Janet Chow

Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders

Neurodevelopmental disorders, including autism spectrum disorder (ASD), are defined by core behavioral impairments; however, subsets of individuals display a spectrum of gastrointestinal (GI) abnormalities. We demonstrate GI barrier defects and microbiota alterations in the maternal immune activation (MIA) mouse model that is known to display features of ASD. Oral treatment of MIA offspring with the human commensal Bacteroides fragilis corrects gut permeability, alters microbial composition, and ameliorates defects in communicative, stereotypic, anxiety-like and sensorimotor behaviors. MIA offspring display an altered serum metabolomic profile, and B. fragilis modulates levels of several metabolites. Treating naive mice with a metabolite that is increased by MIA and restored by B. fragilis causes certain behavioral abnormalities, suggesting that gut bacterial effects on the host metabolome impact behavior. Taken together, these findings support a gut-microbiome-brain connection in a mouse model of ASD and identify a potential probiotic therapy for GI and particular behavioral symptoms in human neurodevelopmental disorders.

Host-Bacterial Symbiosis in Health and Disease

All animals live in symbiosis. Shaped by eons of co-evolution, host-bacterial associations have developed into prosperous relationships creating mechanisms for mutual benefits to both microbe and host. No better example exists in biology than the astounding numbers of bacteria harbored by the lower gastrointestinal tract of mammals. The mammalian gut represents a complex ecosystem consisting of an extraordinary number of resident commensal bacteria existing in homeostasis with the hosts immune system. Most impressive about this relationship may be the concept that the host not only tolerates, but has evolved to require colonization by beneficial microorganisms, known as commensals, for various aspects of immune development and function. The microbiota provides critical signals that promote maturation of immune cells and tissues, leading to protection from infections by pathogens. Gut bacteria also appear to contribute to non-infectious immune disorders such as inflammatory bowel disease and autoimmunity. How the microbiota influences host immune responses is an active area of research with important implications for human health. This review synthesizes emerging findings and concepts that describe the mutualism between the microbiota and mammals, specifically emphasizing the role of gut bacteria in shaping an immune response that mediates the balance between health and disease. Unlocking how beneficial bacteria affect the development of the immune system may lead to novel and natural therapies based on harnessing the immunomodulatory properties of the microbiota.

Modeling an autism risk factor in mice leads to permanent immune dysregulation

Increasing evidence highlights a role for the immune system in the pathogenesis of autism spectrum disorder (ASD), as immune dysregulation is observed in the brain, periphery, and gastrointestinal tract of ASD individuals. Furthermore, maternal infection (maternal immune activation, MIA) is a risk factor for ASD. Modeling this risk factor in mice yields offspring with the cardinal behavioral and neuropathological symptoms of human ASD. In this study, we find that offspring of immune-activated mothers display altered immune profiles and function, characterized by a systemic deficit in CD4+ TCRβ+ Foxp3+ CD25+ T regulatory cells, increased IL-6 and IL-17 production by CD4+ T cells, and elevated levels of peripheral Gr-1+ cells. In addition, hematopoietic stem cells from MIA offspring exhibit altered myeloid lineage potential and differentiation. Interestingly, repopulating irradiated control mice with bone marrow derived from MIA offspring does not confer MIA-related immunological deficits, implicating the peripheral environmental context in long-term programming of immune dysfunction. Furthermore, behaviorally abnormal MIA offspring that have been irradiated and transplanted with immunologically normal bone marrow from either MIA or control offspring no longer exhibit deficits in stereotyped/repetitive and anxiety-like behaviors, suggesting that immune abnormalities in MIA offspring can contribute to ASD-related behaviors. These studies support a link between cellular immune dysregulation and ASD-related behavioral deficits in a mouse model of an autism risk factor.

A Pathobiont of the Microbiota Balances Host Colonization and Intestinal Inflammation

The gastrointestinal tract harbors a diverse microbiota that has coevolved with mammalian hosts. Though most associations are symbiotic or commensal, some resident bacteria (termed pathobionts) have the potential to cause disease. Bacterial type VI secretion systems (T6SSs) are one mechanism for forging host-microbial interactions. Here we reveal a protective role for the T6SS of Helicobacter hepaticus, a Gram-negative bacterium of the intestinal microbiota. H. hepaticus mutants with a defective T6SS display increased numbers within intestinal epithelial cells (IECs) and during intestinal colonization. Remarkably, the T6SS directs an anti-inflammatory gene expression profile in IECs, and CD4+ T cells from mice colonized with T6SS mutants produce increased interleukin-17 in response to IECs presenting H. hepaticus antigens. Thus, the H. hepaticus T6SS limits colonization and intestinal inflammation, promoting a balanced relationship with the host. We propose that disruption of such balances contributes to human disorders such as inflammatory bowel disease and colon cancer.

Getting the Bugs out of the Immune System: Do Bacterial Microbiota “Fix” Intestinal T Cell Responses?

Proinflammatory T helper 17 (Th17) cells control infections caused by microbial pathogens. Surprisingly, several recent reports now reveal that symbiotic gut bacteria modulate Th17 cell differentiation and function in the gastrointestinal tract. As various autoimmune and allergic disorders are mediated by uncontrolled T cell responses, immune regulation by the microbiota may have direct implications for human health.

Ultrastructure and complex polar architecture of the human pathogen Campylobacter jejuni

Campylobacter jejuni is one of the most successful food‐borne human pathogens. Here we use electron cryotomography to explore the ultrastructure of C. jejuni cells in logarithmically growing cultures. This provides the first look at this pathogen in a near‐native state at macromolecular resolution (~5 nm). We find a surprisingly complex polar architecture that includes ribosome exclusion zones, polyphosphate storage granules, extensive collar‐shaped chemoreceptor arrays, and elaborate flagellar motors.

119. Modeling an autism risk factor in mice leads to permanent changes in the immune system

Increasing evidence suggests a role for the immune system in autism spectrum disorders (ASD) pathogenesis. Studies have reported immune dysregulation in the brain, periphery and gastrointestinal tract in ASD. Furthermore, maternal infection (immune activation, MIA) is a risk factor for ASD. Modelling this risk factor in mice yields offspring with the cardinal behavioral and neuropathological symptoms of human ASD. In this study, we ask if MIA offspring also exhibit abnormal neural, peripheral or enteric immunity. We find that these offspring display altered immune profiles and function. In addition, hematopoietic stem cells (HSCs) from MIA offspring exhibit altered lineage potential and differentiation. To examine whether immune dysfunction contributes to ASD pathogenesis, we behaviorally assess MIA offspring that have been repopulated with naive bone marrow. To explore the potential for prenatal programming of long-term immune dysfunction, we examine whether transferring HSCs from MIA offspring into naive mice can induce cell-autonomous immune abnormalities.