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Basic Definitions and Concepts: Organization of the Gut Microbiome.
New claims are frequently made for a role for the microbiome in a disease or disorder previously considered remote from the gut. The microbiome has been linked to such seemingly unrelated entities as depression, anorexia nervosa, autism, Parkinson disease, allergy, and asthma. Although many of these proposals have been based on animal studies, explorations of the microbiome in human disease continue to proliferate, facilitated by technologies that provide a detailed assessment of the microbial inhabitants of our gastrointestinal tract and their biological activities and metabolic products. With these technologies come new terminologies, which are identified in this article.
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Gut Microbiota Regulates Food Intake in a Rodent Model of Intermittent Limited Access to Palatable Food.
OBJECTIVE: Binge-eating disorder is characterized by recurrent episodes of consumption of large amounts of food within a short period of time, without compensatory purging behaviors. This disease is a major public health issue and is associated with numerous comorbidities, encompassing anxiety and depression. The gut microbiota has been proposed to be an important player in the onset or maintenance of eating disorders. Here, we aim to better delineate the potential role of the gut microbiota in binge-eating disorder. METHOD: We used a model of intermittent limited access to palatable food where eight-week-old C57Bl/6 female mice had access during 2 h, every 2 days over a 10-day period, to a high-fat/high-sucrose diet. Half of the animals received antibiotics to deplete their gut microbiota. Eating behavior and other behavioral parameters were compared between groups. RESULTS: We observed an increase in food intake as well as tachyphagia during the intermittent access to high-fat/high-sucrose diet. We demonstrate that gut microbiota depletion further increases food intake during these episodes and promotes binge-eating behavior. No impact on anxiety or depressive-like behavior was observed in animals. DISCUSSION: These results show that the gut microbiota is involved in the control of food intake during episodes of binge-eating. This strengthens the potential role of the gut bacteria in binge-eating disorder and the interest in therapeutic strategies aiming at modulating the patients' gut microbiota to treat this eating disorder.
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Viewing Psychiatric Disorders Through Viruses: Simple Architecture, Burgeoning Implications.
A growing interest in the comprehensive pathogenic mechanisms of psychiatric disorders from the perspective of the microbiome has been witnessed in recent decades; the intrinsic link between microbiota and brain function through the microbiota-gut-brain axis or other pathways has gradually been realized. However, little research has focused on viruses-entities characterized by smaller dimensions, simpler structures, greater diversity, and more intricate interactions with their surrounding milieu compared to bacteria. To date, alterations in several populations of bacteriophages and viruses have been documented in both mouse models and patients with psychiatric disorders, including schizophrenia, major depressive disorder, autism spectrum disorder, and Alzheimer's disease, accompanied by metabolic disruptions that may directly or indirectly impact brain function. In addition, eukaryotic virus infection-mediated brain dysfunction provides insights into the psychiatric pathology involving viruses. Efforts towards virus-based diagnostic and therapeutic approaches have primarily been documented. However, limitations due to the lack of large-scale cohort studies, reliability, clinical applicability, and the unclear role of viruses in microbiota interactions pose a challenge for future studies. Nevertheless, it is conceivable that investigations into viruses herald a new era in the field of precise psychiatry.
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Acyloxyacyl hydrolase is a host determinant of gut microbiome-mediated pelvic pain.
