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Gut microbiota modulate neurobehavior through changes in brain insulin sensitivity and metabolism.
Obesity and diabetes in humans are associated with increased rates of anxiety and depression. To understand the role of the gut microbiome and brain insulin resistance in these disorders, we evaluated behaviors and insulin action in brain of mice with diet-induced obesity (DIO) with and without antibiotic treatment. We find that DIO mice have behaviors reflective of increased anxiety and depression. This is associated with decreased insulin signaling and increased inflammation in in the nucleus accumbens and amygdala. Treatment with oral metronidazole or vancomycin decreases inflammation, improves insulin signaling in the brain and reduces signs of anxiety and depression. These effects are associated with changes in the levels of tryptophan, GABA, BDNF, amino acids, and multiple acylcarnitines, and are transferable to germ-free mice by fecal transplant. Thus, changes in gut microbiota can control brain insulin signaling and metabolite levels, and this leads to altered neurobehaviors.
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The gut microbiome and inflammation in obsessive-compulsive disorder patients compared to age- and sex-matched controls: a pilot study.
OBJECTIVE: To compare the gut microbiome profile (by way of taxon analysis and indices of β- and α-diversity) and inflammatory markers (C-reactive protein [CRP], interleukin-6[IL-6] and tumour necrosis factor-α [TNF-α]) of obsessive-compulsive disorder (OCD) outpatients and non-psychiatric community controls. METHODS: We collected morning stool and blood samples from 21 non-depressed, medication-free OCD patients and 22 age- and sex-matched non-psychiatric community controls. Microbiota analysis was performed using Illumina sequencing of the V3 region of 16S rRNA; serum CRP samples were analysed using immunoturbidimetry and plasma IL-6/TNF-α were examined by high-sensitivity ELISA. Multiple comparisons were corrected for using the false discovery rate (α = 0.05). RESULTS: Compared to controls, the OCD group presented lower species richness/evenness (α-diversity, Inverse Simpson) and lower relative abundance of three butyrate producing genera (Oscillospira, Odoribacter and Anaerostipes). Compared to controls, mean CRP, but not IL-6 and TNF-α, was elevated OCD patients. CRP revealed moderate to strong associations with psychiatric symptomatology. CONCLUSION: To our knowledge, this is the first investigation of the gut microbiome in OCD. In addition, our findings lend further support for the potential association of inflammation and OCD. These results suggest the gut microbiome may be a potential pathway of interest for future OCD research.
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Effects of microbiota transplantation and the role of the vagus nerve in gut-brain axis in animals subjected to chronic mild stress.
INTRODUCTION: Currently, there is a growing emphasis on the study of intestinal signaling as an influencer in the pathophysiology of neuropsychiatric diseases, and the gut-brain axis is recognized as a communication route through endocrine, immune, and neural pathways (vagus nerve). Studies have shown that diets that modify the microbiota can reduce stress-related behavior and hypothalamic-pituitary-adrenal axis activation. Investigators have used fecal microbiota transplantation (FMT) approaches to demonstrate that stress-related microbiota composition plays a causal role in behavioral changes. AIM: We hypothesized that FMT may present immunomodulatory, biochemical, endocrine, cognitive, and behavioral benefits in stress situations and that these changes can be mediated via the vagus nerve. METHODS: Animals were subjected to a chronic mild stress (CMS) protocol. In one experiment, animals were divided into five groups: control, control + FMT, control + FMT + CMS, CMS + saline, and CMS + FMT. The animals received FMT, and behavioral tests were performed; cytokine and carbonyl levels were measured. In a second experiment, animals were submitted to vagotomy and divided into two groups: CMS + FMT and CMS + vagotomy + FMT. RESULTS: Animals submitted to the CMS protocol or that received FMT from stressed animals showed behavioral changes and changes in neuroactive substances (increased IL-6 and TNF-α levels and carbonyl proteins). The FMT of healthy donors improved the analyzed parameters. In addition, vagotomy influenced beneficial FMT results, confirmed by behavioral testing and protein carbonyl in the hippocampus. CONCLUSION: Manipulation of the microbiota reversed the behavioral and biochemical changes induced by the CMS protocol, and the vagus nerve influenced the gut-brain axis response.
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Therapeutically targeting the consequences of HIV-1-associated gastrointestinal dysbiosis: Implications for neurocognitive and affective alterations.
