FIGURE 3.

Endocrine, immune, metabolic and vagal direct and indirect pathways for bidirectional communication of the gut-brain axis. Changes in the bacterial abundances and development of gut dysfunctional state (dysbiosis) impacts host and Central Nervous System (CNS) functions, often associated to disease. Consequently, there is a shift in microbial-derived products. Short-chain fatty acids (SCFAs), derived from the microbial digestion of dietary fiber, play a crucial role in the regulation of microglia and brain immune responses. The production of SCFAs, neuroprotective biochemicals essential to host metabolism, is compromised under a state of intestinal dysbiosis, which impacts the CNS function. Increased levels of Trimethylamine N-oxide (TMAO), a gut microbial-mediated metabolite, has been linked to aging and cognitive impairment. The microbial metabolism of tryptophan, leading to the production of, for instance, the neurotransmitter serotonin, is also compromised under dysbiotic states. On the other hand, stress at the CNS level can impact intestinal function and promote gut microbial perturbations. Thus, the CNS is capable of recruiting the same mechanisms to modulate the gut microbial composition, such as by the stimulus of cortisol secretion. Cortisol can have an influence on immune cells recruitment and cytokines secretion, as well as on the epithelial barrier permeability. Compromised integrity of the gut epithelial barrier allows the translocation of overgrowth pathobionts and neurotoxic microbial fragments, such as lipopolysaccharides (LPS), which can later reach and cross a compromised blood-brain barrier. The microbes and their secreted metabolites shape the host-immune system and vice-versa. A dysbiotic intestinal microbiota can hijack the host-immune system and modulate the inflammasome signaling. Note: figure was adopted from references (Grenham et al., 2011; Cryan and Dinan, 2012).