Dysbiosis of gut microbiota is associated with many pathologies, yet host factors modulating microbiota remain unclear. Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating condition of chronic pelvic pain often with comorbid urinary dysfunction and anxiety/depression, and recent studies find fecal dysbiosis in patients with IC/BPS. We identified the locus encoding acyloxyacyl hydrolase, Aoah, as a modulator of pelvic pain severity in a murine IC/BPS model. AOAH-deficient mice spontaneously develop rodent correlates of pelvic pain, increased responses to induced pelvic pain models, voiding dysfunction, and anxious/depressive behaviors. Here, we report that AOAH-deficient mice exhibit dysbiosis of gastrointestinal (GI) microbiota. AOAH-deficient mice exhibit an enlarged cecum, a phenotype long associated with germ-free rodents, and a "leaky gut" phenotype. AOAH-deficient ceca showed altered gene expression consistent with inflammation, Wnt signaling, and urologic disease. 16S sequencing of stool revealed altered microbiota in AOAH-deficient mice, and GC-MS identified altered metabolomes. Cohousing AOAH-deficient mice with wild-type mice resulted in converged microbiota and altered predicted metagenomes. Cohousing also abrogated the pelvic pain phenotype of AOAH-deficient mice, which was corroborated by oral gavage of AOAH-deficient mice with stool slurry of wild-type mice. Converged microbiota also alleviated comorbid anxiety-like behavior in AOAH-deficient mice. Oral gavage of AOAH-deficient mice with anaerobes cultured from IC/BPS stool resulted in exacerbation of pelvic allodynia. Together, these data indicate that AOAH is a host determinant of normal gut microbiota, and dysbiosis associated with AOAH deficiency contributes to pelvic pain. These findings suggest that the gut microbiome is a potential therapeutic target for IC/BPS.
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Gut Microbiota Modulation of Dementia Related Complications.
Recent advances in microbial pathogen research have highlighted the potential of gut microbe-based microbial medicine. One of the most extensively studied biological pathways is the gut-brain axis, which has been shown to reverse neurological disorders. Evidence from animal-based studies of dysbiosis suggest complex behavioral changes, such as alterations in sociability and anxiety, can be modulated through gut microbiota. Specifically, mental disorders include major depression, bipolar disorder, and schizophrenia. Gastrointestinal diseases can be reversed by modulating gut microbiota. Dementia and its related mechanisms are also amenable to modulation of the gut microbiota. This review focuses on the role of gut microbiota in dementia by discussing the effects on depressive symptoms, cognitive function, mood, behavioral changes, chronic stress, and the prospects of the microbiota-gut-brain axis for dementia. Although animal models have revealed promising approaches for treating dementia through the modulation of the gut microbiota, it may be premature to incorporate these interventions into standard clinical practice. The heterogeneity of findings from clinical trials and randomized control trials has yet to convincingly demonstrate the efficacy of modulation in reversing dementia and its related complications.
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Gut microbiome and tissue metabolomics reveal the compatibility effects of Xiaoyaosan on depression based on "gut-liver-kidney" axis.
BACKGROUND: Depression affects not only the central nervous system, but also the peripheral system. Xiaoyaosan (XYS), a classical traditional Chinese medicine (TCM) prescription, exhibits definite anti-depression effects demonstrated both clinically and experimentally. However, its compatibility has not been entirely revealed due partly to the complex compositions of herbs contained. AIM: Based on the strategy of "Efficacy Group", this study aimed to reveal the compatibility of XYS from the perspective of "gut-liver-kidney" axis. METHODS: Firstly, XYS was divided into two efficacy groups, i.e. Shugan (SG) and Jianpi (JP) groups. Classic behaviors of rats were measured to confirm the anti-depression effects of XYS and its two efficacy groups. On top of this, gut microbiota analysis and kidney metabolomics were performed by 16S rRNA sequencing and 1H NMR, respectively. RESULTS: We found that XYS and its efficacy groups significantly regulated the abnormalities of behaviors and kidney metabolism of depressed rats, as well as intestinal disorders, but to different degrees. The regulatory effects of XYS and its efficacy groups on behaviors and kidney metabolomics of depressed rats had the same order, i.e. XYS > SG > JP, while the order of regulating gut microbiota was XYS > JP > SG. Both XYS and its efficacy groups significantly ameliorated gut microbiota disturbed, especially significant modulation of Peptostreptococcaceae. XYS significantly regulated nine kidney metabolites, while SG and JP regulated four and five differential metabolites, respectively, indicating that the two efficacy groups synergistically exhibited anti-depression effects, consequently contributing to the overall anti-depression effects of XYS. CONCLUSION: The current findings not only innovatively demonstrate the anti-depression effects and compatibility of XYS from the perspective of "gut-liver-kidney" axis, comprehensively using "Efficacy Group" strategy, macro behavioristics, metabolome and microbiome, and also provide a new perspective, strategy, and methodology for studying complex diseases and the compatibility of TCMs.
