Microbes and Autoimmunity in Neuropsychiatric Illness
The concept that specific types of infectious illness may be associated with neuropsychiatric disturbances, especially those occurring in close proximity of geography and time, has a long history. Perfect is credited with first questioning whether the cause of a case of insanity was 'the epidemic catarrh, more generally known by the name of influenza'. Later, epidemiologic reports, however, present inconsistent data regarding a link between infection and neuropsychiatric disorder. Variability in central nervous system (CNS) outcomes after infection likely reflects differences in exposure timing or in type or severity of host immune responses to the agent. The wide range of microbes linked to neuropsychiatric disorders ( Table 1 ) also suggests that activation of shared immune signaling cascades by broad sets of conserved molecular signatures (pathogen-associated molecular patterns, PAMPs) may contribute nonspecifically to CNS disturbance.
A complication in delineating the relationship of a particular pathogen to a particular neuropsychiatric disorder is that even if the link is real, it may nonetheless be nonspecific, both in terms of the type of infectious agent capable of inducing brain dysfunction, as well as in the neurobehavioral features that follow. An expanding body of studies using animal models of infection-related developmental disorders reports persistent effects on offspring brain development and behavior following prenatal or early postnatal exposures to noninfectious agents that mimic actual infection with influenza virus, such as polyinosinic:polycytidylic acid (poly I:C, a form of synthetic, double-stranded RNA), or a bacterium, such as lipopolysaccharide (LPS, or bacterial endotoxin), illustrating the importance of maternal immune responses as modifiers of postinfectious sequelae in the offspring. Findings from these studies suggest that CNS damage requires the presence of innate immune and inflammatory molecules that disrupt brain development, as well as their cognate receptors, such as toll receptor-like (TLR)3 and TLR4 (for double-stranded RNA and bacterial sequences, respectively). Infectious agents can share PAMPs, sequence motifs that are recognized by pattern recognition receptors on macrophages, dendritic cells and other components of the innate immune system, as well as on microglia. In addition to the behavioral disturbances reminiscent of ASD, schizophrenia and OCD, maternal immune activation is also associated with persistent changes in offspring immune responses, both in the peripheral blood and in brain. Specific immune effects identified in adult offspring after prenatal immune challenge in one study in the maternal immune activation mouse model included persistent reductions in T regulatory (Treg) cells and shifts toward a T helper type 2 (Th2) cytokine phenotype (associated with autoimmune or allergic disorders). Intriguingly, correction of the immune disturbances in these adult mice through bone marrow transplantation also abolished the autism-like behavior deficits. In addition to this overlap in neurodevelopmental consequences after prenatal and postnatal virus-like and bacteria-like exposures, exposure of infant mice to environmental contaminants such as the organic compound, toluene, is associated with upregulated expression of cytokine genes in hippocampus. Thus, increasing evidence suggests that it is the presence of innate immune molecules, as opposed to direct infection of neurons and glial cells, that mediates these effects.
It is increasingly apparent that the presence of certain commensal organisms in the gut is essential for proper brain development and function. Behavioral abnormalities have also been shown to be modified through the introduction of specific probiotics, bacteria or feces in animal models. One mechanism by which changes in the microbiome may alter the CNS is through the bacterial production of harmful products that compromise the integrity of the epithelial barrier of the intestine, allowing entry of bacterial products or proteins with neuroactive properties into the circulation. Consistently with the potential contribution of the microbiome to the pathogenesis of neuropsychiatric disturbances, children with ASD were found to have elevated urinary levels of p-cresol (4-methylphenol), an organic compound produced by gut bacteria that contain the enzymes for its synthesis but that can also occur as an environmental contaminant. A study from our group identified a rarely reported microbe, Sutterella, in the adherent microbiota of the ileum and cecum of ASD children with gastrointestinal disturbances and a high rate of behavioral regression, but not in age-matched and sex-matched gastrointestinal control children. These children also have deficiencies in the expression of disaccharidase and glucose transporter genes in the gastrointestinal tract, along with abnormal representation of bacteria in their microbiota. Although the contribution of these abnormalities to behavioral disturbances is unknown, abnormal patterns of intestinal microbiota are also observed in autoimmune diseases such as Type 1 diabetes.
