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Evaluating the efficacy and mechanisms of a ketogenic diet as adjunctive treatment for people with treatment-resistant depression: A protocol for a randomised controlled trial.
BACKGROUND: One-third of people with depression do not respond to antidepressants, and, after two adequate courses of antidepressants, are classified as having treatment-resistant depression (TRD). Some case reports suggest that ketogenic diets (KDs) may improve some mental illnesses, and preclinical data indicate that KDs can influence brain reward signalling, anhedonia, cortisol, and gut microbiome which are associated with depression. To date, no trials have examined the clinical effect of a KD on TRD. METHODS: This is a proof-of-concept randomised controlled trial to investigate the efficacy of a six-week programme of weekly dietitian counselling plus provision of KD meals, compared with an intervention involving similar dietetic contact time and promoting a healthy diet with increased vegetable consumption and reduction in saturated fat, plus food vouchers to purchase healthier items. At 12 weeks we will assess whether participants have continued to follow the assigned diet. The primary outcome is the difference between groups in the change in Patient Health Questionnaire-9 (PHQ-9) score from baseline to 6 weeks. PHQ-9 will be measured at weeks 2, 4, 6 and 12. The secondary outcomes are the differences between groups in the change in remission of depression, change in anxiety score, functioning ability, quality of life, cognitive performance, reward sensitivity, and anhedonia from baseline to 6 and 12 weeks. We will also assess whether changes in reward sensitivity, anhedonia, cortisol awakening response and gut microbiome may explain any changes in depression severity. DISCUSSION: This study will test whether a ketogenic diet is an effective intervention to reduce the severity of depression, anxiety and improve quality of life and functioning ability for people with treatment-resistant depression.
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Fulfilled Mind, Healthy Gut? Relationships of Eudaimonic Psychological Well-Being With the Gut Microbiome in Postmenopausal Women.
OBJECTIVE: Eudaimonic facets of psychological well-being (PWB), like purpose in life and sense of mastery, are associated with healthy aging. Variation in the gut microbiome may be one pathway by which mental health influences age-related health outcomes. However, associations between eudaimonic PWB and the gut microbiome are understudied. We examined whether purpose in life and sense of mastery, separately, were associated with features of the gut microbiome in older women. METHODS: Participants were from the Mind-Body Study ( N = 206, mean age = 61 years), a substudy of the Nurses' Health Study II cohort. In 2013, participants completed the Life Engagement Test and the Pearlin Mastery Scale. Three months later, up to two pairs of stool samples were collected, 6 months apart. Covariates included sociodemographics, depression, health status, and health behaviors. Analyses examined associations of PWB with gut microbiome taxonomic diversity, overall community structure, and specific species/pathways. To account for multiple testing, statistical significance was established using Benjamini-Hochberg adjusted p values (i.e., q values ≤0.25). RESULTS: We found no evidence of an association between PWB and gut microbiome alpha diversity. In multivariate analysis, higher purpose levels were significantly associated with lower abundance of species previously linked with poorer health outcomes, notably Blautia hydrogenotrophica and Eubacterium ventriosum ( q values ≤0.25). No significant associations were found between PWB and metabolic pathways. CONCLUSIONS: These findings offer early evidence suggesting that eudaimonic PWB is linked with variation in the gut microbiome, and this might be one pathway by which PWB promotes healthy aging.
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Characterization of changes in the gut microbiota associated with eating disorders.
