The Gut Microbiome as a Regulator of the Neuroimmune Landscape.

The gut microbiome influences many host physiologies, spanning gastrointestinal function, metabolism, immune homeostasis, neuroactivity, and behavior. Many microbial effects on the host are orchestrated by bidirectional interactions between the microbiome and immune system. Imbalances in this dialogue can lead to immune dysfunction and immune-mediated conditions in distal organs including the brain. Dysbiosis of the gut microbiome and dysregulated neuroimmune responses are common comorbidities of neurodevelopmental, neuropsychiatric, and neurological disorders, highlighting the importance of the gut microbiome-neuroimmune axis as a regulator of central nervous system homeostasis. In this review, we discuss recent evidence supporting a role for the gut microbiome in regulating the neuroimmune landscape in health and disease.

Extending genetic risk for Alzheimer's disease from host to holobiont.

The gut microbiota is implicated in risk for Alzheimer's disease (AD). A study in Science reports that depleting gut bacteria in mice with genetic risk for AD reduces neuropathology in a sex-dependent manner. This is reversed by administering short-chain fatty acids, suggesting that specific bacterial metabolites increase susceptibility to AD.

SnapShot: The microbiota-gut-brain axis.

Animals have co-evolved with a vast diversity of microorganisms, collectively named the microbiome, which are important modulators of host gastrointestinal, immune, metabolic, and behavioral functions. In this SnapShot, we provide an overview of the neurodevelopmental and functional influence of host-microbial interactions in the "microbiota-gut-brain axis," which refers to the bidirectional communication between the central nervous system and the gastrointestinal microbiome. To view this SnapShot, open or download the PDF.

The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet.

The ketogenic diet (KD) is used to treat refractory epilepsy, but the mechanisms underlying its neuroprotective effects remain unclear. Here, we show that the gut microbiota is altered by the KD and required for protection against acute electrically induced seizures and spontaneous tonic-clonic seizures in two mouse models. Mice treated with antibiotics or reared germ free are resistant to KD-mediated seizure protection. Enrichment of, and gnotobiotic co-colonization with, KD-associated Akkermansia and Parabacteroides restores seizure protection. Moreover, transplantation of the KD gut microbiota and treatment with Akkermansia and Parabacteroides each confer seizure protection to mice fed a control diet. Alterations in colonic lumenal, serum, and hippocampal metabolomic profiles correlate with seizure protection, including reductions in systemic gamma-glutamylated amino acids and elevated hippocampal GABA/glutamate levels. Bacterial cross-feeding decreases gamma-glutamyltranspeptidase activity, and inhibiting gamma-glutamylation promotes seizure protection in vivo. Overall, this study reveals that the gut microbiota modulates host metabolism and seizure susceptibility in mice.

IL-33 Changes Our "Gut Feelings" about Serotonin.

Many studies highlight direct interactions between immune cells and enteric neurons, but whether immune signals can indirectly modulate enteric function through neurotransmitter regulation is poorly understood. In this issue of Immunity, Chen et al. reveal how IL-33 induces intestinal serotonin to promote gut motility.

Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis.

The gastrointestinal (GI) tract contains much of the body's serotonin (5-hydroxytryptamine, 5-HT), but mechanisms controlling the metabolism of gut-derived 5-HT remain unclear. Here, we demonstrate that the microbiota plays a critical role in regulating host 5-HT. Indigenous spore-forming bacteria (Sp) from the mouse and human microbiota promote 5-HT biosynthesis from colonic enterochromaffin cells (ECs), which supply 5-HT to the mucosa, lumen, and circulating platelets. Importantly, microbiota-dependent effects on gut 5-HT significantly impact host physiology, modulating GI motility and platelet function. We identify select fecal metabolites that are increased by Sp and that elevate 5-HT in chromaffin cell cultures, suggesting direct metabolic signaling of gut microbes to ECs. Furthermore, elevating luminal concentrations of particular microbial metabolites increases colonic and blood 5-HT in germ-free mice. Altogether, these findings demonstrate that Sp are important modulators of host 5-HT and further highlight a key role for host-microbiota interactions in regulating fundamental 5-HT-related biological processes.

Perinatal Interactions between the Microbiome, Immunity, and Neurodevelopment.

The microbiome modulates host immune function across the gastrointestinal tract, peripheral lymphoid organs, and central nervous system. In this review, we highlight emerging evidence that microbial effects on select immune phenotypes arise developmentally, where the maternal and neonatal microbiome influence immune cell ontogeny in the offspring during gestation and early postnatal life. We further discuss roles for the perinatal microbiome and early-life immunity in regulating normal neurodevelopmental processes. In addition, we examine evidence that abnormalities in microbiota-neuroimmune interactions during early life are associated with altered risk of neurological disorders in humans. Finally, we conclude by evaluating the potential implications of microbiota-immune interventions for neurological conditions. Continued progress toward dissecting mechanistic interactions between the perinatal microbiota, immune system, and nervous system might uncover fundamental insights into how developmental interactions across physiological systems inform later-life health and disease.

