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Examining the Role of Microbiota in Emotional Behavior: Antibiotic Treatment Exacerbates Anxiety in High Anxiety-Prone Male Rats.
Intestinal microbiota are essential for healthy gastrointestinal function and also broadly influence brain function and behavior, in part, through changes in immune function. Gastrointestinal disorders are highly comorbid with psychiatric disorders, although biological mechanisms linking these disorders are poorly understood. The present study utilized rats bred for distinct emotional behavior phenotypes to examine relationships between emotionality, the microbiome, and immune markers. Prior work showed that Low Novelty Responder (LR) rats exhibit high levels of anxiety- and depression-related behaviors as well as myriad neurobiological differences compared to High Novelty Responders (HRs). Here, we hypothesized that the divergent HR/LR phenotypes are accompanied by changes in fecal microbiome composition. We used next-generation sequencing to assess the HR/LR microbiomes and then treated adult HR/LR males with an antibiotic cocktail to test whether it altered behavior. Given known connections between the microbiome and immune system, we also analyzed circulating cytokines and metabolic factors to determine relationships between peripheral immune markers, gut microbiome components, and behavioral measures. There were no baseline HR/LR microbiome differences, and antibiotic treatment disrupted the microbiome in both HR and LR rats. Antibiotic treatment exacerbated aspects of HR/LR behavior, increasing LRs' already high levels of anxiety-like behavior while reducing passive stress coping in both strains. Our results highlight the importance of an individual's phenotype to their response to antibiotics, contributing to the understanding of the complex interplay between gut microbes, immune function, and an individual's emotional phenotype.
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Swimming Exercise Modulates Gut Microbiota in CUMS-Induced Depressed Mice.
BACKGROUND: Gut microbiota is associated with anxiety and depression, while exercise has been proved to alleviate depressive symptoms. However, the interaction of exercise, depression, and gut microbiota remains unclear. METHODS: Male C57/BL6J mice were exposed to chronic unpredictable mild stress (CUMS) for 6 weeks and then were subjected to a 5-week swimming program. Behavioral tests, including sucrose preference test (SPT), open field test (OFT), elevated plus-maze (EPM) test, and tail suspension test (TST), were conducted to assess the anxiety-like and depressive behaviors. Gut microbiota analysis was carried out after sample collection. RESULTS: This study showed that CUMS induced depressive behaviors, but swimming exercise increased sucrose preference rate in the SPT, increased time in the center and number of rearing in the OFT, decreased time in the closed arm and increased time in the open arm in EPM, and decreased immobility time in the TST. Firmicutes were the predominant phylum in the gut microbiome, followed by the phyla Bacteroidetes and Proteobacteria. We further found that CUMS and swimming influenced the relative abundance of the genus Desulfovibrio, genus Streptococcus, genus p-75-a5. Among the metabolic pathways, aromatic biogenic amine degradation (PWY-7431), mono-trans and polycis decaprenyl phosphate biosynthesis (PWY-6383), chlorosalicylate degradation (PWY-6107), mycothiol biosynthesis (PWY1G-0), mycolyl-arabinogalactan-peptidoglycan complex biosynthesis (PWY-6397), toluene degradation I (aerobic) (via o-cresol) (PWY-5180), toluene degradation II (aerobic) (via 4-methylcatechol) (PWY-5182), and starch degradation III (PWY-6731) may be related to the mechanism of anti-depression effect. CONCLUSION: Swimming exercise reverses CUMS-induced depressive behaviors, and the alteration of gut microbiota composition and regulation of microbiota metabolic pathways are involved.
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What Is the Role of Gut Microbiota in Obesity Prevalence? A Few Words about Gut Microbiota and Its Association with Obesity and Related Diseases.
Obesity is becoming the most dangerous lifestyle disease of our time, and its effects are already being observed in both developed and developing countries. The aim of this study was to investigate the impact of gut microbiota on the prevalence of obesity and associated morbidities, taking into consideration underlying molecular mechanisms. In addition to exploring the relationship between obesity and fecal microorganisms with their metabolites, the study also focused on the factors that would be able to stimulate growth and remodeling of microbiota. Assessed articles were carefully classified according to a predetermined criterion and were critically appraised and used as a basis for conclusions. The considered articles and reviews acknowledge that intestinal microbiota forms a multifunctional system that might significantly affect human homeostasis. It has been proved that alterations in the gut microbiota are found in obese and metabolically diseased patients. The imbalance of microbiome composition, such as changes in Bacteroidetes/Firmicutes ratio and presence of different species of genus Lactobacillus, might promote obesity and comorbidities (type 2 diabetes mellitus, hypertension, dyslipidemia, depression, obstructive sleep apnea). However, there are also studies that contradict this theory. Therefore, further well-designed studies are needed to improve the knowledge about the influence of microbiota, its metabolites, and probiotics on obesity.