BACKGROUND & AIMS: Eating disorders are serious pathologies with a strong negative impact on patients' quality of life and mortality. The gut microbiota was recently proposed as one of the potential factors involved in eating disorders. To gain a better understanding of the potential role of the gut microbiota in these diseases, we explored its composition in patients with all typical forms of eating disorders. METHODS: We used 16S rRNA sequencing to compare the composition of the faecal microbiota of patients with anorexia nervosa, bulimia nervosa or binge-eating disorder, with that of healthy individuals. RESULTS: Our results demonstrate that each type of eating disorder is associated with a specific gut bacterial signature. We observed, for example, a decrease in the relative abundances of Agathobacter and Romboutsia genera and an increase in Pseudomonas in patients diagnosed with anorexia, while patients diagnosed with binge-eating disorder exhibit a decrease in the relative abundances of Akkermansia and Intestinimonas genera and an increase in Streptococcus, Eggerthella and Proteus. We also highlight a heterogeneity in gut microbiota composition in different subcategories of eating disorders. By focusing on the comorbidities reported by patients, we finally identified several bacterial taxa, such as Acidaminococcus and Eggerthella genera, whose level correlates with the occurrence of anxiety or depressive-like symptoms. CONCLUSION: Together, our work demonstrates that eating disorders are associated with specific changes in gut microbiota composition and highlight the necessity to finely stratify patients to identify robust microbial signatures. In addition, we identified bacterial taxa correlating with comorbidities and decreased quality of life reported by patients. Our results now pave the way for determining the predictive value of the abundance of these taxa on the duration of the pathology or on the likelihood of relapse. They also constitute a valuable resource to further demonstrate the causal role of the gut microbiota in the onset or chronicisation of eating disorders.
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Electroconvulsive Therapy Changes Immunological Markers in Patients With Major Depressive Disorder: A Scoping Review.
Major depressive disorder (MDD) is a highly prevalent and disabling condition. As such, understanding the causes of and treatment options for MDD is critical. Electroconvulsive therapy (ECT) remains the gold standard depression treatment, but the molecular mechanisms that underlie its effects are still largely unknown. One such explanation hinges on the immuno-inflammatory correlates of ECT treatment, given mounting evidence supporting the inflammatory hypothesis of depression. This review aims to provide an overview of the suggested immunomodulatory effects of ECT and the predictive value of immune biomarkers in relation to treatment outcomes and side effects. We conducted a preregistered, systematic literature search utilizing MEDLINE (PubMed), Embase (Elsevier), and PsycINFO (EBSCO) databases. We employed keywords related to MDD, ECT, gut microbiome, and the immune system. We only included human subjects research published between 1985 and January 13, 2021. Twenty-six unique studies were included in our analyses. Findings indicate a proinflammatory profile associated with MDD, with immune biomarkers exhibiting acute and chronic changes following ECT. Consistently, lower baseline interleukin 6 levels and higher C-reactive protein levels are correlated with a greater reduction in depressive symptoms following ECT. Furthermore, included studies emphasize the predictive value of peripheral immune changes, specifically interleukin 6 and tumor necrosis factor α, on cognitive outcomes following ECT. Given these results, further exploration of the potential roles of immunomodulatory effects on ECT treatment outcomes, as well as adverse cognitive side effects, is indicated.
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Genetically Proxied Associations Among 473 Gut Microbial Taxa, 1,400 Circulating Metabolites, and Mental and Behavioral Disorders: A Mendelian Randomization Study.
Mental and behavioural disorders substantially impair everyday functioning, yet the biological mechanisms through which the gut microbiome may contribute to psychiatric vulnerability remain insufficiently characterized. We jointly analysed genome-wide association study data for 473 gut microbial taxa, approximately 1,400 circulating metabolites, and seven mental and behavioural disorders, including schizophrenia, obsessive-compulsive disorder, post-traumatic stress disorder, attention-deficit/hyperactivity disorder, chronic depression, bulimia nervosa, and hypersomnia. Mendelian randomization was used to estimate genetically proxied associations among these traits, and two-step MR was used to evaluate candidate statistical mediation by circulating metabolites. We identified FDR-supported associations for eight microbial taxa across four disorders: UBA8904, Dorea, and Ruminococcus A sp000432335 with ADHD; Pseudomonas aeruginosa, Bifidobacterium kashiwanohense, and CAG-273 sp003534295 with chronic depression; Syntrophorhabdia with bulimia nervosa; and Aneurinibacillales with hypersomnia. Twelve circulating metabolites were statistically consistent with partial mediation of candidate microbiota-disorder associations. Glycocholate glucuronide (1) accounted for an estimated 5.95% of the Syntrophorhabdia-bulimia nervosa association, whereas 5-dodecenoate (12:1n7) was consistent with mediation of 8.28% of the inverse association between CAG-273 sp003534295 and chronic depression. Target enrichment prioritized lipid metabolism and neuroactive ligand-receptor interaction pathways for further study. The inverse association between genetically predicted 5-dodecenoate and depression was reproduced in an independent depression GWAS. These findings nominate candidate microbiota-metabolite pathways for mechanistic investigation; however, residual horizontal pleiotropy and linkage-disequilibrium-related confounding cannot be excluded, and the results should not be interpreted as definitive causal evidence.
