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Psycho-Pharmacomicrobiomics: A Systematic Review and Meta-Analysis.
BACKGROUND: Understanding the interactions between the gut microbiome and psychotropic medications (psycho-pharmacomicrobiomics) could improve treatment stratification strategies in psychiatry. In this systematic review and meta-analysis, we first explored whether psychotropics modify the gut microbiome; second, we investigated whether the gut microbiome affects the efficacy and tolerability of psychotropics. METHODS: Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we searched (November 2022) for longitudinal and cross-sectional studies that investigated the effect of psychotropics on the gut microbiome. The primary outcome was the difference in diversity metrics (alpha and beta) before and after treatment with psychotropics (longitudinal studies) and in medicated compared with unmedicated individuals (cross-sectional studies). Secondary outcomes included the association between gut microbiome and efficacy and tolerability outcomes. Random effect meta-analyses were conducted on alpha diversity metrics, while beta diversity metrics were pooled using distance data extracted from graphs. Summary statistics included standardized mean difference and Higgins I2 for alpha diversity metrics and F and R values for beta diversity metrics. RESULTS: Nineteen studies were included in our synthesis; 12 investigated antipsychotics and 7 investigated antidepressants. Results showed significant changes in alpha (4 studies; standard mean difference: 0.12; 95% CI: 0.01-0.23; p = .04; I2: 14%) and beta (F = 15.59; R2 = 0.05; p < .001) diversity metrics following treatment with antipsychotics and antidepressants, respectively. Altered gut microbiome composition at baseline was associated with tolerability and efficacy outcomes across studies, including response to antidepressants (2 studies; alpha diversity; standard mean difference: 2.45; 95% CI: 0.50-4.40; p < .001, I2: 0%). CONCLUSIONS: Treatment with psychotropic medications is associated with altered gut microbiome composition, and the gut microbiome may in turn influence the efficacy and tolerability of these medications.
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Effect of PEGylated Liposomalization of Oxaliplatin on the Gut Microbiota in Mice.
Dysbiosis is a contributing factor in various conditions, including depressive disorder and irritable bowel syndrome. Key drivers of dysbiosis include stress exposure, chronic unbalanced diet, and exposure to certain pharmacological medications. While the platinum-based anticancer agent oxaliplatin (l-OHP) induces dysbiosis, it remains unclear whether liposomal encapsulation impacts this microbiota disruption. Here, we evaluated characteristics of the colonic microbiota in male C57BL/6J mice administered l-OHP or its PEGylated liposomal formulation (Lipo-l-OHP). On Day 7 following treatment with l-OHP or Lipo-l-OHP (total dose: 16 mg/kg), all mice developed mechanical allodynia, while those receiving l-OHP, but not Lipo-l-OHP, exhibited reduced body weight gain. On Day 7, mice treated with l-OHP or Lipo-l-OHP showed a trend toward reduced α-diversity of the colonic microbiota compared with untreated mice in a control group; however, α-diversity remained significantly higher in the Lipo-l-OHP group than in the l-OHP group. β-Diversity analysis revealed the distinct patterns in microbiota composition among the 3 groups. At the bacterial genus level, the relative abundances of unclassified Muribaculaceae spp., Lachnospiraceae NK4A136 group spp., Bacteroides spp., and Clostridium sensu stricto 1 spp. were significantly altered in the l-OHP group, but not in the Lipo-l-OHP group, compared with those in the control group. Interestingly, the abundances of unclassified Muribaculaceae spp. and Lachnospiraceae NK4A136 group spp. were positively correlated, and Bacteroides spp. was negatively correlated, with body weight changes in mice on Day 7. Collectively, our findings demonstrated that PEGylated liposomalization of l-OHP partially ameliorates l-OHP-induced dysbiosis in mice.
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Compositional maturation of the microbiome and adaptive immunity in the postnatal period.
INTRODUCTION: Recent research has highlighted the role of the gut microbiome in shaping the development and function of the mammalian immune system. Interactions between these complex networks of microbes and host cells serve not only to train major aspects of adaptive and innate immunity but also to establish commensal host-microbe relationships and symbiosis throughout the lifespan. T-cells are a critical aspect of this paradigm, acting as intermediates between the microbiome and many aspects of host health and disease. Despite a large body of literature examining these interactions, we have yet to completely understand how the ontogeny of these systems co-evolves across the lifespan and how the emergence of specific T-cell-microbe signals relates to key developmental milestones. METHODS: To answer this question, this work conducted a compositional integrative analysis on deep immune and microbiome profiling of wild-type C57Bl/6 mice across the first two weeks of life, post-weaning, and young adulthood. RESULTS: The results show that T-cell ontogeny follows different developmental trends in mucosal and peripheral immune compartments and that temporal trends in microbial community abundance creates a modular network of associations between specific taxa and functional T-cell subsets. DISCUSSION: These results provide insight into the longitudinal development of microbiota-immune system interactions throughout the lifespan, as well as the mechanistic relevance of microbiota-derived signals at key developmental milestones.
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Investigating the presence of microbiota-based phenotypes in irritable bowel syndrome.
