Modulation of the microbiota is an evolving strategy as a part of a comprehensive approach to lifestyle wellness (1). Each individual has their own specific gut microbiota and a variety of exogenous factors can affect the composition of host gut microbiota, including diet, infection, lifestyle, use of antibiotics and hygiene preferences. Diet changes, such as high energy-dense diets and high-sugar diets, induce gut microbial dysbiosis, increase gut inflammation and microglia activation, and disrupt vagal gut-brain communication (2,3).

Treatment Options

Research has indicated that diet can greatly influence the gut microbiota composition, which in turn affects the host’s health profoundly. Dietary changes can account for up to 57% of gut microbiota changes, whereas host genes account for no more than 12% (4).

Both short and long-term diets have a profound influence on the microbiome profile. The consumption of complex carbohydrates and plant-based foods positively influences microbial composition, synthesis of anti-inflammatory metabolites, and host health (5).

The microbiota utilises dietary vitamins and minerals, and accordingly, these micronutrients represent potential mechanisms to modify the gut microbiota (6,7,8).

There is limited evidence available for specific treatment options in gut-brain axis dysfunction, however, the underlying mechanism is gut dysbiosis, therefore ensuring a healthy and diverse microbiome is the goal of any intervention.

Table 1. Factors influencing the microbiome and gut-brain axis

Mechanisms of Action

The microbiome affects the brain via various mechanisms (19,22,23):

• Blood-brain barrier development and permeability is associated with gut microbiota and microbial metabolites. Permeability decreases upon colonization of gut microbiota or upon administration of the short-chain fatty acids (SCFAs) butyrate, which is normally produced as a result of bacterial fermentation in the gut
• Maturation and function of microglial cells, known as the resident macrophages of the CNS, is constantly controlled by gut microbiota. Alterations of gut microbiota indirectly affect microglia function by changing cell proportions and creating an immature phenotype, possibly by altering the circulating levels of pro-inflammatory and anti-inflammatory cytokines
• Development of the enteric nervous system, which controls the entire GI tract
• Contributions to adult neurogenesis in the hippocampus
• LPS on the surface of gram-negative bacteria can affect the brain by mediating immune cells and vagus nerves
• Probiotics can reduce inflammation by enhancing the integrity of the gut barrier, thereby preventing further bacterial translocation
• At the physiological level, probiotic consumption often results in cortisol reduction, increase in faecal serotonin concentrations or reduction in natural killer cells
• The microbiome produces a substantial proportion of potentially neuroactive compounds, neurotransmitters and metabolites, such as GABA, serotonin, dopamine and L-dopa, which exert well-documented psychological effects. The microbiome also produces SCFAs which enter the systemic circulation and have been shown to exert central effects indirectly or directly on the ENS and CNS. SCFAs are not only released into the serum but have been shown in experimental studies to cross the blood-brain barrier, reinforcing the integrity of the BBB and impacting the physiology of cells in the CNS, such as the maturation of microglia

Stress

Activation of the HPA axis by stress leads to cortisol secretion which can affect gut integrity, motility and mucus secretion, leading to a change in the composition of the gut microbiota metabolism (24).

Immunological and cytokine activity

Bacteria can both enhance or inhibit the secretion of pro- and anti-inflammatory cytokines. Beneficial bacteria can stimulate the release of anti-inflammatory cytokines, while others trigger pro-inflammatory cytokine expression. Probiotics and prebiotics can also physically bind to pattern-recognition receptors, inhibiting the release of pro-inflammatory cytokines and enhancing the expression of anti-inflammatory cytokines (22).

Vagus nerve

The vagus nerve enables bidirectional communication between the gut and the brain. It is primarily composed of sensory fibres and serves as the primary afferent pathway for transferring microbial and immune information from the gut to the CNS (23). Traumatic brain injury leads to dysautonomia via the vagal nuclei complex and vagus nerve. These changes can lead to diverse altered gastrointestinal function including mucosal ischemia, mucosal atrophy and activation of intestinal inflammatory cascades. These reactions can occur 3 hours following brain injury and can last for more than 7 days (25).

Tryptophan-kynurenine metabolism

The balance between the processing of tryptophan into its metabolites kynurenine and serotonin is considered to play an important role in bacteria-brain signalling. The bulk of systemic tryptophan in the body is metabolized into kynurenine and elevated kynurenine generation is associated with depression and reduced neuroprotection. Gut bacteria intervene in the metabolism of tryptophan into kynurenine, and can both increase or decrease kynurenine biosynthesis, depending on which bacteria are involved. Probiotics have been shown to reduce kynurenine levels. The mechanistic component underlying bacterial effects on kynurenine levels may occur via inhibition of the enzymes that contribute to its biosynthesis (22).

Figure 1. Interaction pathways of the microbiota-gut-brain axis (26) CC BY 4.0

Takeaway on the Gut-Brain Axis

• The gut-brain axis is an increasing focus of attention, given the recent understanding regarding the importance of the gut microbiota in influencing brain and behaviour
• Recent studies have reported that diverse forms of neuropsychiatric disorders (such as autism, depression, anxiety, and schizophrenia) are associated with variations in the microbiome, by microbial substrates, and by exogenous prebiotics, antibiotics, and probiotics (24). In most instances, it has yet to be determined if the aberrant microbiota contributes to the disease or is a result of the disease (8)
• Recent research has shown that gut microbiota can regulate the development and function of microglia, mediate neurophysiological processes including neurotransmission, CNS immune activation and blood-brain barrier integrity (23)
• Diet is a primary contributing factor in shaping the composition of the gut microbiota. Other influencing factors include genetics, antibiotic use and disease, all of which need to be taken into consideration (8)
• Research on the microbiota-gut-brain axis is still preliminary. Much of the knowledge on the relationship comes from pre-clinical studies and uncertainty remains regarding the generalizability of controlled animal studies to the more multifaceted pattern of human pathophysiology, especially with regard to the therapeutic potential for neuropsychiatric health (5). Caution should be taken in using the probiotics applied in animal models into human clinics (27)