Microbial translocation reflects a gut commensal community that is imbalanced or dysbiotic and that fosters a cycle of inflammation, barrier compromise, and bowel dysfunction. A healthy gut is required for digestion, nutrient absorption, metabolism, maintenance of gut-blood barrier integrity, and development of host immunity (Ismail and Hooper 2005; Round et al. 2010; Smith and Garrett 2011; Sommer and Backhed 2013). Gut function is coordinated by a diverse community of bacteria, viruses, fungi, and archaea, which are at equilibrium with host cell activities (Dinan and Cryan 2015; Sandhya et al. 2016). This equilibrium can be disrupted by stress, diet, antibiotics, toxins, infectious agents, and products generated by host genetics (Sandhya et al. 2016). Thus, for schizophrenia, dysbiosis of the gut microbiome is important to document because it provides a mechanism of GI-localized inflammation that has systemic consequences that are relevant to neuroinflammation and the brain. Importantly, translocated GI products act as triggers of the body’s systemic immune machinery, such as the complement pathway, put in motion to clear antigens perceived as foreign from the bloodstream (Brenchley et al. 2006; Lambert 2009; Sandler and Douek 2012). Complement also has important functions in the brain which include the removal of inappropriate synapses, and the genetic and functional associations of this pathway with schizophrenia have been reported and reviewed elsewhere (Nimgaonkar et al. 2017; Presumey et al. 2017; Sekar et al. 2016). Physical access to the brain is a converging and critical consideration in this context, both with respect to translocated gut products and immune molecules. Endothelial barrier defects at both the blood-gut and blood-brain barriers present pathologies that are consistent with a compromised gut-brain pathway operative in schizophrenia (Kannan et al. 2017). Findings from studies employing various approaches suggest an altered function of endothelial cells and BBB permeability associated with schizophrenia (Greene et al. 2017; Khandaker and Dantzer 2016; Severance et al. 2015a). For example, markers of endothelial cell activation including the selectin family of adhesion molecules have been found to be elevated in schizophrenia (Iwata et al. 2007; Khandaker and Dantzer 2016). This endothelial cell activation in the BBB has been shown to follow systemic inflammation and is associated with the translocation of inflammatory cells into the brain (D’Mello and Swain 2014; Khandaker and Dantzer 2016). Accompanying this activation are increased monocyte levels and monocyte infiltration of the BBB which are consistent with the elevations of sCD14 reported in the previous section.

The ability to interrogate rodent models in a germ-free setting has provided much insight regarding the possible mechanisms by which gut microbes are actively engaged in biological pathways that regulate the gut-brain axis. Importantly, these studies allow associations to be made and solidified without a plethora of confounding variables that often accompany and cloud results from clinical studies. Summarily, in the absence of a gut microbiome, the brain fails to develop normally (Sampson and Mazmanian 2015). Altered brain biochemistry, cognition, and behaviors are repeatedly demonstrated following manipulations of gut microbiota in germ-free and/or pathogen-specific animals (Collins et al. 2012; Diaz Heijtz et al. 2011; Erny et al. 2015; Foster and McVey Neufeld 2013; Hsiao et al. 2013; Luczynski et al. 2016; Stilling et al. 2014). In the germ-free setting, such abnormalities included alterations of myelination, microglial regulation, neurogenesis, and neurotransmitter abundances such as serotonin and precursor tryptophan and trophic factors. These deficits were recovered with further manipulations or corrections of bacterial compositions, vagotomy, and administration of probiotics and/or antibiotics. As relevant to schizophrenia, a revealing set of experiments were those that showed how directly the gut microbiota can impact BBB permeability (Braniste et al. 2014). The absence of a microbiome increased BBB permeability, and this defect was restored following transplantation of germ-free animals with a normal microbiota. Thus, garnered from these studies is evidence of some of the most promising pathways in support of a gut-brain axis including the following: (1) the parasympathetic nervous system and related enteric innervation including the vagus nerve, (2) the neuroendocrine system including stress hormones and the HPA axis, (3) metabolic pathways including microbially generated short-chain fatty acids that bind to G protein-coupled receptors and that are epigenetic modulators, (4) the circulatory system which enables the delivery of gut-generated neuroactive metabolites and neurotransmitters to the vicinity of the brain, and (5) the immune system which is extensively referenced throughout this chapter (Alam et al. 2017; Berger et al. 2009; Dinan et al. 2018; El Aidy et al. 2014).

Of interest are metagenomic and 16S rRNA gene sequencing studies of the oropharyngeal and fecal microbiomes in people with schizophrenia and psychoses compared to controls (Castro-Nallar et al. 2015; Schwarz et al. 2018; Shen et al. 2018; Yolken et al. 2015). In the oropharyngeal microbiome, the genera lactobacilli and bifidobacteria were more abundant in schizophrenia compared to controls, and intriguingly, these are the genera that help to modulate inflammation (Castro-Nallar et al. 2015). Similarly, the oropharyngeal microbiome in schizophrenia contained altered levels of the phage, Lactobacillus phiadh, which infects Lactobacillus gasseri, a bacteria that functions in part to maintain epithelial cell integrity and to modulate the immune system (Yolken et al. 2015). Differences in fecal lactobacilli were also observed in patients with first-episode psychosis compared to controls, and numbers of these taxa were particularly elevated in those who were most treatment resistant (Schwarz et al. 2018). In another study of the fecal microbiome, case-control differences in numerous taxa were observed including an elevation of the phylum, Proteobacteria, and those taxa that functioned in metabolic pathways (Shen et al. 2018).

Clinical trials of probiotics in schizophrenia can be similarly informative regarding potentially correcting a microbe- or gut-based pathology. In a randomized, placebo-controlled trial of adjunctive probiotics in schizophrenia, improved GI function was reported, but there was no change in the severity of psychiatric symptoms associated with probiotic treatment (Dickerson et al. 2014). Serologically, there were significant alterations in an array of immune proteins that pathway analyses indicated were suggestive of improved GI epithelial and immune pathologies associated with probiotic treatment (Tomasik et al. 2015). Of interest also is how other non-bacterial components of the microbiome might influence these clinical trial findings. For example, in healthy people, commensal yeast species cohabitate with resident bacteria in a homeostatic balance. If this balance is shifted perhaps by diet or antibiotics, bacterial dysbioses, species depletion, and yeast overgrowth can result (Kim and Sudbery 2011). In the probiotic trial cited above, we found evidence for improvement in psychiatric symptoms associated with probiotics, but only in those who were not positive for these invasive yeast infections (Severance et al. 2017). C. albicans was, in fact, particularly overrepresented in individuals with schizophrenia compared to controls, and these yeast-positive individuals had correspondingly more cognitive impairments and severe psychiatric symptoms (Severance et al. 2016a, 2017).