Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice.

Autism spectrum disorder (ASD) manifests as alterations in complex human behaviors including social communication and stereotypies. In addition to genetic risks, the gut microbiome differs between typically developing (TD) and ASD individuals, though it remains unclear whether the microbiome contributes to symptoms. We transplanted gut microbiota from human donors with ASD or TD controls into germ-free mice and reveal that colonization with ASD microbiota is sufficient to induce hallmark autistic behaviors. The brains of mice colonized with ASD microbiota display alternative splicing of ASD-relevant genes. Microbiome and metabolome profiles of mice harboring human microbiota predict that specific bacterial taxa and their metabolites modulate ASD behaviors. Indeed, treatment of an ASD mouse model with candidate microbial metabolites improves behavioral abnormalities and modulates neuronal excitability in the brain. We propose that the gut microbiota regulates behaviors in mice via production of neuroactive metabolites, suggesting that gut-brain connections contribute to the pathophysiology of ASD.

The Central Nervous System and the Gut Microbiome.

Neurodevelopment is a complex process governed by both intrinsic and extrinsic signals. While historically studied by researching the brain, inputs from the periphery impact many neurological conditions. Indeed, emerging data suggest communication between the gut and the brain in anxiety, depression, cognition, and autism spectrum disorder (ASD). The development of a healthy, functional brain depends on key pre- and post-natal events that integrate environmental cues, such as molecular signals from the gut. These cues largely originate from the microbiome, the consortium of symbiotic bacteria that reside within all animals. Research over the past few years reveals that the gut microbiome plays a role in basic neurogenerative processes such as the formation of the blood-brain barrier, myelination, neurogenesis, and microglia maturation and also modulates many aspects of animal behavior. Herein, we discuss the biological intersection of neurodevelopment and the microbiome and explore the hypothesis that gut bacteria are integral contributors to development and function of the nervous system and to the balance between mental 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.

Microbiota regulate social behaviour via stress response neurons in the brain.

Social interactions among animals mediate essential behaviours, including mating, nurturing, and defence1,2. The gut microbiota contribute to social activity in mice3,4, but the gut-brain connections that regulate this complex behaviour and its underlying neural basis are unclear5,6. Here we show that the microbiome modulates neuronal activity in specific brain regions of male mice to regulate canonical stress responses and social behaviours. Social deviation in germ-free and antibiotic-treated mice is associated with elevated levels of the stress hormone corticosterone, which is primarily produced by activation of the hypothalamus-pituitary-adrenal (HPA) axis. Adrenalectomy, antagonism of glucocorticoid receptors, or pharmacological inhibition of corticosterone synthesis effectively corrects social deficits following microbiome depletion. Genetic ablation of glucocorticoid receptors in specific brain regions or chemogenetic inactivation of neurons in the paraventricular nucleus of the hypothalamus that produce corticotrophin-releasing hormone (CRH) reverse social impairments in antibiotic-treated mice. Conversely, specific activation of CRH-expressing neurons in the paraventricular nucleus induces social deficits in mice with a normal microbiome. Via microbiome profiling and in vivo selection, we identify a bacterial species, Enterococcus faecalis, that promotes social activity and reduces corticosterone levels in mice following social stress. These studies suggest that specific gut bacteria can restrain the activation of the HPA axis, and show that the microbiome can affect social behaviours through discrete neuronal circuits that mediate stress responses in the brain.

Integrated Multi-Cohort Analysis of the Parkinson's Disease Gut Metagenome.

BACKGROUND: The gut microbiome is altered in several neurologic disorders, including Parkinson's disease (PD). OBJECTIVES: The aim is to profile the fecal gut metagenome in PD for alterations in microbial composition, taxon abundance, metabolic pathways, and microbial gene products, and their relationship with disease progression. METHODS: Shotgun metagenomic sequencing was conducted on 244 stool donors from two independent cohorts in the United States, including individuals with PD (n = 48, n = 47, respectively), environmental household controls (HC, n = 29, n = 30), and community population controls (PC, n = 41, n = 49). Microbial features consistently altered in PD compared to HC and PC subjects were identified. Data were cross-referenced to public metagenomic data sets from two previous studies in Germany and China to determine generalizable microbiome features. RESULTS: We find several significantly altered taxa between PD and controls within the two cohorts sequenced in this study. Analysis across global cohorts returns consistent changes only in Intestinimonas butyriciproducens. Pathway enrichment analysis reveals disruptions in microbial carbohydrate and lipid metabolism and increased amino acid and nucleotide metabolism in PD. Global gene-level signatures indicate an increased response to oxidative stress, decreased cellular growth and microbial motility, and disrupted intercommunity signaling. CONCLUSIONS: A metagenomic meta-analysis of PD shows consistent and novel alterations in functional metabolic potential and microbial gene abundance across four independent studies from three continents. These data reveal that stereotypic changes in the functional potential of the gut microbiome are a consistent feature of PD, highlighting potential diagnostic and therapeutic avenues for future research. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Peripheral neuronal activation shapes the microbiome and alters gut physiology.

