Introduction to the Special Issue “The Brain-Gut Axis”

Abstract

Abstract

This special Issue presents comprehensive and state-of-the-art advances in supporting the crucial role of the bidirectional interactions between the Brain-Gut Axis in health and diseases with an emphasis on the microbiome-gut-brain axis and its implications in variety of neurological disorders.

Graphic Abstract

There are intimate connections between the brain and the digestive system. Gut microbiota dysbiosis activates the intestinal immune system, enhances intestinal permeability and bacterial translocation, leading to neuroinflammation, epigenetic changes, cerebrovascular alterations, amyloid β formation and α-synuclein protein aggregates. These alterations may participate in the development of hypertension, Alzheimer, Parkinson, stroke, epilepsy and autism. Brainstem nuclei such as the nucleus tractus solitarius (NTS) and the dorsal motor nucleus of the vagus (DMV) regulate gastric motor function by way of bidirectional inputs through the vagus nerve.

The field of Brain-Gut interactions has grown exponentially during the past decades. The major importance of this field has been recognized initially in the control of gastrointestinal function. In this issue, Gillis et al. (2021) provide a comprehensive analysis of the brainstem circuitries regulating the gastric motor function with an emphasis on the participation of the nucleus tractus solitarius and the dorsal motor nucleus of the vagus. Their review details the involvement of GABAergic, cholinergic, noradrenergic, opioid and nitrergic neurons and their interactions in the vago-vagal reflex and delineates the cell specific efferent outputs from the dorsal motor nucleus to control tonic and phasic contractions in the proximal vs distal part of the stomach.

More recently, the field of brain-gut interactions has expanded and received growing interest with the recognition of complex cross-talks between gut microbiota alterations and brain disorders, including neurodegenerative and psychiatric illnesses, inflammatory and eating disorder. The mechanisms of these interactions include the enteric nervous system, autonomic nervous system, hypothalamic-pituitary-adrenocortical hormones, the immune and enteroendocrine systems along with metabolites and neuromodulatory molecules released by gut bacteria (Spielman et al. 2018). This is highlighted in five review articles assessing the gut microflora dysbiosis and the pathogenesis of epilepsy, Alzheimer disease (AD), Parkinson disease (PD), stroke, autism and hypertension.

Yue et al. (2021) provide a thorough documentation of the neurotransmitters and neural regulators synthetized by bacteria and neuroanatomical pathways involved in the gut-brain axis as a background to address growing experimental and clinical evidence pointing to the alterations of the microbiota-gut-brain axis at the onset and susceptibility to epilepsy. Therapeutic modalities based on gut microbiota interventions and potential beneficial effects on drug-resistant epilepsy is also addressed. Likewise, Janeiro et al. (2021) document experimental evidence of dysbiosis in AD models and patients contributing to neuroinflammation, cerebrovascular alterations and amyloid β formation and thereby influencing the pathophysiology and progression of AD. Similarly, regarding PD which is associated with α- synuclein protein aggregates, Dogra et al. (2021) document numerous reports on changes in gut microbiota composition in PD patients and the impact on the enteric nervous system and neuro inflammatory response. In particular, they outlined experimental evidence of the production of gut microbial toxins leading to α-synuclein in the enteric nervous system, propagating through the vagal nerve to the central nervous system in a prion-like manner and eventually leading to the early gastrointestinal (constipation) and neurological manifestations of PD.

Zhao et al. (2021) detailed current reports showing that microbiota composition is altered in stroke patients and experimental models as well as in the context of stroke risk factors namely hypertension, diabetes, atherosclerosis and obesity and dysbiosis. Whether gut microbiota intervention will uncover new therapeutic strategy is also addressed. Souders et al. (2021) summarized the significant relationships between gut dysbiosis, inflammatory processes and hypertension pointing to the role of tumor necrosis factor alpha, short chain fatty acid and oxidative stress based on the literature review and transcriptome analysis.

The gut-brain axis has received extensive attention also in relation with intestinal hypersensitivity linked with inflammatory bowel disease and stress which is appraised in two articles. Lyubashina et al. (2020) detailed clinical and experimental evidence supporting supraspinal mechanisms in visceral hypersensitivity in the context of gut inflammation or injury with the involvement of the brainstem, thalamus, hypothalamus, amygdala and hippocampus, with the alterations in glutamic acid, neuropeptide Y, corticotropin releasing factor, cannabinoid 1 receptor, microglia activation and increased inflammatory cytokines. Higgins et al. (2021) emphasize epigenomic regulatory mechanisms in chronic stress-related visceral hyperalgesia and outline the amygdala and peripheral pathways including, primary afferents, intestinal barrier dysfunction and microbiome alterations leading to epigenetic changes.

Lastly, Iruzubieta et al. (2020)’s original article on human colonic enteric nervous system revealed the presence of cilia and proliferative markers of immature neurons in the interstitial cells of cajal (ICC), and immature neurons markers in peripheral glial cells with primary cilia. They put forward the concept of adult neurogenesis in the human colonic enteric nervous system with the ICC serving as original neural stem cells giving rise to glial cells which will become immature and then mature neurons.

Author Contributions

YT and JMS equally contributed to the conception, design, drafting and revising the manuscript.

Funding

The funding was supported by Georgetown University.

Data Availability

All data are included in this published article.

Declarations

Conflict of interest

The authors declare that they have no conflicts of interest.