Irritable bowel syndrome (IBS) is heterogenous disorder of gut-brain interaction, with a key role for the dysregulated host-gut microbiota interplay. IBS subtyping is based only on symptoms of bowel habits, reflecting limited insight into underlying biological mechanisms. This study aimed to define microbiota-based IBS phenotypes and to compare these to traditional stool-based subtyping. The study utilized data from the Maastricht IBS cohort. Gut microbiota composition was analysed using shotgun metagenomic sequencing. Faecal volatile organic compounds (VOCs) were measured by gas chromatography mass spectrometry. Dietary intake and gastrointestinal and mental health symptoms were assessed using a food frequency questionnaire, the Dutch Healthy Diet-15 index, the gastrointestinal symptom rating scale, and hospital anxiety and depression scores, respectively. Machine-learning approaches were applied to identify microbiota-based phenotypical clusters, which were compared with established Rome III subtypes, and associated with faecal VOCs, gastrointestinal symptom severity, diet and mental health. 178 IBS patients and 134 healthy controls were included. Gut microbiota composition distinguished IBS patients from healthy controls with an AUCROC 0 · 8. This discriminatory profile was not associated with Rome III subtypes, while statistically significant associations were found with faecal VOCs profiles (i.e.R= 0 · 67,p= 4 · 46e-4) and symptom severity scores of abdominal pain (p= 0 · 05), reflux (p= 0 · 03), diarrhoea (p= 0 · 01) and depression (p< 0 · 001). Dietary associations varied across clusters. These results suggest that gut microbiota profiling might provide a basis to define relevant IBS endotypes. Further exploration and validation efforts into this direction are needed using longitudinal studies to refine IBS patient stratification ultimately.
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Gut microbiome-brain interactions in anorexia nervosa: Potential mechanisms and regulatory strategies.
Anorexia nervosa (AN) is a psychiatric disorder characterised by malnutrition, fear of weight gain, and body image disturbances. The aetiology of AN is complex, and may involve environmental factors, genetic factors, and biochemical factors, with the latter meaning that AN may be closely associated with neurons, neurotransmitters, and hormones related to appetite and emotional regulation. In addition, an increasing number of studies have shown there is a link between the intestinal microbiota and psychiatric disorders, such as depression. However, few studies and reviews have focused on AN and gut microbes. Accordingly, in this review, we examine the potential pathogenesis of AN in terms of changes in the gut microbiota and its metabolites, and their effects on AN. The neurobiological function of the nervous system in relation to AN are also been mentioned. Furthermore, we suggest future research directions for this field, and note that probiotics may be developed for use as dietary supplements to help alleviate AN in patients.
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Changes in the stool and oropharyngeal microbiome in obsessive-compulsive disorder.
Although the etiology of obsessive-compulsive disorder (OCD) is largely unknown, it is accepted that OCD is a complex disorder. There is a known bi-directional interaction between the gut microbiome and brain activity. Several authors have reported associations between changes in gut microbiota and neuropsychiatric disorders, including depression or autism. Furthermore, a pediatric-onset neuropsychiatric OCD-related syndrome occurs after streptococcal infection, which might indicate that exposure to certain microbes could be involved in OCD susceptibility. However, only one study has investigated the microbiome of OCD patients to date. We performed 16S ribosomal RNA gene-based metagenomic sequencing to analyze the stool and oropharyngeal microbiome composition of 32 OCD cases and 32 age and gender matched controls. We estimated different α- and β-diversity measures and performed LEfSe and Wilcoxon tests to assess differences in bacterial distribution. OCD stool samples showed a trend towards lower bacterial α-diversity, as well as an increase of the relative abundance of Rikenellaceae, particularly of the genus Alistipes, and lower relative abundance of Prevotellaceae, and two genera within the Lachnospiraceae: Agathobacer and Coprococcus. However, we did not observe a different Bacteroidetes to Firmicutes ratio between OCD cases and controls. Analysis of the oropharyngeal microbiome composition showed a lower Fusobacteria to Actinobacteria ratio in OCD cases. In conclusion, we observed an imbalance in the gut and oropharyngeal microbiomes of OCD cases, including, in stool, an increase of bacteria from the Rikenellaceae family, associated with gut inflammation, and a decrease of bacteria from the Coprococcus genus, associated with DOPAC synthesis.
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Possible links between gut-microbiota and attention-deficit/hyperactivity disorders in children and adolescents.
An association between gut-microbiota and several neuropsychiatric conditions including autism, depression, anxiety, schizophrenia, and attention-deficit/hyperactivity disorder (ADHD) has been observed. Despite being the most prevalent neurodevelopmental disorders in children and adolescents worldwide, the etiology and curative approaches to treatment of ADHD remain unclear. There is a probability that gut-microbiota may contribute to ADHD via bidirectional communication between the gut and brain, a system known as the "gut-brain axis". Although a mechanistic link in the gut-brain axis in ADHD has been proposed, there is still a lack of information about the correlation of the microbiome profile with the mechanisms involved. The objective of this review was to summarize the diversity of the gut-microbiota and taxonomic profiles in children and adolescents with ADHD. In this review, we have provided an overview of the association between ADHD and gut-microbiota. The evidence pertinent to potentially distinctive gut-microbiota in children and adolescents with ADHD is also discussed and compared to that of their non-ADHD peers. Finally, the implications and future directions for investigation into the gut microbiome in ADHD patients are proposed.