The gastrointestinal (GI) tract is innervated by intrinsic neurons of the enteric nervous system (ENS) and extrinsic neurons of the central nervous system and peripheral ganglia. The GI tract also harbors a diverse microbiome, but interactions between the ENS and the microbiome remain poorly understood. Here, we activate choline acetyltransferase (ChAT)-expressing or tyrosine hydroxylase (TH)-expressing gut-associated neurons in mice to determine effects on intestinal microbial communities and their metabolites as well as on host physiology. The resulting multi-omics datasets support broad roles for discrete peripheral neuronal subtypes in shaping microbiome structure, including modulating bile acid profiles and fungal colonization. Physiologically, activation of either ChAT+ or TH+ neurons increases fecal output, while only ChAT+ activation results in increased colonic contractility and diarrhea-like fluid secretion. These findings suggest that specific subsets of peripherally activated neurons differentially regulate the gut microbiome and GI physiology in mice without involvement of signals from the brain.

Commensal bacteria play a role in mating preference of Drosophila melanogaster.

Development of mating preference is considered to be an early event in speciation. In this study, mating preference was achieved by dividing a population of Drosophila melanogaster and rearing one part on a molasses medium and the other on a starch medium. When the isolated populations were mixed, "molasses flies" preferred to mate with other molasses flies and "starch flies" preferred to mate with other starch flies. The mating preference appeared after only one generation and was maintained for at least 37 generations. Antibiotic treatment abolished mating preference, suggesting that the fly microbiota was responsible for the phenomenon. This was confirmed by infection experiments with microbiota obtained from the fly media (before antibiotic treatment) as well as with a mixed culture of Lactobacillus species and a pure culture of Lactobacillus plantarum isolated from starch flies. Analytical data suggest that symbiotic bacteria can influence mating preference by changing the levels of cuticular hydrocarbon sex pheromones. The results are discussed within the framework of the hologenome theory of evolution.

True, justified, belief? Partisanship weakens the positive effect of news media literacy on fake news detection.

To investigate how people assess whether politically consistent news is real or fake, two studies (N = 1,008; N = 1,397) with adult American participants conducted in 2020 and 2022 utilized a within-subjects experimental design to investigate perceptions of news accuracy. When a mock Facebook post with either fake (Study 1) or real (Study 2) news content was attributed to an alternative (vs. a mainstream) news outlet, it was, on average, perceived to be less accurate. Those with beliefs reflecting News Media Literacy demonstrated greater sensitivity to the outlet's status. This relationship was itself contingent on the strength of the participant's partisan identity. Strong partisans high in News Media Literacy defended the accuracy of politically consistent content, even while recognizing that an outlet was unfamiliar. These results highlight the fundamental importance of looking at the interaction between user-traits and features of social media news posts when examining learning from political news on social media.

The hologenome theory of evolution contains Lamarckian aspects within a Darwinian framework.

The hologenome theory of evolution emphasizes the role of microorganisms in the evolution of animals and plants. The theory posits that the holobiont (host plus all of its symbiont microbiota) is a unit of selection in evolution. Genetic variation in the holobiont that can occur either in the host and/or in the microbial symbiont genomes (together termed hologenome) can then be transmitted to offspring. In addition to the known modes of variation, i.e. sexual recombination, chromosomal rearrangement and mutation, variation in the holobiont can occur also via two mechanisms that are specific to the hologenome theory: amplification of existing microorganisms and acquisition of novel strains from the environment. These mechanisms are Lamarckian in that (i) they are regulated by 'use and disuse' (of microbes) and (ii) the variations in the hologenome are transmitted to offspring, thus satisfying also the Lamarckian principle of 'inheritance of acquired characteristics'. Accordingly, the hologenome theory incorporates Lamarckian aspects within a Darwinian framework, accentuating both cooperation and competition within the holobiont and with other holobionts.

The Microbiome Activates CD4 T-cell-mediated Immunity to Compensate for Increased Intestinal Permeability.