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Antidepressant effects of total iridoids of Valeriana jatamansi via the intestinal flora-blood-brain barrier pathway.
CONTEXT: Valeriana jatamansi Jones [syn. V. wallichii DC, (Valerianaceae)] (VJJ) is used to treat depression. OBJECTIVE: To explore the effects of total iridoids of VJJ extract (TIV) on chronic unpredictable mild stress (CUMS) in mice. MATERIALS AND METHODS: VJJ roots and rhizomes were extracted with 70% ethanol. CUMS rats were treated daily with fluoxetine (2.6 mg/kg, i.g.) or TIV (5.7, 11.4, and 22.8 mg/kg, i.g.) for 14 days. Male Kun Ming mice on normal chow and 0.5% CMC-Na solution were used as a control. Behavioural tests included the tail suspension (TST) and sucrose preference tests (SPT). Evans blue staining was used to evaluate blood-brain barrier (BBB) permeability. Western blotting was used to measure zonula occludens-1 (ZO-1) and occludin expression. 16S rRNA sequencing was used to analyse intestinal flora abundance. Tax4Fun was used to predict KEGG metabolic pathways. RESULTS: TIV treatment reduced TST time (117.35 ± 8.23 or 108.95 ± 6.76 vs. 144.45 ± 10.30 s), increased SPT (55.83 ± 7.24 or 53.12 ± 13.85 vs. 38.98 ± 5.43%), increased the abundance of phylum Firmicutes (86.99 ± 0.03 vs. 60.88 ± 0.19%) and genus Lactobacillus (75.20 ± 0.19 vs. 62.10 ± 0.13%), reduced the abundance of phylum Bacteroidetes (6.69 ± 0.06 or 11.50 ± 0.09 vs. 25.07 ± 0.20%). TIV increased carbohydrate metabolism (14.50 ± 3.00 × 10-3 or 14.60 ± 2.00 × 10-3 or 14.90 ± 2.00 × 10-3 vs.13.80 ± 4.00 × 10-3%), replication and repair functions (5.60 ± 1.00 × 10-3 or 5.60 ± 1.00 × 10-3 vs. 5.10 ± 4.00 × 10-3%), reduced the frequency of infectious disease (1.60 ± 2.00 × 10-4 or 1.90 ± 5.00 × 10-4 or 1.80 ± 3.00 × 10-4 vs. 2.20 ± 7.00 × 10-3%), BBB permeability (0.77 ± 0.30 vs. 1.81 ± 0.33 μg/g), and up-regulated the expression of ZO-1 (1.42-fold, 1.60-fold, 1.71-fold) and occludin (1.79-fold, 2.20-fold). CONCLUSIONS: TIV may modulate the intestinal flora, thereby inducing the expression of ZO-1 and occludin, protecting the BBB and exerting an antidepressant effect.
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The gut microbiome and depression: a review.
BACKGROUND: Recent explorations into the gut microbiome of humans and animals reveal implications in chronic physical and mental health disorders. Relatively little is known regarding the relationship of gut microbiome and depression. In the current review, we reviewed existing scientific data related to the gut microbiome and healthy patients versus patients with depression. Additionally, scientific literature containing the utility of microbiome interventions to improve depression symptoms was reviewed. METHODS: A PubMed and Clinical Key literature search combined the key terms 'gut,' 'microbiome,' 'bacteria,' and 'depression' to identify studies investigating these relationships. RESULTS: 76 relevant articles were identified. Human and animal studies reviewed examined marked alterations in the dominant bacterial phyla in the gut of individuals with depression, the connection between leaky gut and neuroinflammation in depression, brain regulatory centers impacted by changes in the gut microbiome, and the benefits of the addition of a probiotic/prebiotic for gut and mental health. CONCLUSIONS: The current review confirmed the suspected direct communication between the gut microbiome, brain functioning, and depression. Additionally, studies suggest antibiotics disrupt the gut microbiome. There are important implications for psychiatrists in providing opportunities for intervention and enhancement of current treatments for individuals with depression.