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.

Microbes REV up Host Metabolism around the Clock.

There is increasing evidence that the microbiome regulates host metabolism, but specific mechanisms underlying these interactions remain poorly understood. In a recent paper in Science, Wang et al. (2017) reveal that the gut microbiota regulates the expression of circadian-clock genes to impact host lipid metabolism and body composition.

The maternal microbiome modulates fetal neurodevelopment in mice.

'Dysbiosis' of the maternal gut microbiome, in response to challenges such as infection1, altered diet2 and stress3 during pregnancy, has been increasingly associated with abnormalities in brain function and behaviour of the offspring4. However, it is unclear whether the maternal gut microbiome influences neurodevelopment during critical prenatal periods and in the absence of environmental challenges. Here we investigate how depletion and selective reconstitution of the maternal gut microbiome influences fetal neurodevelopment in mice. Embryos from antibiotic-treated and germ-free dams exhibited reduced brain expression of genes related to axonogenesis, deficient thalamocortical axons and impaired outgrowth of thalamic axons in response to cell-extrinsic factors. Gnotobiotic colonization of microbiome-depleted dams with a limited consortium of bacteria prevented abnormalities in fetal brain gene expression and thalamocortical axonogenesis. Metabolomic profiling revealed that the maternal microbiome regulates numerous small molecules in the maternal serum and the brains of fetal offspring. Select microbiota-dependent metabolites promoted axon outgrowth from fetal thalamic explants. Moreover, maternal supplementation with these metabolites abrogated deficiencies in fetal thalamocortical axons. Manipulation of the maternal microbiome and microbial metabolites during pregnancy yielded adult offspring with altered tactile sensitivity in two aversive somatosensory behavioural tasks, but no overt differences in many other sensorimotor behaviours. Together, our findings show that the maternal gut microbiome promotes fetal thalamocortical axonogenesis, probably through signalling by microbially modulated metabolites to neurons in the developing brain.

The Microbiome and Host Behavior.

The microbiota is increasingly recognized for its ability to influence the development and function of the nervous system and several complex host behaviors. In this review, we discuss emerging roles for the gut microbiota in modulating host social and communicative behavior, stressor-induced behavior, and performance in learning and memory tasks. We summarize effects of the microbiota on host neurophysiology, including brain microstructure, gene expression, and neurochemical metabolism across regions of the amygdala, hippocampus, frontal cortex, and hypothalamus. We further assess evidence linking dysbiosis of the gut microbiota to neurobehavioral diseases, such as autism spectrum disorder and major depression, drawing upon findings from animal models and human trials. Finally, based on increasing associations between the microbiota, neurophysiology, and behavior, we consider whether investigating mechanisms underlying the microbiota-gut-brain axis could lead to novel approaches for treating particular neurological conditions.

Mitochondrial and Purinergic Dysregulation Promote Abnormal Behavior in Mice.

Increasing evidence implicates immune dysregulation in the development of neurological disorders. Recent research by Fan and colleagues deepens our understanding of how physical stress alters the immune system to promote anxiety-like behavior.

Emerging roles for the intestinal microbiome in epilepsy.

The gut microbiome is emerging as a key regulator of brain function and behavior and is associated with symptoms of several neurological disorders. There is emerging evidence that alterations in the gut microbiota are seen in epilepsy and in response to seizure interventions. In this review, we highlight recent studies reporting that individuals with refractory epilepsy exhibit altered composition of the gut microbiota. We further discuss antibiotic treatment and infection as microbiome-related factors that influence seizure susceptibility in humans and animal models. In addition, we evaluate how the microbiome may mediate effects of the ketogenic diet, probiotic treatment, and anti-epileptic drugs on reducing both seizure frequency and severity. Finally, we assess the open questions in interrogating roles for the microbiome in epilepsy and address the prospect that continued research may uncover fundamental insights for understanding risk factors for epilepsy, as well as novel approaches for treating refractory epilepsy.

Host Genetic Background and Gut Microbiota Contribute to Differential Metabolic Responses to Fructose Consumption in Mice.