Infection and Neuropsychiatric Illness
The concept that specific types of infectious illness may be associated with neuropsychiatric disturbances, especially those occurring in close proximity of geography and time, has a long history. Perfect is credited with first questioning whether the cause of a case of insanity was 'the epidemic catarrh, more generally known by the name of influenza'. Later, epidemiologic reports, however, present inconsistent data regarding a link between infection and neuropsychiatric disorder. Variability in central nervous system (CNS) outcomes after infection likely reflects differences in exposure timing or in type or severity of host immune responses to the agent. The wide range of microbes linked to neuropsychiatric disorders ( Table 1 ) also suggests that activation of shared immune signaling cascades by broad sets of conserved molecular signatures (pathogen-associated molecular patterns, PAMPs) may contribute nonspecifically to CNS disturbance.
Pathogens
A complication in delineating the relationship of a particular pathogen to a particular neuropsychiatric disorder is that even if the link is real, it may nonetheless be nonspecific, both in terms of the type of infectious agent capable of inducing brain dysfunction, as well as in the neurobehavioral features that follow. An expanding body of studies using animal models of infection-related developmental disorders reports persistent effects on offspring brain development and behavior following prenatal or early postnatal exposures to noninfectious agents that mimic actual infection with influenza virus, such as polyinosinic:polycytidylic acid (poly I:C, a form of synthetic, double-stranded RNA), or a bacterium, such as lipopolysaccharide (LPS, or bacterial endotoxin), illustrating the importance of maternal immune responses as modifiers of postinfectious sequelae in the offspring. Findings from these studies suggest that CNS damage requires the presence of innate immune and inflammatory molecules that disrupt brain development, as well as their cognate receptors, such as toll receptor-like (TLR)3 and TLR4 (for double-stranded RNA and bacterial sequences, respectively). Infectious agents can share PAMPs, sequence motifs that are recognized by pattern recognition receptors on macrophages, dendritic cells and other components of the innate immune system, as well as on microglia. In addition to the behavioral disturbances reminiscent of ASD, schizophrenia and OCD, maternal immune activation is also associated with persistent changes in offspring immune responses, both in the peripheral blood and in brain. Specific immune effects identified in adult offspring after prenatal immune challenge in one study in the maternal immune activation mouse model included persistent reductions in T regulatory (Treg) cells and shifts toward a T helper type 2 (Th2) cytokine phenotype (associated with autoimmune or allergic disorders). Intriguingly, correction of the immune disturbances in these adult mice through bone marrow transplantation also abolished the autism-like behavior deficits. In addition to this overlap in neurodevelopmental consequences after prenatal and postnatal virus-like and bacteria-like exposures, exposure of infant mice to environmental contaminants such as the organic compound, toluene, is associated with upregulated expression of cytokine genes in hippocampus. Thus, increasing evidence suggests that it is the presence of innate immune molecules, as opposed to direct infection of neurons and glial cells, that mediates these effects.
Microbiome
It is increasingly apparent that the presence of certain commensal organisms in the gut is essential for proper brain development and function. Behavioral abnormalities have also been shown to be modified through the introduction of specific probiotics, bacteria or feces in animal models. One mechanism by which changes in the microbiome may alter the CNS is through the bacterial production of harmful products that compromise the integrity of the epithelial barrier of the intestine, allowing entry of bacterial products or proteins with neuroactive properties into the circulation. Consistently with the potential contribution of the microbiome to the pathogenesis of neuropsychiatric disturbances, children with ASD were found to have elevated urinary levels of p-cresol (4-methylphenol), an organic compound produced by gut bacteria that contain the enzymes for its synthesis but that can also occur as an environmental contaminant. A study from our group identified a rarely reported microbe, Sutterella, in the adherent microbiota of the ileum and cecum of ASD children with gastrointestinal disturbances and a high rate of behavioral regression, but not in age-matched and sex-matched gastrointestinal control children. These children also have deficiencies in the expression of disaccharidase and glucose transporter genes in the gastrointestinal tract, along with abnormal representation of bacteria in their microbiota. Although the contribution of these abnormalities to behavioral disturbances is unknown, abnormal patterns of intestinal microbiota are also observed in autoimmune diseases such as Type 1 diabetes.