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A Linkable, Polycarbonate Gut Microbiome-Distal Tumor Chip Platform for Interrogating Cancer Promoting Mechanisms.
Gut microbiome composition is tied to diseases ranging from arthritis to cancer to depression. However, mechanisms of action are poorly understood, limiting development of relevant therapeutics. Organ-on-chip platforms, which model minimal functional units of tissues and can tightly control communication between them, are ideal platforms to study these relationships. Many gut microbiome models are published to date but devices are typically fabricated using oxygen permeable polydimethylsiloxane, requiring interventions to support anaerobic bacteria. To address this challenge, a platform is developed where the chips are fabricated entirely from gas-impermeable polycarbonate without tapes or gaskets. These chips replicate polarized villus-like structures of the native tissue. Further, they enable co-cultures of commensal anaerobic bacteria Blautia coccoides on the surface of gut epithelia for two days within a standard incubator. Another complication of commonly used materials in organ-on-chip devices is high ad-/absorption, limiting applications in high-resolution microscopy and biomolecule interaction studies. For future communication studies between gut microbiota and distal tumors, an additional polycarbonate chip design is developed to support hydrogel-embedded tissue culture. These chips enable high-resolution microscopy with all relevant processing done on-chip. Designed for facile linking, this platform will make a variety of mechanistic studies possible.
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Co-Occurrence of Symptoms and Gut Microbiota Composition Before Neoadjuvant Chemotherapy and Radiation Therapy for Rectal Cancer: A Proof of Concept.
PURPOSE: To examine a) whether there are significant differences in gut microbial diversity and in the abundance of gut microbial taxa; and b) differences in predicted functional pathways of the gut microbiome between those participants with high co-occurring symptoms and those with low co-occurring symptoms, prior to neoadjuvant chemotherapy and radiation therapy (CRT) for rectal cancer. METHODS: Rectal cancer patients (n = 41) provided stool samples for 16 S rRNA gene sequencing and symptom ratings for fatigue, sleep disturbance, and depressive symptoms prior to CRT. Descriptive statistics were computed for symptoms. Gut microbiome data were analyzed using QIIME2, LEfSe, and the R statistical package. RESULTS: Participants with high co-occurring symptoms (n = 19) had significantly higher bacterial abundances of Ezakiella, Clostridium sensu stricto, Porphyromonas, Barnesiella, Coriobacteriales Incertae Sedis, Synergistiaceae, Echerichia-Shigella, and Turicibacter compared to those with low co-occurring symptoms before CRT (n = 22). Biosynthesis pathways for lipopolysaccharide, L-tryptophan, and colanic acid building blocks were enriched in participants with high co-occurring symptoms. Participants with low co-occurring symptoms showed enriched abundances of Enterococcus and Lachnospiraceae, as well as pathways for β-D-glucoronosides, hexuronide/hexuronate, and nicotinate degradation, methanogenesis, and L-lysine biosynthesis. CONCLUSION: A number of bacterial taxa and predicted functional pathways were differentially abundant in patients with high co-occurring symptoms compared to those with low co-occurring symptoms before CRT for rectal cancer. Detailed examination of bacterial taxa and pathways mediating co-occurring symptoms is warranted.
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Maternal probiotic Lactocaseibacillus rhamnosus HN001 treatment alters postpartum anxiety, cortical monoamines, and the gut microbiome.
Peripartum mood and anxiety disorders (PMADs) affect 15-20% of peripartum women and are well known to disrupt infant caregiving. A recent study in humans reported that anxiety and depressive symptoms were alleviated by peripartum treatment with the probiotic, Lactocaseibacillus rhamnosus HN001. The current study determined the effects of chronic Lactocaseibacillus rhamnosus HN001 (HN001) treatment on postpartum affective and caregiving behaviors in a laboratory rodent model. Female rats were given probiotic overnight in their drinking water, or untreated water, from the first day of pregnancy through postpartum day 10. To determine whether the HN001 effects were influenced by a background of stress, half the females underwent chronic variable pregnancy stress and the other half remained undisturbed. The results revealed that, even without pregnancy stress, HN001 reduced postpartum anxiety-related behavior, increased variability in behavioral fragmentation when dams interacted with pups, increased time away from pups, and decreased prefrontal cortex norepinephrine (NE), dopamine (DA) and serotonin (5-HT). Probiotic plus stress consistently reduced the latency to float in the forced swim test, increased DA and 5-HT turnovers in the prefrontal cortex, increased hippocampal NE, and reduced hypothalamic DA. Fecal microbe alpha and beta diversities were lower postpartum than prepartum, which was prevented by the probiotic treatment and/or stress. Across the entire sample lower postpartum anxiety behavior was associated with lower fecal Bacteroides dorei. This study reveals novel information about how L. rhamnosus HN001 influences postpartum behavior and microbiota-gut-brain physiology in female laboratory rats, with implications for probiotic supplement use by pregnant and postpartum women.