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Specific Changes in the Mammalian Gut Microbiome as a Biomarker for Oxytocin-Induced Behavioral Changes.
Prolonged exposure to psychiatric pharmacological agents is often associated with marked gastrointestinal phenomena, including changes in food intake, bowel motility, gastric emptying, and transit time. Those changes are reflected in the gut microbiota composition of the patient and can, therefore, be objectively measured. This is in contrast to the standard psychiatric evaluation of patients, which includes symptoms that are subjectively assessed (i.e., mood, anxiety level, perception, thought disorders, etc.). The association between a drug's effect on the microbiota and psychiatric symptoms may allow for quantifiable surrogate markers of treatment effectiveness. Changes in the levels of specific drug-sensitive bacterial species can, thus, potentially serve as biomarkers for the intake and effectiveness of psychiatric drugs. Here, we show substantial microbiota changes that were associated with oxytocin administration and the decreased anxiety/depression-like behaviors it conferred in a rat model of corticosterone-induced stress. Compared with oxytocin, citalopram produced more minor effects on the rats' microbiota. Alterations in the gut microbiota may, therefore, reflect the consumption and effectiveness of some psychiatric drugs.
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Physiological and cognitive changes after treatments of cyclophosphamide, methotrexate, and fluorouracil: implications of the gut microbiome and depressive-like behavior.
INTRODUCTION: Chemotherapy-induced cognitive impairment colloquially referred to as chemobrain is a poorly understood phenomenon affecting a highly variable proportion of patients with breast cancer. Here we investigate the association between anxiety and despair-like behaviors in mice treated with cyclophosphamide, methotrexate, and fluorouracil (CMF) along with host histological, proteomic, gene expression, and gut microbial responses. METHODS: Forced swim and sociability tests were used to evaluate depression and despair-like behaviors. The tandem mass tag (TMT) proteomics approach was used to assess changes in the neural protein network of the amygdala and hippocampus. The composition of gut microbiota was assessed through 16S rRNA gene sequencing. Finally, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to evaluate changes in intestinal gap junction markers. RESULTS AND DISCUSSION: We observed that CMF induced social and despair-like behavior in mice 96 hours following treatment. Proteomic analysis identified changes in various proteins related to progressive neurological disease, working memory deficit, primary anxiety disorder, and gene expression revealing increases in NMDA and AMPA receptors in both the hippocampus and the amygdala because of CMF treatment. These changes finally, we observed immediate changes in the microbial population after chemotherapy treatment, with a notable abundance of Muribaculaceae and Romboutsia which may contribute to changes seen in the gut.
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Unveiling the rumen-microbiome-brain circuit: a unique dimension of gut-brain axis in ruminants.
Gut-brain communication via the peripheral neural network is vital for regulating local digestive function and systemic physiology. Gut microbiota, which produces a wide array of neuroactive compounds, is a critical modulator in this bidirectional dialog. Perturbations in the gut microbiota have been implicated in neurological disorders such as depression and stress. Distinct from humans and other monogastric animals, ruminants possess a unique, microbially dense gastrointestinal compartment, the rumen, that facilitates the digestion of fibrous plant materials. These ruminal microbes are likely key contributors to rumen-brain crosstalk. Unlike certain microbe-derived neuroactive compounds produced in the hindgut that are minimally absorbed and primarily excreted in feces, those generated in rumen can reach the small intestine, where they are largely absorbed and affect central nervous system through systemic regulation in addition to the vagal pathway. Notably, emerging evidence suggests that rumen microbiota dysbiosis under stress is associated with abnormal behavior, altered hormonal and neurotransmitter levels. In this review, we introduce the concept of the rumen-microbiome-brain axis by comparing the anatomical structures and microbial characteristics of the intestine and the rumen, emphasizing the neuroactive potential of rumen microbiome and underlying mechanisms. Advances in this frontier hold tremendous promise to reveal a novel dimension of the gut-microbiome-brain axis, providing transformative opportunities to improve ruminant welfare, productivity, and agricultural sustainability.
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Age-dependent effects of gut microbiota metabolites on brain resident macrophages.
