart.org/detail/269019/ear by CCX; https://www.needpix.com/photo/169098/intestines-bowel-guts-intestinal-gastrointestinal-digestive-system-abdominal-biology-science. https://openclipart.org/detail/17622/simple-cartoon-mouse-1 by lemmling; https://openclipart.org/detail/182185/man-shape by Onsemeliot.