Highlights • The mucosal microbiome may play a role in human psychiatric disorders. • The oro-pharyngeal microbiota is different in schizophrenia vs. controls. • GI inflammation is increased in ...schizophrenia and bipolar disorder. • Antibiotics may alter the microbiome and affect psychiatric symptoms. • Clinical trials which alter gut microbiota may test hypotheses about their role.
Highlights • The annual environmental deposit of cat feces in the US is 1.2 million tons. • Toxoplasma gondii oocysts may remain viable for several years and thus accumulate. • In favored cat ...defecation sites, oocysts may accumulate in very high numbers. • The accumulation of T. gondii oocysts may be a major public health problem.
Toxoplasma exposure can elicit cellular and humoral immune responses. In the case of chronic Toxoplasma infection, these immune responses are long-lasting. Some studies suggest that pre-existing ...immunity from Toxoplasma infection can shape immune responses and resistance to other pathogens and brain insults later in life. Much evidence has been generated suggesting Toxoplasma infection may contribute to cognitive impairment in the elderly. However, there have also been studies that disagree with the conclusion. Toxoplasma has many strain types, with virulence being the most notable difference. There is also considerable variation in the outcomes following Toxoplasma exposure ranging from resolved to persistent infection. Therefore, the brain microenvironment, particularly cellular constituents, differs based on the infecting strain (virulent versus hypovirulent) and infection stage (resolved versus persistent). Such difference might play a critical role in determining the outcome of the host on subsequent challengings to the brain. The ability of Toxoplasma strains to set up distinct stages for neurodegenerative pathology through varying degrees of virulence provides unique experimental tools for characterizing these pathways.
•Models of Toxoplasma infection allow study of how neurotropic organisms influence AD development.•Studies show mixed results connecting Toxoplasma seropositivity and cognitive function and AD.•Hypovirulent strain infection in mice confers protection against other pathogens and CNS insults.•Host immune surveillance that required to control Toxoplasma reactivation differs among strains.•Strain-specific neuroinflammation may set the stage for distinct outcomes of brain insults.
Abstract Autoimmunity, gastrointestinal (GI) disorders and schizophrenia have been associated with one another for a long time. This paper reviews these connections and provides a context by which ...multiple risk factors for schizophrenia may be related. Epidemiological studies strongly link schizophrenia with autoimmune disorders including enteropathic celiac disease. Exposure to wheat gluten and bovine milk casein also contribute to non-celiac food sensitivities in susceptible individuals. Co-morbid GI inflammation accompanies humoral immunity to food antigens, occurs early during the course of schizophrenia and appears to be independent from antipsychotic-generated motility effects. This inflammation impacts endothelial barrier permeability and can precipitate translocation of gut bacteria into systemic circulation. Infection by the neurotropic gut pathogen, Toxoplasma gondii , will elicit an inflammatory GI environment. Such processes trigger innate immunity, including activation of complement C1q, which also functions at synapses in the brain. The emerging field of microbiome research lies at the center of these interactions with evidence that the abundance and diversity of resident gut microbiota contribute to digestion, inflammation, gut permeability and behavior. Dietary modifications of core bacterial compositions may explain inefficient gluten digestion and how immigrant status in certain situations is a risk factor for schizophrenia. Gut microbiome research in schizophrenia is in its infancy, but data in related fields suggest disease-associated altered phylogenetic compositions. In summary, this review surveys associative and experimental data linking autoimmunity, GI activity and schizophrenia, and proposes that understanding of disrupted biological pathways outside of the brain can lend valuable information regarding pathogeneses of complex, polygenic brain disorders.
•Genetic research on schizophrenia has been disappointing.•The heritability of schizophrenia has been over-estimated.•What appears to be genetic may be infectious.•For patients this is good news ...since treatment of non-genetic causes is more feasible.
In recent years schizophrenia has been assumed to be largely a genetic disease with heritability estimates, derived primarily from family and twin studies, of 80%–85%. However, the results of genetic research on schizophrenia have not yielded results consistent with that estimate of heritability. In particular, extensive genetic studies have not led to new methods for diagnosis and treatment. An examination of the twin studies on which heritability is based shows why such studies exaggerate the genetic component of schizophrenia. In addition, the effects of infectious agents such as Toxoplasma gondii and the composition of the microbiome can produce a clinical picture that would also appear to be largely genetic due to familial aggregation and a role for a partial genetic contribution to the immune system. It is concluded that the genetic component of schizophrenia may have been overestimated and an increased focus on gene-environmental interactions is likely to accelerate research progress on this disease.
Complex interactions between the immune system and the brain might have important aetiological and therapeutic implications for neuropsychiatric brain disorders. A possible association between ...schizophrenia and the immune system was postulated over a century ago, and is supported by epidemiological and genetic studies pointing to links with infection and inflammation. Contrary to the traditional view that the brain is an immunologically privileged site shielded behind the blood-brain barrier, studies in the past 20 years have noted complex interactions between the immune system, systemic inflammation, and the brain, which can lead to changes in mood, cognition, and behaviour. In this Review, we describe some of the important areas of research regarding innate and adaptive immune response in schizophrenia and related psychotic disorders that, we think, will be of interest to psychiatric clinicians and researchers. We discuss potential mechanisms and therapeutic implications of these findings, including studies of anti-inflammatory drugs in schizophrenia, describe areas for development, and offer testable hypotheses for future investigations.