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The bidirectional interaction between antidepressants and the gut microbiota: are there implications for treatment response?
This review synthesizes the evidence on associations between antidepressant use and gut microbiota composition and function, exploring the microbiota's possible role in modulating antidepressant treatment outcomes. Antidepressants exert an influence on measures of gut microbial diversity. The most consistently reported differences were in β-diversity between those exposed to antidepressants and those not exposed, with longitudinal studies supporting a potential causal association. Compositional alterations in antidepressant users include an increase in the Bacteroidetes phylum, Christensenellaceae family, and Bacteroides and Clostridium genera, while a decrease was found in the Firmicutes phylum, Ruminococcaceae family, and Ruminococcus genus. In addition, antidepressants attenuate gut microbial differences between depressed and healthy individuals, modulate microbial serotonin transport, and influence microbiota's metabolic functions. These include lyxose degradation, peptidoglycan maturation, membrane transport, and methylerythritol phosphate pathways, alongside gamma-aminobutyric acid metabolism. Importantly, baseline increased α-diversity and abundance of the Roseburia and Faecalibacterium genera, in the Firmicutes phylum, are associated with antidepressant response, emerging as promising biomarkers. This review highlights the potential for gut microbiota as a predictor of treatment response and emphasizes the need for further research to elucidate the mechanisms underlying antidepressant-microbiota interactions. More homogeneous studies and standardized techniques are required to confirm these initial findings.
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Genetics-mediated regulation of intestinal gene expression on microbiome contributes to human disease heritability.
The gut microbiome plays fundamental roles in physiological and pathological processes, yet its interaction with host gene expression and contribution to disease remain underexplored. Here, we integrate the genetic regulatory maps of 116 microbial genera with gene expression quantitative trait loci (eQTLs) and DNA methylation QTLs (mQTLs) in three intestinal tissues to dissect host-microbiome interaction. We identify 6088, 5810, and 2398 gene-to-microbiome regulatory loci in the transverse colon, sigmoid colon, and ileum, respectively. Among these, 13.2% of genes show broad regulatory effects on multiple genera, with functional enrichments in developmental, metabolic, and immune-related pathways. Integrative analysis with genome-wide association studies (GWASs) reveals 283 microbiome-dependent disease loci. We observe pleiotropic effects mediated by the gene-to-microbiome regulation at both microbiome and disease layers. Notably, we predict and experimentally validate the suppressive effect of Allisonella on depression through regulating bile acid abundance, and the regulation of Parasutterella on short-chain fatty acid and its contribution to allergic rhinitis. The gene-microbiome-disease regulatory maps are available at our interactive database ( https://xiongxslab.github.io/microbiomeMR/ ).
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Modulation of Gut Microbiome in Ecstasy/MDMA-Induced Behavioral and Biochemical Impairment in Rats and Potential of Post-Treatment with Anacyclus pyrethrum L. Aqueous Extract to Mitigate Adverse Effects.
