Our results document that antibodies directed against the opportunistic fungal pathogen, C. albicans, were elevated in distinct subsets of individuals with psychiatric disorders. For some of these individuals, females in particular, C. albicans antibodies were associated with reduced cognitive functioning. Elevated C. albicans could be attributable to extraneous lifestyle or somatic variables for some subgroups, but for others, such as males with schizophrenia, no confounders were evident suggesting the possibility that exposure to this pathogen could be a risk factor for this psychiatric disorder. Sex-specific patterns reflected expectations that yeast overgrowth is found in the female reproductive tract, during immunosuppression and in association with homelessness. C. albicans antibody patterns in both sexes preliminarily implicated the GI tract as a source of microbial dysbioses in both schizophrenia and bipolar disorder. Follow-up studies are required to determine how unregulated C. albicans growth might impact the gut–brain axis in psychiatric disorders.

Many of our observations mirrored epidemiological and sex-specific expectations of heightened exposure to C. albicans in women, in those who were immunocompromised and in people who had a history of homelessness. In this regard, these antibody associations with lifestyle and somatic conditions represented conceptual controls. The portion of our analyses with males showed the most direct and strongest linkage of C. albicans antibodies with schizophrenia, and this association was independent of potential confounders such as age, race, antipsychotic medication, homelessness, socioeconomic status, and a history of cancer. The similarly significant antibody elevation in males with bipolar disorder was found to be purely a function of increased exposures to this pathogen due to a past period of homelessness. In women, we were not able to detect significant differences in strict comparisons of antibody levels among the diagnostic groups. This finding seems logical given that the female reproductive anatomy is prone to yeast infections. Thus, women are likely exposed more often to C. albicans overgrowth regardless of psychiatric status and so any disease-related association might be obscured. Intriguingly, however, it was women who exhibited C. albicans associations with decreased cognition, suggesting that elimination of the overgrowth might help to improve cognition-associated symptoms. We can speculate that this significant association of yeast antibodies with cognition, which is not observed in control women in spite of an equivalent rate of exposure, is consistent with a gene by environmental etiology of psychiatric disorders.16,17 In this scenario, the exposure to an immunopathogenic substance or agent in an individual with a genetically encoded immune system or endothelial barrier defect could be prone to CNS compromise by potentially neurotrophic pathogens or by peripherally generated immune factors.18,19 A role for peripherally acting systems in a CNS disorder was also supported by our findings that antibody levels were higher in people who reported GI conditions compared with those who did not. This GI connection was independent of those variables identified as confounders and preliminarily points toward a GI route of C. albicans immune response generation, perhaps signaling the presence of gut dysbiosis. Our findings, therefore, may be consistent with the hypothesis that disturbance to the gut microbiome in psychiatric disorders can lead to translocation of gut-related products, including those that are derived from fungi, into systemic circulation.18–20

These data also serve in part as biological validation of our recently published next-generation sequencing of the oropharyngeal microbiome, where among several dysregulated bacterial species, we detected elevated abundances of the fungal Candida spp., C. dubliensis, in people with schizophrenia compared with controls.21 Fungal material has been found in the cerebrospinal fluid and brains of patients with Alzheimer’s disease and amyotrophic lateral sclerosis.22–24 Although these recent reports support the possibility that the C. albicans organism is directly pathogenic to the brain, yeast alternatively may provide a source of toxic breakdown products or digested bioactive peptides that could elicit an antifungal immune response and have the propensity to cross the blood–gut and blood–brain barriers. Yeasts also synthesize cyclic dipeptides and based on research in other disciplines, it is further possible that these peptides activate apoptotic pathways associated with neuronal function.25 Certain metabolic products of yeast including propionic acid have been implicated in autism.26 Yeasts are also known producers of neurotransmitters including noradrenaline by Saccharomyces spp and serotonin by Candida spp.27

The hypothesis that infectious agents contribute to the etiopathophysiology of psychiatric disorders is most often applied in a context of pathogen exposure or immune activation during critical prenatal neurodevelopmental time windows.6,28–35 It is more difficult to ascertain whether infection or activation of the infectious disease process during one’s lifetime contributes to an increased risk for the development of mental illness. Nevertheless, there is an expansive literature base that aims to understand how pathogen-specific and generalized immune dysregulation extrinsic to the prenatal setting might contribute to future psychiatric disorders.35–42 In many of these studies, as well as in our own assays, an IgG antibody-based measure was used and this index does not differentiate current infections from past exposures. In the data not shown, we tested a random sample of 88 individuals for acute C. albicans infection using an IgM antibody, a measure that generally reflects a more recent infection. We found that ~9% of these samples were positive for IgM, whereas 32% were positive for IgG, suggesting that for most individuals, C. albicans overgrowth occurred sometime in the more distant past. Longitudinal investigations are required to more directly address the issue of postnatal exposures and psychiatric disorder development. Interestingly, studies of military cohorts have documented IgG elevations against a number of antigens, including pathogens, as early as 2 years prior to the diagnosis of disease.43–45

Several methodological, analytical, and conceptual factors limit the extent to which our results can be interpreted. From a technical standpoint, given that there are over 150 species of Candida, it is possible that the commercial immunoassay kit that we used also detected exposures to other similarly immunogenic Candidal species, including the many that are benign and importantly the few that are pathogenic. In our data analyses, it was not possible for us to correct for all of the multiple variables including lifestyle characteristics that might contribute to our findings. For example, information regarding immunosuppression from sources other than cancer treatment was not available for our study analyses. We addressed potentially confounding basic demographic factors by including these variables in our multiple regressions models. In this manner and as described earlier, we were able to find that a history of homelessness significantly accounted for the elevated C. albicans exposures in males with bipolar disorder. Of note, none of the other demographic factors (age, race, and socioeconomic status) were independently or interactively associated with C. albicans IgG levels. We applied multiple comparison testing for the basic interdiagnostic group analyses; however, applying this correction to the smaller sample size sub-category comparisons would have eliminated detection of informative associations. Therefore, such sub-analyses including the GI associations remain preliminary and support the exploratory nature of this paper. Although our results demonstrate an absence of effect of antipsychotic medications on C. albicans IgG levels, we did not have information regarding over-the-counter or prescription treatments of the somatic conditions evaluated in this study.

In conclusion, our initial results suggested the absence of differential C. albicans IgG levels between psychiatric cases and controls. However, when sexes were evaluated separately, numerous significant disease-specific associations of this fungus with lifestyle, somatic conditions, and cognitive measures were evident. It may be premature to list this pathogen as a risk factor for disease causation, but its status as a comorbidity requires clinical attention. During health care evaluation, inquiry regarding the presence of symptoms of C. albicans infections would help to identify individuals in need of treatment. Furthermore, the early identification of active infection might be an indicator of those at risk for cognitive decline; however, future research is necessary to investigate this connection. In people who have or who are prone to C. albicans overgrowth, dietary management geared toward correcting microbial imbalances may be considered. In the long term, more research is required to understand the mechanisms that trigger pathogenicity of fungal commensals and how this might impact brain function in psychiatric disorders.