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Metagenomic analysis reveals gut bacterial signatures for diagnosis and treatment outcome prediction in bipolar depression.
BACKGROUND: We aimed to characterize gut microbial alterations in depressed patients with bipolar disorder (BD) following quetiapine monotherapy and explored its potential for disease diagnosis and outcome prediction. METHODS: Fecal samples were obtained from 60 healthy individuals and 62 patients in acute depressive episodes. All patients received one-month quetiapine treatment after enrollment. The structure of gut microbiota was measured with metagenomic sequencing, and its correlation with clinical profiles and brain function as indicated by resting-state functional magnetic resonance imaging was analyzed. Random forest models based on bacterial species were constructed to distinguish patients from controls, and responders from non-responders, respectively. RESULTS: BD patients displayed specific alterations in gut microbial diversity and composition. Quetiapine treatment increased the diversity of microbial communities and changed the composition. The abundance of Clostridium bartlettii was negatively associated with age, baseline depression severity, while positively associated with spontaneous neural oscillation in the hippocampus. Tree-based classification models for (1) patients and controls and (2) responders and non-responders showed an area under the curve of 0.733 and 0.800, respectively. CONCLUSION: Our findings add new evidence to the existing literature regarding gut dysbiosis in BD and reveal the potential of microbe-based biomarkers for disease diagnosis and treatment outcome prediction.
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The multiple effects of fecal microbiota transplantation on diarrhea-predominant irritable bowel syndrome (IBS-D) patients with anxiety and depression behaviors.
BACKGROUND: Anxiety and depression are complications in Irritable bowel syndrome (IBS) patients. In this study, we recruited 18 IBS patients with mild-modest anxiety and depression behaviors, and after the screening, we defined the FMT treatment group (n = 9) and the control group (n = 9). The IBS symptom severity scale (IBS-SSS), Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HAM-D), Irritable Bowel Syndrome Quality of Life (IBS-QOL) and Bristol stool scale (BSS) were evaluated one week before FMT (baseline), one-week-, one-month-, two-month-, and three-month-following FMT. Meanwhile, we determined the SCFAs in the patient's feces and serum and continued the metagenomic analysis of the microorganisms in the patient's feces. RESULTS: The results showed that the patient's anxiety and depression behavior gradually improved with FMT treatment. Moreover, the illness and quality of life had also been relieved significantly. The content of isovaleric acid and valeric acid was significantly reduced in the FMT group compared to the Col group. Metagenomic analysis showed that FMT treatment decreased the abundance of Faecalibacterium, Eubacterium and Escherichia. From KEGG functional analysis, we confirmed that the top five abundant pathways were "bacterial chemotaxis, "flagellar assembly", "glycine, serine and threonine metabolism", "apoptosis", and "bacterial invasion of epithelial cells". CONCLUSIONS: FMT treatment can effectively alleviate the anxiety and depression behaviors of IBS-D patients and reduce the IBS-SSS score, indicating that FMT can improve patients' symptoms. The high throughput sequencing results show that Bifidobacterium and Escherichia play the most critical role in the formation and recovery of IBS-D patients. The GC/MS data indicated that faeces isovaleric acid and valeric acid might be more suitable as a metabolic indicator of IBS-D remission. Trial registration ChiCTR, ChiCTR1900024924, Registered 3 August 2019, https://www.chictr.org.cn/showproj.aspx?proj=41676 .