The gut microbiota modulates gastrointestinal homeostasis in experimental animals through direct and indirect chemical signaling with the nervous system [25,26]. An example of direct signaling is the regulated expression of brain-derived neurotrophic factor (BDNF), a neuronal factor associated with depression, by short-chain fatty acids (SCFAs) produced in the gut [27]. SCFAs are lipids produced by the gut microbiome that can influence the central nervous system (CNS) through the regulation of the immune system, neuroplasticity, expression of various genes, and epigenetic changes [27]. The gut microbiome can also influence the host’s appetite, feeding behaviors, and digestion through indirect chemical signaling. For example, within gut epithelium, the microbiota can regulate the production of endocrine signals, such as the hormone glucagon-like peptide 1 (GLP-1), from the enteroendocrine cells [28]. As such, germ-free (GF) mice that lack an endogenous microbiota have lower food consumption as compared to conventional mice with intact microbiota [29]. In addition, the gut microbiota has been related to the typical ASD behaviors in mice. For example, GF mice exhibit anti-sociality and prefer to spend time exploring an empty compartment as compared to where another mouse companion is present [30]. Diets play a part in brain health as well. Foods high in sodium trigger a proinflammatory response in the intestine, e.g., increased secretion by T helper 17 (TH17) cells of the proinflammatory cytokine interleukin-17 (IL-17) into the bloodstream. IL-17, in turn, inhibits the production of nitric oxide by neuroparenchymal vascular endothelial cells, impairing cerebral perfusion and thus cognition [31].

The gut microbiota also modulates the production and synthesis of neurotransmitters in the hosts. For example, in silico and in vitro studies [32,33] have shown that microorganisms such as Bacteriodes, Bifidobacterium, Parabacteriodes, and Escherichia spp. can produce γ-aminobutyric acid (GABA), a neurotransmitter that regulates neuronal cell hyperactivity associated with stress, anxiety, and fear [34]. In vivo studies in rats using Bifidobacterium strains from humans [32] and cell culture studies [35] have shown an upregulated expression of GABA. However, it has not been demonstrated that the GABA produced by Bifidobacterium is resorbed from the gut and circulates in the body to affect the brain. In male GF mice, gut bacteria, through interacting with the enteroendocrine cells, play a vital role in the production of serotonin (5-hydroxytryptamine), a neurotransmitter that regulates body functions such as mood, cognition, learning, reward, memory, digestion, wound healing, and sexual desire [11]. The production of serotonin can be affected by microbial metabolites such as SCFAs, tryptophan, indole, and secondary bile acids [36,37]. It is also important to note that most neurotransmitters produced by the microbiota, such as serotonin, aminobutyric acid, and dopamine, cannot reach the brain directly due to the blood–brain barrier. However, in rats [38], neurotransmitters can cross the blood–brain barrier indirectly through neurotransmitter precursors, such as tryptophan (serotonin precursor), before being converted into active neurotransmitters [39,40,41]. The mechanisms of neurotransmitters produced from the gut microbiota to influence the functions of other body parts have not been well-established, presenting an avenue for future research focusing on the interactions between the gut and brain. It was hypothesized that, in the gut, tryptophan undergoes three major metabolic pathways, e.g., the 5-HT, kynurenine, and AhR ligand pathways, which may be directly or indirectly controlled by saprophytic flora [42].