BACKGROUND & AIMS: Despite a prominent association, chronic intestinal barrier loss is insufficient to induce disease in human subjects or experimental animals. We hypothesized that compensatory mucosal immune activation might protect individuals with increased intestinal permeability from disease. We used a model in which intestinal barrier loss is triggered by intestinal epithelial-specific expression of constitutively active myosin light chain kinase (CA-MLCK). Here we asked whether constitutive tight junction barrier loss impacts susceptibility to enteric pathogens. METHODS: Acute or chronic Toxoplasma gondii or Salmonella typhimurium infection was assessed in CA-MLCK transgenic or wild-type mice. Germ-free mice or those lacking specific immune cell populations were used to investigate the effect of microbial-activated immunity on pathogen translocation in the context of increased intestinal permeability. RESULTS: Acute T gondii and S typhimurium translocation across the epithelial barrier was reduced in CA-MLCK mice. This protection was due to enhanced mucosal immune activation that required CD4+ T cells and interleukin 17A but not immunoglobulin A. The protective mucosal immune activation in CA-MLCK mice depended on segmented filamentous bacteria (SFB), because protection against early S typhimurium invasion was lost in germ-free CA-MLCK mice but could be restored by conventionalization with SFB-containing, not SFB-deficient, microbiota. In contrast, chronic S typhimurium infection was more severe in CA-MLCK mice, suggesting that despite activation of protective mucosal immunity, barrier defects ultimately result in enhanced disease progression. CONCLUSIONS: Increased epithelial tight junction permeability synergizes with commensal bacteria to promote intestinal CD4+ T-cell expansion and interleukin 17A production that limits enteric pathogen invasion.

Specialized metabolites from the microbiome in health and disease.

The microbiota, and the genes that comprise its microbiome, play key roles in human health. Host-microbe interactions affect immunity, metabolism, development, and behavior, and dysbiosis of gut bacteria contributes to disease. Despite advances in correlating changes in the microbiota with various conditions, specific mechanisms of host-microbiota signaling remain largely elusive. We discuss the synthesis of microbial metabolites, their absorption, and potential physiological effects on the host. We propose that the effects of specialized metabolites may explain present knowledge gaps in linking the gut microbiota to biological host mechanisms during initial colonization, and in health and disease.

Bacteria-induced sexual isolation in Drosophila.

Commensal bacteria can induce sexual isolation between populations of Drosophila. This phenomenon has implications for speciation, and raises questions about its behavioral and developmental mechanisms, which are not yet known. In this Extra View, we discuss related work by others, bearing directly on these issues, and we speculate about how bacteria might influence fly behavior. There are many reports of interaction between Drosophila and their microbiota that significantly impacts mating preferences. Sexual isolation can be enhanced or reduced by altering the culture media, or the microbiota inhabiting those media. More dramatically, the endoparasite Wolbachia has induced strong mate preferences in some instances. While a sudden, ecologically induced shift in mating preferences falls far short of the changes required for speciation, it might be a first step in that direction. We hypothesize that bacteria-induced sexual isolation is caused by chemosensory cues. In our experiments, bacteria altered the profile of cuticular hydrocarbons, which function as sex pheromones. Commensal bacteria may act directly on these hydrocarbons, or they may affect their synthesis. Alternatively, bacterial metabolites might perfume the flies in ways that affect mate choice. In that event, habituation or conditioning likely plays a role.

Symbiotic bacteria are responsible for diet-induced mating preference in Drosophila melanogaster, providing support for the hologenome concept of evolution.

Diet-induced mating preference in Drosophila melanogaster results from amplification of the commensal bacterium Lactobacillus plantarum, providing a new role for gut microbiota and support for the hologenome concept of evolution. When the flies were treated with antibiotics prior to changing their diet, mating preference did not occur. These data also indicate that other potentially beneficial bacteria could be irreversibly lost by antibiotic treatment and that their replacement could provide a health benefit. We suggest that D. melanogaster can be a useful model organism to study the activities of gut microbiota and their interaction with the immune system.

Healthy corals maintain Vibrio in the VBNC state.

