Numerous risk factors for schizophrenia can be reconciled through a common enteric source. These risk factors include systemic and localized inflammation, compromised endothelial barriers, IgG sensitivities to food antigens, exposure to viral and parasitic pathogens, and autoimmunity. The gut in a homeostatic state equates with a functional digestive system, cellular barrier stability and properly regulated recognition of self and non-self antigens, as managed by a complex community of resident microbes. Our studies address how environmental and genetic factors relate to GI dysfunction, impact the resident gut microbiota and result in dysregulation of processes in the host central nervous system. We hypothesize that disturbance to GI equilibria activates peripheral immune factors including complement pathway components that function in synaptic pruning. We evaluate these issues with peripheral immune biomarkers and deep sequencing in a number of case-control psychiatric cohorts that include antipsychotic-naïve individuals. Although certain medications and lifestyle factors might affect GI functioning, our findings support a GI pathology inherent to the schizophrenia disease process and a role for the gut-brain axis in complex brain disorders. The identification of those individuals affected by GI-related risk factors will enable appropriate and individualized treatments to be designed and tested for efficacy of both gut and brain-related symptoms.