The failure to find genes of major effect in schizophrenia has refocused attention on nongenetic, including infectious factors. In a previous study, antibodies to Toxoplasma gondii were found to be ...elevated in 23 studies of schizophrenia (OR 2.73; 95% CI 2.10-3.60). The current study replicates this finding with 15 additional studies (OR 2.71; 95% CI 1.93-3.80) and compares this with other identified schizophrenia risk factors. The highest risk factors are having an affected mother (relative risks RR 9.31; 95% CI 7.24-11.96), father (RR 7.20; 95% CI 5.10-10.16), or sibling (RR 6.99; 95% CI 5.38-9.08) or being the offspring of immigrants from selected countries (RR 4.5; 95% CI 1.5-13.1). Intermediate risk factors, in addition to infection with T. gondii, include being an immigrant from and to selected countries (RR 2.7; 95% CI 2.3-3.2), being born in (RR 2.24; 95% CI 1.92-2.61) or raised in (RR 2.75; 95% CI 2.31-3.28) an urban area, cannabis use (OR 2.10-2.93; 95% CI 1.08-6.13), having minor physical anomalies (OR 2.23; 95% CI 1.42-3.58), or having a father 55 or older (OR 2.21-5.92; 95% CI 1.46-17.02). Low-risk factors include a history of traumatic brain injury (OR 1.65; 95% CI 1.17-2.32), sex abuse in childhood (OR 1.46; 95% CI 0.84-2.52), obstetrical complications (OR 1.29-1.38; 95% CI 1.00-1.84), having a father 45 or older (OR 1.21-1.66; 95% CI 1.09-2.01), specific genetic polymorphisms (OR 1.09-1.24; 95% CI 1.06-1.45), birth seasonality (OR 1.07-1.95; 95% CI 1.05-2.91), maternal exposure to influenza (RR 1.05; 95% CI 0.98-1.12), or prenatal stress (RR 0.98-1.00; 95% CI 0.85-1.16).
The 2017 American College of Neuropychopharmacology (ACNP) conference hosted a Study Group on 4 December 2017, Establishing best practice guidelines to improve the rigor, reproducibility, and ...transparency of the maternal immune activation (MIA) animal model of neurodevelopmental abnormalities. The goals of this session were to (a) evaluate the current literature and establish a consensus on best practices to be implemented in MIA studies, (b) identify remaining research gaps warranting additional data collection and lend to the development of evidence-based best practice design, and (c) inform the MIA research community of these findings. During this session, there was a detailed discussion on the importance of validating immunogen doses and standardizing the general design (e.g., species, immunogenic compound used, housing) of our MIA models both within and across laboratories. The consensus of the study group was that data does not currently exist to support specific evidence-based model selection or methodological recommendations due to lack of consistency in reporting, and that this issue extends to other inflammatory models of neurodevelopmental abnormalities. This launched a call to establish a reporting checklist focusing on validation, implementation, and transparency modeled on the ARRIVE Guidelines and CONSORT (scientific reporting guidelines for animal and clinical research, respectively). Here we provide a summary of the discussions in addition to a suggested checklist of reporting guidelines needed to improve the rigor and reproducibility of this valuable translational model, which can be adapted and applied to other animal models as well.
The body's microbiome represents an actively regulated network of novel mechanisms that potentially underlie the etiology and pathophysiology of a wide range of diseases. For complex brain disorders ...such as schizophrenia, understanding the cellular and molecular pathways that intersect the bidirectional gut-brain axis is anticipated to lead to new methods of treatment. The means by which the microbiome might differ across neuropsychiatric and neurological disorders are not known. Brain disorders as diverse as schizophrenia, major depression, Parkinson's disease and multiple sclerosis appear to share a common pathology of an imbalanced community of commensal microbiota, often measured in terms of a leaky gut phenotype accompanied by low level systemic inflammation. While environmental factors associated with these disease states might contribute to intestinal pathologies, products from a perturbed microbiome may also directly promote specific signs, symptoms and etiologies of individual disorders. We hypothesize that in schizophrenia, it is the putatively unique susceptibility related to genes that modulate the immune system and the gut-brain pleiotropy of these genes which leads to a particularly neuropathological response when challenged by a microbiome in dysbiosis. Consequences from exposure to this dysbiosis may occur during pre- or post-natal time periods and thus may interfere with normal neurodevelopment in those who are genetically predisposed. Here, we review the evidence from the literature which supports the idea that the intersection of the microbiome and immune gene susceptibility in schizophrenia is relevant etiologically and for disease progression. Figuring prominently at both ends of the gut-brain axis and at points in between are proteins encoded by genes found in the major histocompatibility complex (MHC), including select MHC as well as non-MHC complement pathway genes.
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