Vibrio species play an important role in the health and disease of corals. To gain a better understanding of the interactions between Vibrio and coral holobionts we examined the growth of Vibrio in the mucus of the coral Oculina patagonica while the mucus was attached and detached from the coral. Fresh mucus contained ca. 10(2) Vibrio cfu ml(-1) , representing c. 1% of the total viable count. Incubation of detached mucus resulted in a 50 000-fold increase in Vibrio cfu from 1 to 4 h, corresponding to 60% of the total viable counts. This large increase in Vibrio would require an unreasonable doubling time of 11 min. Furthermore, the total microscopic bacterial count increased only 17-fold during the 1-4 h incubation period. These data led to the conclusion that Vibrio species in the mucus were largely in the VBNC state when attached to the coral and 'resuscitated' when the mucus was detached from the coral. We suggest that the coral signal for maintaining Vibrio in the VBNC state is diffusible and unstable. Maintenance of Vibrio in the VBNC state did not require photosynthetic products of the coral holobiont. Vibrio species in the VBNC state may contribute to the health of corals by preventing infections by pathogens.

The evolution of animals and plants via symbiosis with microorganisms.

Animals and plants evolved from prokaryotes and have remained in close association with them. We suggest that early eukaryotic cells, formed by the fusion of two or more prokaryotes, already contained prokaryotic genetic information for aggregation and the formation of multicellular structures. The hologenome theory of evolution posits that a unit of selection in evolution is the holobiont (host plus symbionts). The hologenome is defined as the genetic information of the host and its microbiota, which function in consortium. Genetic variation of the holobiont, the raw material for evolution, can arise from changes in either the host or the symbiotic microbiota genomes. Changes in the hologenome can occur by two processes that are specific to holobionts: microbial amplification and acquisition of novel strains from the environment. Recent data from culture-independent studies provides considerable support of the hologenome theory: (i) all animals and plants contain abundant and diverse microbiota, (ii) the symbiotic microbiota affects the fitness of their host and (iii) symbiotic microorganisms are transmitted from parent to offspring. Consideration of the dynamic aspects of symbioses of hosts with their diverse microbiota leads to the conclusion that holobionts can evolve not only via Darwinian but also by adaptive Lamarckian principles.

The phage-driven microbial loop in petroleum bioremediation.

During the drilling process and transport of crude oil, water mixes with the petroleum. At oil terminals, the water settles to the bottom of storage tanks. This drainage water is contaminated with emulsified oil and water-soluble hydrocarbons and must be treated before it can be released into the environment. In this study, we tested the efficiency of a continuous flow, two-stage bioreactor for treating drainage water from an Israeli oil terminal. The bioreactor removed all of the ammonia, 93% of the sulfide and converted 90% of the total organic carbon (TOC) into carbon dioxide. SYBR Gold staining indicated that reactor 1 contained 1.7 × 10(8) bacteria and 3.7 × 10(8) phages per millilitre, and reactor 2 contained 1.3 × 10(8) bacteria and 1.7 × 10(9) phages per millilitre. The unexpectedly high mineralization of TOC and high concentration of phage in reactor 2 support the concept of a phage-driven microbial loop in the bioremediation of the drainage water. In general, application of this concept in bioremediation of contaminated water has the potential to increase the efficiency of processes.

Bacterial growth on coral mucus.

Coral mucus-degrading bacteria were isolated by an enrichment culture procedure. The isolates were able to grow as pure cultures on 10% sterilized mucus in seawater, yielding 10(8) CFU/ml. The isolates, mostly Vibrio strains, were classified by classical and molecular methods. When carbon, nitrogen, and phosphorus compounds were added separately to the mucus medium, there was no increase in CFUs; however, when they were added together, there was a large increase in cell yield. The indigenous bacterial population of coral mucus increased from 10(3) to 10(8) CFU/ml when incubated at 30 degrees C for 11 h, changing from a heterogeneous community to a Vibrio-dominated population. Factors which regulate the abundance and diversity of coral mucus bacteria are discussed.

Stop codons affect 5' splice site selection by surveillance of splicing.

Pre-mRNA splicing involves recognition of a consensus sequence at the 5' splice site (SS). However, only some of the many potential sites that conform to the consensus are true ones, whereas the majority remain silent and are not normally used for splicing. We noticed that in most cases the utilization of such a latent intronic 5' SS for splicing would introduce an in-frame stop codon into the resultant mRNA. This finding suggested a link between SS selection and maintenance of an ORF within the mRNA. Here we tested this idea by analyzing the splicing of pre-mRNAs in which in-frame stop codons upstream of a latent 5' SS were mutated. We found that splicing with the latent site is indeed activated by such mutations. Our findings predict the existence of a checking mechanism, as a component of the nuclear pre-mRNA splicing machine, to ensure the maintenance of an ORF. This notion is highly important for accurate gene expression, as perturbations that would lead to splicing at these latent sites are expected to introduce in-frame stop codons into the majority of mRNAs.