BACKGROUND: It is unclear how high fructose consumption induces disparate metabolic responses in genetically diverse mouse strains. OBJECTIVE: We aimed to investigate whether the gut microbiota contributes to differential metabolic responses to fructose. METHODS: Eight-week-old male C57BL/6J (B6), DBA/2J (DBA), and FVB/NJ (FVB) mice were given 8% fructose solution or regular water (control) for 12 wk. The gut microbiota composition in cecum and feces was analyzed using 16S ribosomal DNA sequencing, and permutational multivariate ANOVA (PERMANOVA) was used to compare community across mouse strains, treatments, and time points. Microbiota abundance was correlated with metabolic phenotypes and host gene expression in hypothalamus, liver, and adipose tissues using Biweight midcorrelation. To test the causal role of the gut microbiota in determining fructose response, we conducted fecal transplants from B6 to DBA mice and vice versa for 4 wk, as well as gavaged antibiotic-treated DBA mice with Akkermansia for 9 wk, accompanied with or without fructose treatment. RESULTS: Compared with B6 and FVB, DBA mice had significantly higher Firmicutes to Bacteroidetes ratio and lower baseline abundance of Akkermansia and S24-7 (P < 0.05), accompanied by metabolic dysregulation after fructose consumption. Fructose altered specific microbial taxa in individual mouse strains, such as a 7.27-fold increase in Akkermansia in B6 and 0.374-fold change in Rikenellaceae in DBA (false discovery rate <5%), which demonstrated strain-specific correlations with host metabolic and transcriptomic phenotypes. Fecal transplant experiments indicated that B6 microbes conferred resistance to fructose-induced weight gain in DBA mice (F = 43.1, P < 0.001), and Akkermansia colonization abrogated the fructose-induced weight gain (F = 17.8, P < 0.001) and glycemic dysfunctions (F = 11.8, P = 0.004) in DBA mice. CONCLUSIONS: Our findings support that differential microbiota composition between mouse strains is partially responsible for host metabolic sensitivity to fructose, and that Akkermansia is a key bacterium that confers resistance to fructose-induced metabolic dysregulation.

Defining Dysbiosis in Disorders of Movement and Motivation.

The gut microbiota has emerged as a critical player in shaping and modulating brain function and has been shown to influence numerous behaviors, including anxiety and depression-like behaviors, sociability, and cognition. However, the effects of the gut microbiota on specific disorders associated with thalamo-cortico-basal ganglia circuits, ranging from compulsive behavior and addiction to altered sensation and motor output, are only recently being explored. Wholesale depletion and alteration of gut microbial communities in rodent models of disorders, such as Parkinson's disease, autism, and addiction, robustly affect movement and motivated behavior. A new frontier therefore lies in identifying specific microbial alterations that affect these behaviors and understanding the underlying mechanisms of action. Comparing alterations in gut microbiota across multiple basal-ganglia associated disease states allows for identification of common mechanistic pathways that may interact with distinct environmental and genetic risk factors to produce disease-specific outcomes.

The Gut and Its Microbiome as Related to Central Nervous System Functioning and Psychological Well-being: Introduction to the Special Issue of Psychosomatic Medicine.

Accumulating evidence indicates bidirectional associations between the brain and the gut microbiome with both top-down and bottom-up processes. This article describes new developments in brain-gut interactions as an introduction to a special issue of Psychosomatic Medicine, based on a joint symposium of the American Psychosomatic Society and the American Gastroenterological Association. Literature review articles indicate that several psychiatric disorders are associated with altered gut microbiota, whereas evidence linking functional gastrointestinal disorders and dysbiosis has not been firmly established. The association between dysbiosis with obesity, metabolic syndrome, and Type 2 diabetes mellitus is still inconclusive, but evidence suggests that bariatric surgery may favorably alter the gut microbial community structure. Consistent with the literature linking psychiatric disorders with dysbiosis is that life adversity during childhood and certain temperaments that develop early in life are associated with altered gut microbiota, particularly the Prevotella species. Some studies reported in this issue support the hypothesis that brain-gut interactions are adversely influenced by reduced functional activation of the hippocampus and autonomic nervous system dysregulation. The evidence for the effects of probiotics in the treatment of Clostridium difficile colitis is relatively well established, but effects on mental health and psychophysiological stress reactivity are either inconclusive or still in progress. To conceptualize brain-gut interactions, a holistic, systems-based perspective on health and disease is needed, integrating gut microbial with environmental ecology. More translational research is needed to examine the mental and physical health effects of prebiotics and probiotics, in well-phenotyped human populations with sufficiently large sample sizes.

The placental interleukin-6 signaling controls fetal brain development and behavior.

Epidemiological studies show that maternal immune activation (MIA) during pregnancy is a risk factor for autism. However, mechanisms for how MIA affects brain development and behaviors in offspring remain poorly described. To determine whether placental interleukin-6 (IL-6) signaling is required for mediating MIA on the offspring, we generated mice with restricted deletion of the receptor for IL-6 (IL-6Rα) in placental trophoblasts (Cyp19-Cre+;Il6rafl/fl), and tested offspring of Cyp19-Cre+;Il6rafl/fl mothers for immunological, pathological and behavioral abnormalities following induction of MIA. We reveal that MIA results in acute inflammatory responses in the fetal brain. Lack of IL-6 signaling in trophoblasts effectively blocks MIA-induced inflammatory responses in the placenta and the fetal brain. Furthermore, behavioral abnormalities and cerebellar neuropathologies observed in MIA control offspring are prevented in Cyp19-Cre+;Il6rafl/fl offspring. Our results demonstrate that IL-6 activation in placenta is required for relaying inflammatory signals to the fetal brain and impacting behaviors and neuropathologies relevant to neurodevelopmental disease.