The major neuronal pathway facilitating gut–brain interactions is the vagus nerve that extends from the brainstem to innervate both the gut and enteric nervous system [43]. Influenced by the gut microbiota, the enteroendocrine cells produce chemical stimuli, such as neurotransmitters, hormones, and metabolites, to trigger the production of chemoreceptors that activate mechanoreceptors to relay signals from the vagus nerve to the CNS [44]. Neurotransmitters, integral to the gut–brain interactions, can be produced by the gut microbiota through the metabolism of indigestible fibers such as cellulose, lignin, beta-glucans, and pectin. Specifically, dopamine and norepinephrine are produced by members of the Bacillus family; GABA by the Bifidobacteria family; GABA and acetylcholine by the Lactobacilli family; norepinephrine and serotonin by the Escherichia family; and serotonin by the Enterococcus and Streptococcus families [13]. In addition, Bacteroides spp. regulate the development of enteric cells in mice, which play important roles in the maintenance of neuronal networks and regulation of gut homeostasis [9,45]. Healthy development and activation of microglia, the innate immune cells of the brain, are likewise modulated by microbiota. In separate studies, GF mice treated with SCFAs and Bifidobacterium spp. exhibited restoration of microglial morphology and functions [12,14].

Gut dysbiosis can contribute to metabolic disorders in the liver of both humans and experimental animals, such as alcoholic and non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis, primary sclerosing cholangitis, cholestatic liver disease, hepatocellular carcinoma, and cirrhosis [46,47,48,49,50,51,52,53]. In the bidirectional relationship, communication with each other is connected through the portal vein, biliary tract, and systemic circulation in humans. From the intestine, microbial metabolites are transported to the liver through the portal vein. Meanwhile, to maintain gut eubiosis and control bacterial overgrowth, bile salts and antimicrobial molecules are transported from the liver to the intestinal lumen through the biliary tract [54,55,56].

In mice, an impaired synergistic relationship within the gut microbiota can lead to gut dysbiosis and reduce the activation of important receptors such as membrane G protein-coupled receptor TGR5 and nuclear bile acid receptor FXR. Such impairment can lead to a decrease in secondary bile acids synthesis, followed by the retention of bile salt, bacterial overgrowth, and liver disease that may potentially progress to liver failure [57,58]. One example would be hepatic encephalopathy, a typical disease model of a dysregulated gut–liver–brain axis. Symptoms from hepatic encephalopathy can be alleviated by improving the axis via treatment with Lactobacillus in mice [59] and fecal translocation in mice with steatohepatitis [60,61]. It was recently postulated that in mice and humans, a sustained damage to the inner gut vascular barrier in the gastrointestinal tract is a key player along the gut–liver–brain axis, as it has the ability to influence beyond the liver to distal organs including the brain [62].

Hepatic dysfunction can lead to CNS dysfunction through alterations in CNS blood flow, the presence of inflammatory metabolites, excess bile acids, and accumulation of neurotoxic compounds such as ammonia in mice [63,64,65]. In patients with chronic liver conditions, neurological symptoms such as fatigue, anxiety, social withdrawal, depression, and sleep disturbance have been observed [66]. It has been recently shown that potential mechanistic avenues within the gut–liver–brain axis may be altered in the setting of chronic liver diseases, which subsequently contribute to the neurological disorders mentioned above [67,68,69,70,71,72].

Cytokine-mediated signaling is thought to affect the neurotransmission within the basal ganglia and cause CNS dysfunction. In the setting of intrahepatic inflammation, liver immune cells produce proinflammatory cytokines such as IL-6, IL-1β, and tumor necrosis factor (TNF)-α. These inflammatory cytokines can induce neurological changes by affecting the peripheral neural signaling; they can also enter the CNS through systemic circulation and the disrupted blood–brain barrier to affect the neurons within [73].

The vagus nerve, as mentioned in the section on gut–brain interactions, is the major neuronal pathway for the communication between the gastrointestinal tract and CNS. The vagus nerve is bilateral, with the left and right nerves in part having distinct functions. In several studies, the left vagus nerve has been shown to carry the signals from the liver to the brain [74]. Through this pathway, recent work has portrayed a new neuroimmune pathway in which the liver has demonstrated gut-dependent sensing and signaling to promote an anti-inflammatory state through the brain. Upon the sensing of luminal contents in the gastrointestinal tract, the liver afferent vagal fibers transmit sensory inputs to the nucleus tractus solitarius of the brainstem to induce and maintain gut T-regulatory cells through enteric neurons and parasympathetic nerve signaling [75].