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.

Autism spectrum disorder (ASD) is a serious neurodevelopmental disorder that affects one in 45 children in the United States, with a similarly striking prevalence in countries around the world. However, mechanisms underlying its etiology and manifestations remain poorly understood. While ASD is diagnosed based on the presence and severity of impaired social communication and repetitive behavior, immune dysregulation and gastrointestinal issues are common co-morbidities. The microbiome is an integral part of human physiology; recent studies show that changes in the gut microbiota can modulate gastrointestinal physiology, immune function and even behavior. Links between particular bacteria from the indigenous gut microbiota and phenotypes relevant to ASD raise the important question of whether microbial dysbiosis plays a role in the development or presentation of ASD symptoms. Here we review reports of microbial dysbiosis in ASD. We further discuss potential effects of the microbiota on ASD-associated symptoms, drawing upon signaling mechanisms for reciprocal interactions between the microbiota, immunity, gut function and behavior. In addition, we discuss recent findings supporting a role for the microbiome as an interface between environmental and genetic risk factors that are associated with ASD. These studies highlight the integration of pathways across multiple body systems that together can impact brain and behavior and suggest that changes in the microbiome may contribute to symptoms of neurodevelopmental disease.

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.

Summary “Dysbiosis” of the maternal gut microbiome, in response to challenges such as infection 1 , altered diet 2 and stress 3 during pregnancy, has been increasingly associated with abnormalities in offspring brain function and behavior 4 . However, whether the maternal gut microbiome influences neurodevelopment during critical prenatal periods and in the absence of environmental challenge is poorly understood. 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 exhibit reduced expression of genes related to axonogenesis, deficient thalamocortical axons and impaired thalamic axon outgrowth in response to cell-extrinsic factors. Gnotobiotic colonization of microbiota-depleted dams with a limited consortium of bacteria prevents abnormalities in fetal brain gene expression and thalamocortical axonogenesis. Metabolomic profiling reveals that the maternal microbiota regulates numerous small molecules in the maternal serum and brains of fetal offspring. Select microbiota-dependent metabolites promote axon outgrowth from fetal thalamic explants. Moreover, maternal supplementation with the metabolites abrogates deficiencies in fetal thalamocortical axons. Manipulation of the maternal microbiome and microbial metabolites during pregnancy yields adult offspring with altered tactile sensitivity in two aversive somatosensory behavioral tasks, with no overt differences in many other sensorimotor behaviors. Altogether, these findings reveal that the maternal gut microbiome promotes fetal thalamocortical axonogenesis, likely by signaling of microbially modulated metabolites to neurons in the developing brain.

In the Experimental Models and Subject Details: Bacteria section of the STAR Methods and the Key Resource Table of the above article, the ATCC strain number for Akkermansia muciniphila was incorrectly listed as BAA845. The correct number is BAA835. Additionally, in the legend of Figure 6B, the correct sentence should be, ''Biochemicals, identified by Random Forests classification of colonic lumenal (left) and serum (right) metabolomes, that contribute most highly to the discrimination of seizure-susceptible (SPF CD, Abx KD) from seizure-protected (SPF KD, AkkPb KD) groups. n = 8 cages/group.'' These errors, which have been corrected online and in the print version, do not affect the conclusions in the study, and we apologize for any inconvenience that it may have caused.

The gut microbiota regulates levels of serotonin (5-hydroxytryptamine, 5-HT) in the intestinal epithelium and lumen 1-5. However, whether 5-HT plays a functional role in bacteria from the gut microbiota remains unknown. We demonstrate that elevating levels of intestinal lumenal 5-HT by oral supplementation or by genetic deficiency in the host 5-HT transporter (SERT) increases the relative abundance of spore-forming members of the gut microbiota, which were previously reported to promote host 5-HT biosynthesis. Within this microbial community, we identify Turicibacter sanguinis as a gut bacterium that expresses a neurotransmitter sodium symporter (NSS)-related protein with sequence and structural homology to mammalian SERT. T. sanguinis imports 5-HT through a mechanism that is inhibited by the selective 5-HT reuptake inhibitor, fluoxetine. 5-HT reduces expression of sporulation factors and membrane transporters in T. sanguinis, which is reversed by fluoxetine exposure. Treating T. sanguinis with 5-HT or fluoxetine modulates its competitive colonization in the gastrointestinal tract of antibiotic-treated mice. In addition, fluoxetine reduces the membership of T. sanguinis in the gut microbiota of conventionally-colonized mice. Host association with T. sanguinis alters intestinal expression of multiple gene pathways, including those important for lipid and steroid metabolism, with corresponding reductions in host systemic triglyceride levels and inguinal adipocyte size. Altogether, these findings support the notion that select bacteria indigenous to the gut microbiota signal bidirectionally with the host serotonergic system to promote their fitness in the intestine. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Opioid use for long-term pain management is limited by adverse side effects, such as hyperalgesia and negative affect. Neuroinflammation in the brain and spinal cord is a contributing factor to the development of symptoms associated with chronic opioid use. Recent studies have described a link between neuroinflammation and behavior that is mediated by a gut-brain signaling axis, where alterations in indigenous gut bacteria contribute to several inflammation-related psychopathologies. As opioid receptors are highly expressed within the digestive tract and opioids influence gut motility, we hypothesized that systemic opioid treatment will impact the composition of the gut microbiota. Here, we explored how opioid treatments, and cessation, impacts the mouse gut microbiome and whether opioid-induced changes in the gut microbiota influences inflammation-driven hyperalgesia and impaired reward behavior. Male C57Bl6/J mice were treated with either intermittent or sustained morphine. Using 16S rDNA sequencing, we describe changes in gut microbiota composition following different morphine regimens. Manipulation of the gut microbiome was used to assess the causal relationship between the gut microbiome and opioid-dependent behaviors. Intermittent, but not sustained, morphine treatment was associated with microglial activation, hyperalgesia, and impaired reward response. Depletion of the gut microbiota via antibiotic treatment surprisingly recapitulated neuroinflammation and sequelae, including reduced opioid analgesic potency and impaired cocaine reward following intermittent morphine treatment. Colonization of antibiotic-treated mice with a control microbiota restored microglial activation state and behaviors. Our findings suggest that differing opioid regimens uniquely influence the gut microbiome that is causally related to behaviors associated with opioid dependence.

No abstract