In recent years, development of age-related diseases, such as Alzheimer's and Parkinson's disease, as well as other brain disorders, including anxiety, depression, and schizophrenia have been shown to be associated with changes in the gut microbiome. Several factors can induce an alteration in the bacterial composition of the host's gastrointestinal tract. Besides dietary changes and frequent use of antibiotics, the microbiome is also profoundly affected by aging. Levels of microbiota-derived metabolites are elevated in older individuals with age-associated diseases and cognitive defects compared to younger, healthy age groups. The identified metabolites with higher concentration in aged hosts, which include choline and trimethylamine, are known risk factors for age-related diseases. While the underlying mechanisms and pathways remain elusive for the most part, it has been shown, that these metabolites are able to trigger the innate immunity in the central nervous system by influencing development and activation status of brain-resident macrophages. The macrophages residing in the brain comprise parenchymal microglia and non-parenchymal macrophages located in the perivascular spaces, meninges, and the choroid plexus. In this review, we highlight the impact of age on the composition of the microbiome and microbiota-derived metabolites and their influence on age-associated diseases caused by dysfunctional brain-resident macrophages.
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The central role of microglia in major depressive disorder and its potential as a therapeutic target.
Major depressive disorder (MDD) is a complex neuropsychiatric condition whose multifactorial etiology remains incompletely explained by neuron-centric and neurotransmitter hypotheses alone. This review addresses that gap by positioning microglia-the CNS's resident immune cells-as central drivers of MDD pathogenesis. We organize current evidence around five interrelated themes: hypothalamic-pituitary-adrenal (HPA) axis dysfunction, monoaminergic and kynurenine pathway imbalances, neuroinflammatory overactivation, synaptic and white-matter integrity disruption, and gut-brain axis perturbations. In MDD, microglia shift from a surveillant resting state to either an overactivated or functionally inhibited phenotype, exacerbating pathology via aberrant cytokine release, dysregulated synaptic pruning and impaired myelin support. These changes are modulated by genetic susceptibility, sex differences, environmental stressors and microbiome alterations. We then survey translational advances-traditional and novel therapeutics that modulate microglial polarization, emerging blood- and imaging-based biomarkers, and strategies to harness microglia-oligodendrocyte cross-talk for remyelination-and highlight integrative platforms for stratifying inflammation-driven versus non-inflammatory subtypes. Our principal takeaway is that microglia represent a unifying nexus and actionable target for precision interventions tailored to individual biological profiles.
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The very low birth weight infant microbiome and childhood health.
This review describes current understandings about the nature of the very low birth weight infant (VLBW) gut microbiome. VLBW infants often experience disruptive pregnancies and births, and prenatal factors can influence the maturity of the gut and immune system, and disturb microbial balance and succession. Many VLBWs experience rapid vaginal or Caesarean births. After birth these infants often have delays in enteral feeding, and many receive little or no mother's own milk. Furthermore the stressors of neonatal life in the hospital environment, common use of antibiotics, invasive procedures and maternal separation can contribute to dysbiosis. These infants experience gastrointestinal dysfunction, sepsis, transfusions, necrotizing enterocolitis, oxygen toxicity, and other pathophysiological conditions that affect the normal microbiota. The skin is susceptible to dysbiosis, due to its fragility and contact with NICU organisms. Dysbiosis in early life may resolve but little is known about the timing of the development of the signature gut microbiome in VLBWs. Dysbiosis has been associated with a number of physical and behavioral problems, including autism spectrum disorders, allergy and asthma, gastrointestinal disease, obesity, depression, and anxiety. Dysbiosis may be prevented or ameliorated in part by prenatal care, breast milk feeding, skin to skin contact, use of antibiotics only when necessary, and vigilance during infancy and early childhood.
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A Microbiome-Driven Approach to Combating Depression During the COVID-19 Pandemic.
The significant stressors brought about and exacerbated by COVID-19 are associated with startling surges in mental health illnesses, specifically those related to depressive disorders. Given the huge impact of depression on society, and an incomplete understanding of impactful therapeutics, we have examined the current literature surrounding the microbiome and gut-brain axis to advance a potential complementary approach to address depression and depressive disorders that have increased during the COVID-19 pandemic. While we understand that the impact of the human gut microbiome on emotional health is a newly emerging field and more research needs to be conducted, the current evidence is extremely promising and suggests at least part of the answer to understanding depression in more depth may lie within the microbiome. As a result of these findings, we propose that a microbiome-based holistic approach, which involves carefully annotating the microbiome and potential modification through diet, probiotics, and lifestyle changes, may address depression. This paper's primary purpose is to shed light on the link between the gut microbiome and depression, including the gut-brain axis and propose a holistic approach to microbiome modification, with the ultimate goal of assisting individuals to manage their battle with depression through diet, probiotics, and lifestyle changes, in addition to offering a semblance of hope during these challenging times.