Approximately 50 % of the individuals living with human immunodeficiency virus type 1 (HIV-1) are plagued by debilitating neurocognitive impairments (NCI) and/or affective alterations. Sizeable alterations in the composition of the gut microbiome, or gastrointestinal dysbiosis, may underlie, at least in part, the NCI, apathy, and/or depression observed in this population. Herein, two interrelated aims will be critically addressed, including: 1) the evidence for, and functional implications of, gastrointestinal microbiome dysbiosis in HIV-1 seropositive individuals; and 2) the potential for therapeutically targeting the consequences of this dysbiosis for the treatment of HIV-1-associated NCI and affective alterations. First, gastrointestinal microbiome dysbiosis in HIV-1 seropositive individuals is characterized by decreased alpha (α) diversity, a decreased relative abundance of bacterial species belonging to the Bacteroidetes phylum, and geographic-specific alterations in Bacillota (formerly Firmicutes) spp. Fundamentally, changes in the relative abundance of Bacteroidetes and Bacillota spp. may underlie, at least in part, the deficits in γ-aminobutyric acid and serotonin neurotransmission, as well as prominent synaptodendritic dysfunction, observed in this population. Second, there is compelling evidence for the therapeutic utility of targeting synaptodendritic dysfunction as a method to enhance neurocognitive function and improve motivational dysregulation in HIV-1. Further research is needed to determine whether the therapeutics enhancing synaptic efficacy exert their effects by altering the gut microbiome. Taken together, understanding gastrointestinal microbiome dysbiosis resulting from chronic HIV-1 viral protein exposure may afford insight into the mechanisms underlying HIV-1-associated neurocognitive and/or affective alterations; mechanisms which can be subsequently targeted via novel therapeutics.
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Post-stress changes in the gut microbiome composition in rats with different levels of nervous system excitability.
The gut-brain axis is a critical communication system influencing the interactions between the gastrointestinal tract (GI) and the central nervous system (CNS). The gut microbiota plays a significant role in this axis, affecting the development and function of the nervous system. Stress-induced psychopathologies, such as depression and anxiety, have been linked to the gut microbiota, but underlying mechanisms and genetic susceptibility remain unclear. In this study, we examined stress-induced changes in the gut microbiome composition in two rat strains with different levels of nervous system excitability: high threshold (HT strain) and low threshold (LT strain). Rats were exposed to long-term emotional and painful stress using the Hecht protocol, and fecal samples were collected at multiple time points before and after stress exposure. Using 16S rRNA amplicon sequencing, we assessed the qualitative and quantitative changes in the gut microbiota. Our results revealed distinct microbial diversity between the two rat strains, with the HT strain displaying higher diversity compared to the LT strain. Notably, under prolonged stress, the HT strain showed an increase in relative abundance of microorganisms from the genera Faecalibacterium and Prevotella in fecal samples. Additionally, both strains exhibited a decrease in Lactobacillus abundance following stress exposure. Our findings provide valuable insights into the impact of hereditary nervous system excitability on the gut microbiome composition under stress conditions. Understanding the gut-brain interactions in response to stress may open new avenues for comprehending stress-related psychopathologies and developing potential therapeutic interventions targeted at the gut microbiota. However, further research is needed to elucidate the exact mechanisms underlying these changes and their implications for stress-induced disorders. Overall, this study contributes to the growing body of knowledge on the gut-brain axis and its significance in stress-related neurobiology.
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Microbiome-driven alterations in tryptophan metabolism contribute to behavioral comorbidities in the Muc2 knockout mouse model of chronic colitis.
Globally, the incidence of inflammatory bowel disease (IBD) is projected to reach 0.5% of the population by 2030, with increasing recognition of neurobehavioral comorbidities, including anxiety, depression, and cognitive dysfunction. The mechanisms underlying these comorbidities remain unclear but may involve interacting pathways, including microbial dysbiosis, inflammation and imbalanced neurometabolite production. Here, we investigated whether microbiome-associated alterations in neurometabolites are correlated with behavioral changes in a chronic colitis model. Specific pathogen-free (SPF) and germ-free (GF) mucin 2 knockout mice (Muc2-/-) alongside mucin 2 expressing mice (Muc2+/+) were evaluated for behavioral patterns of anxiety, depressive-like patterns and memory dysfunction. Tryptophan and metabolite concentrations were measured in the colon, serum and brain. Blood-brain barrier integrity and neuroimmune activation were assessed through tight-junction protein claudin-5 expression, glial fibrillary acid protein (GFAP) and ionized calcium-binding adaptor molecule 1 (IBA-1) protein expression. Microbiome composition was characterized in relation to the tryptophan utilization pathways. To assess causality, early-life nutrient supplementation was used to address potential metabolite depletion. Female Muc2-/- displayed reduced anxiety-like behavior, while males displayed memory dysfunction. These changes coincided with decreased intestinal tryptophan, kynurenine, and serotonin within the gastrointestinal tract. GF Muc2-/- mice displayed normalized intestinal metabolite levels without concurrent brain metabolite changes. Notably, behavioral phenotypes were lost in GF Muc2-/- mice, revealing a key role for the microbiome played in these comorbidities. Muc2-/- exhibited reduced claudin-5, suggesting impaired blood‒brain barrier integrity. Microbiome analysis revealed a shift towards indole production and NAD+ salvage pathways with reduced abundance of Anaerotruncus, Enterocloster and Intestinimonas. Although early-life nutrient supplementation partially restored colonic tryptophan, it failed to fully rescue behavioral outcomes. Collectively, these findings demonstrate that chronic colitis is associated with microbiome-mediated disruption of host tryptophan metabolism, which correlates with neurobehavioral dysfunction. Targeting microbiome-driven metabolic alterations may represent a therapeutic strategy for both intestinal and neurobehavioral manifestations of IBD.