The use of illicit substances continues to pose a substantial threat to global health, affecting millions of individuals annually. Evidence suggests the existence of a 'brain-gut axis' as the involving connection between the central nervous system and gut microbiome (GM). Dysbiosis of the GM has been associated with the pathogenesis of various chronic diseases, including metabolic, malignant, and inflammatory conditions. However, little is currently known about the involvement of this axis in modulating the GM in response to psychoactive substances. In this study, we investigated the effect of MDMA (3,4-methylenedioxymethamphetamine, "Ecstasy")-dependence on the behavioral and biochemical responses, and the diversity and abundance of the gut microbiome in rats post-treated (or not) with aqueous extract of Anacyclus pyrethrum (AEAP), which has been reported to exhibit anticonvulsant activity. The dependency was validated using the conditioned place preference (CPP) paradigm, behavioral, and biochemical tests, while the gut microbiota was identified using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). The CPP and behavioral tests confirmed the presence of MDMA withdrawal syndrome. Interestingly, treatment with AEAP led to a compositional shift in the GM compared to the MDMA-treated rats. Specifically, the AEAP group yielded a higher relative abundance of Lactobacillus and Bifidobacter, while animals receiving MDMA had higher levels of E. coli. These findings suggest that A. pyrethrum therapy may directly modulate the gut microbiome, highlighting a potential target for regulating and treating substance use disorders.
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Yijung-tang improves thermogenesis and reduces inflammation associated with gut microbiota in hypothyroid rats.
Currently, considerable attention is focused on exploring the potential relationship between herbal medicine (HM) and the gut microbiome in terms of thermoregulation, which is an important aspect of human health, in modern system biology. However, our knowledge of the mechanisms of HM in thermoregulation is inadequate. Here, we demonstrate that the canonical herbal formula, Yijung-tang (YJT), protects against hypothermia, hyperinflammation, and intestinal microbiota dysbiosis in PTU-induced hypothyroid rats. Notably, these properties were associated with alterations in the gut microbiota and signaling crosstalk between the thermoregulatory and inflammatory mediators in the small intestine and brown adipose tissue (BAT). In contrast to the conventional drug L-thyroxine for curing hypothyroidism, YJT has an efficacy for attenuating systematic inflammatory responses, related with depression in intestinal TLR4 and Nod2/Pglyrp1 signaling pathways. Our findings suggest that YJT could promote BAT thermogenesis and prevent systemic inflammation in PTU-induced hypothyroid rats, which was associated with its prebiotic effect on modulating of the gut microbiota and gene expression with relevance in the enteroendocrine function and innate immune systems. These findings may strengthen the rationale of the microbiota-gut-BAT axis for a paradigm shift to enable holobiont-centric medicine.
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Integrated Label-Free and 10-Plex DiLeu Isobaric Tag Quantitative Methods for Profiling Changes in the Mouse Hypothalamic Neuropeptidome and Proteome: Assessment of the Impact of the Gut Microbiome.
Gut microbiota can regulate host physiological and pathological status through gut-brain communications or pathways. However, the impact of the gut microbiome on neuropeptides and proteins involved in regulating brain functions and behaviors is still not clearly understood. To address the problem, integrated label-free and 10-plex DiLeu isobaric tag-based quantitative methods were implemented to compare the profiling of neuropeptides and proteins in the hypothalamus of germ-free (GF)- vs conventionally raised (ConvR)-mice. A total of 2943 endogenous peptides from 63 neuropeptide precursors and 3971 proteins in the mouse hypothalamus were identified. Among these 368 significantly changed peptides (fold changes over 1.5 and a p-value of <0.05), 73.6% of the peptides showed higher levels in GF-mice than in ConvR-mice, and 26.4% of the peptides had higher levels in ConvR-mice than in GF-mice. These peptides were mainly from secretogranin-2, phosphatidylethanolamine-binding protein-1, ProSAAS, and proenkephalin-A. A quantitative proteomic analysis employing DiLeu isobaric tags revealed that 282 proteins were significantly up- or down-regulated (fold changes over 1.2 and a p-value of <0.05) among the 3277 quantified proteins. These neuropeptides and proteins were mainly involved in regulating behaviors, transmitter release, signaling pathways, and synapses. Interestingly, pathways including long-term potentiation, long-term depression, and circadian entrainment were involved. In the present study, a combined label-free and 10-plex DiLeu-based quantitative method enabled a comprehensive profiling of gut microbiome-induced dynamic changes of neuropeptides and proteins in the hypothalamus, suggesting that the gut microbiome might mediate a range of behavioral changes, brain development, and learning and memory through these neuropeptides and proteins.