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Lycopene Alleviates DSS-Induced Colitis and Behavioral Disorders via Mediating Microbes-Gut-Brain Axis Balance.
Gut microbes play significant roles in colitis development. The current study was aimed to uncover the preventive effects of lycopene (LYC), a functional carotenoid component, on colitis and the accompanied behavior disorders. The current study demonstrated that LYC treatment (50 mg/kg body weight/day) for 40 days prevented the dextran sulfate sodium (DSS)-induced gut barrier damages and inflammatory responses in male mice. LYC improved DSS-induced depression and anxiety-like behavioral disorders by suppressing neuroinflammation and prevented synaptic ultrastructure damages by upregulating the expressions of neurotrophic factor and postsynaptic-density protein. Moreover, LYC reshaped the gut microbiome in colitis mice by decreasing the relative abundance of proteobacteria and increasing the relative abundance of Bifidobacterium and Lactobacillus. LYC also elevated the generation of short-chain fatty acids and inhibited the permeability of lipopolysaccharide in colitis mice. In conclusion, LYC ameliorate DSS-induced colitis and behavioral disorders via mediating microbes-gut-brain axis balance.
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Bidirectional relations between the maternal and infant gut microbiome and behavior.
BACKGROUND: An infant's mother is one of the first sources of neonatal microbial colonization, and infant-maternal dyad microbial variations have been linked to childhood behavioral traits and mental health outcomes. However, how the gut microbiome influences mental health, including potential bidirectional relations between mother and child, remains poorly understood. METHOD: Using metagenomic sequencing and behavioral questionnaires, we examined within-person and between-person (mother-infant dyad) associations between the gut microbiota and behavior across the first year of postnatal life (N = 121 dyads; N = 514 stool samples). RESULTS: There were rapid changes in taxa diversity and gut microbiota composition for infants, whereas the maternal microbiome remains relatively constant. Gut microbes and functional terms (e.g., antibiotic resistance genes and virulence factors) were associated with infant temperament but not maternal depression symptoms. Whereas maternal depression was not associated with any maternal taxa or functional terms. CONCLUSIONS: Our findings provide evidence for complex within- and between-person relations between maternal and infant gut microbiomes and behavioral traits. IMPACT: How the gut microbiome influences maternal mental health and infant behavior remains poorly understood. We measured mothers' and infants' gut microbiota composition and behavior across the first year of the infant's life. Individual taxa from the infant, but not the maternal, gut were associated with infant behavioral temperament. Our findings provide evidence for complex bidirectional gut-behavior associations between mothers and infants.
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The gut microbiome in social anxiety disorder: evidence of altered composition and function.
The microbiome-gut-brain axis plays a role in anxiety, the stress response and social development, and is of growing interest in neuropsychiatric conditions. The gut microbiota shows compositional alterations in a variety of psychiatric disorders including depression, generalised anxiety disorder (GAD), autism spectrum disorder (ASD) and schizophrenia but studies investigating the gut microbiome in social anxiety disorder (SAD) are very limited. Using whole-genome shotgun analysis of 49 faecal samples (31 cases and 18 sex- and age-matched controls), we analysed compositional and functional differences in the gut microbiome of patients with SAD in comparison to healthy controls. Overall microbiota composition, as measured by beta-diversity, was found to be different between the SAD and control groups and several taxonomic differences were seen at a genus- and species-level. The relative abundance of the genera Anaeromassillibacillus and Gordonibacter were elevated in SAD, while Parasuterella was enriched in healthy controls. At a species-level, Anaeromassilibacillus sp An250 was found to be more abundant in SAD patients while Parasutterella excrementihominis was higher in controls. No differences were seen in alpha diversity. In relation to functional differences, the gut metabolic module 'aspartate degradation I' was elevated in SAD patients. In conclusion, the gut microbiome of patients with SAD differs in composition and function to that of healthy controls. Larger, longitudinal studies are warranted to validate these preliminary results and explore the clinical implications of these microbiome changes.
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Microbiome influences on neuro-immune interactions in neurodegenerative disease.
Mounting evidence points to a role for the gut microbiome in a wide range of central nervous system diseases and disorders including depression, multiple sclerosis, Alzheimer's disease, Parkinson's disease, and autism spectrum disorder. Moreover, immune system involvement has also been implicated in these diseases, specifically with inflammation being central to their pathogenesis. In addition to the reported changes in gut microbiome composition and altered immune states in many neurological diseases, how the microbiome and the immune system interact to influence disease onset and progression has recently garnered much attention. This chapter provides a review of the literature related to gut microbiome influences on neuro-immune interactions with a particular focus on neurological diseases. Gut microbiome-derived mediators, including short-chain fatty acids and other metabolites, lipopolysaccharide, and neurotransmitters, and their impact on neuro-immune interactions as well as routes by which these interactions may occur are also discussed.