A comparative study on dietary diversity and gut microbial diversity in children with autism spectrum disorder, attention-deficit hyperactivity disorder, their neurotypical siblings, and non-related neurotypical volunteers: a cross-sectional study.

BACKGROUND: Previous research has shown a significant link between gut microbiota in children with autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). However, much remains unknown because of the heterogeneity of disorders and the potential confounders such as dietary patterns and control group variations. METHODS: Children aged 6-12 years who had been clinically diagnosed with ASD and/or ADHD, their unaffected neurotypical siblings, and non-related neurotypical volunteers were recruited cross-sectionally. The ASD diagnosis was confirmed using the Autism Diagnostic Observation Schedule-2 (ADOS-2) in all patients, including those with ADHD. Standardized DNA extraction and sequencing methods were used to compare gut microbial alpha-diversity among the groups. Dietary diversity was calculated from a standardized dietary questionnaire form. We compared the difference in gut microbiome between patients with ASD and/or ADHD with neurotypical siblings and non-related neurotypical controls. RESULTS: Ninety-eight subjects were included in the study (18 with ASD, 19 with ADHD, 20 with both ASD and ADHD, 13 neurotypical siblings, and 28 non-related neurotypical controls). The alpha-diversity indices, such as Chao 1 and Shannon index, showed a significant difference between the groups in a Linear mixed-effect model (F(4, 93) = 4.539, p = .02), (F(4, 93) = 3.185, p = .017), respectively. In a post-hoc pairwise comparison, patients with ASD had lower alpha-diversity compared with non-related controls after Bonferroni correction. Dietary diversity shown in Shannon index did not differ among the groups (F(4, 84) = 1.494, p = .211). CONCLUSIONS: Our study indicates disorder-specific microbiome differences in patients with ASD. In future research on gut microbiota in neurodevelopmental disorders, it is necessary to consider the impact of ASD and ADHD co-occurrence, and strictly control for background information such as diet, to elucidate the gut-microbiota interaction in ASD and ADHD for exploring the potential of therapeutic interventions.

Intestinal metabolites predict treatment resistance of patients with depression and anxiety.

BACKGROUND: The impact of the gut microbiota on neuropsychiatric disorders has gained much attention in recent years; however, comprehensive data on the relationship between the gut microbiome and its metabolites and resistance to treatment for depression and anxiety is lacking. Here, we investigated intestinal metabolites in patients with depression and anxiety disorders, and their possible roles in treatment resistance. RESULTS: We analyzed fecal metabolites and microbiomes in 34 participants with depression and anxiety disorders. Fecal samples were obtained three times for each participant during the treatment. Propensity score matching led us to analyze data from nine treatment responders and nine non-responders, and the results were validated in the residual sample sets. Using elastic net regression analysis, we identified several metabolites, including N-ε-acetyllysine; baseline levels of the former were low in responders (AUC = 0.86; 95% confidence interval, 0.69-1). In addition, fecal levels of N-ε-acetyllysine were negatively associated with the abundance of Odoribacter. N-ε-acetyllysine levels increased as symptoms improved with treatment. CONCLUSION: Fecal N-ε-acetyllysine levels before treatment may be a predictive biomarker of treatment-refractory depression and anxiety. Odoribacter may play a role in the homeostasis of intestinal L-lysine levels. More attention should be paid to the importance of L-lysine metabolism in those with depression and anxiety.

The relationship between sleep, gut microbiota, and metabolome in patients with depression and anxiety: A secondary analysis of the observational study.

BACKGROUND: Growing attention is paid to the association between alterations in the gut microbiota and their metabolites in patients with psychiatric disorders. Our study aimed to determine how gut microbiota and metabolomes are related to the sleep quality among patients with depression and anxiety disorders by analyzing the datasets of our previous study. METHODS: Samples were collected from 40 patients (depression: 32 patients [80.0%]); anxiety disorders: 8 patients [20.0%]) in this study. Gut microbiomes were analyzed using 16S rRNA gene sequencing and gut metabolomes were analyzed by a mass spectrometry approach. Based on the Pittsburgh Sleep Quality Index (PSQI), patients were categorized into two groups: the insomnia group (PSQI score ≥ 9, n = 20) and the non-insomnia group (PSQI score < 9, n = 20). RESULTS: The insomnia group showed a lower alpha diversity in the Chao1 and Shannon indices than the non-insomnia group after the false discovery rate (FDR) correction. The relative abundance of genus Bacteroides showed a positive correlation with PSQI scores in the non-insomnia group. The concentrations of glucosamine and N-methylglutamate were significantly higher in the insomnia group than in the non-insomnia group. CONCLUSIONS: Our findings suggest that specific taxa could affect the sleep quality among patients with depression and anxiety disorders. Further studies are needed to elucidate the impact of sleep on specific gut microbiota and metabolomes in depression and anxiety disorders.

The Potential Impact of Age on Gut Microbiota in Patients with Major Depressive Disorder: A Secondary Analysis of the Prospective Observational Study.

We aimed to investigate the impact of aging on the relationship among the composition of gut microbiota, gastrointestinal (GI) symptoms, and the course of treatment for major depressive disorder (MDD) by analyzing the datasets from our previous study. Patients with MDD were recruited, and their stools were collected at three time points (baseline, midterm, and endpoint) following the usual antidepressant treatment. Gut microbiota were analyzed using 16S rRNA gene sequencing. Patients were categorized into two groups based on their age: the late-life group over 60 years and the middle-aged group under 60 years. GI symptoms were assessed with scores of item 11 of the Hamilton Anxiety Rating Scale. One hundred and ninety samples were collected from 32 patients with MDD. Several gut microbes had higher relative abundances in the late-life group than in the middle-aged group. In addition, the late-life group showed significantly higher diversity in the Chao1 index at baseline compared with the middle-aged group. We further found possible microbial taxa related to GI symptoms in patients with late-life depression. The abundance of several bacterial taxa may contribute to GI symptoms in the late-life depression, and our findings suggest that the therapeutic targets for the application of gut microbiota may differ depending on the age group of patients with depression.

Gastrointestinal symptoms and sensory abnormalities associated with behavioral problems in children with neurodevelopmental disorders.

Behavioral problems directly affect the quality of life of caregivers and children with autism spectrum disorder (ASD) and/or attention-deficit/hyperactivity disorder (ADHD), and is known to be associated with clinical factors such as gastrointestinal (GI) symptoms, sensory abnormalities, intellectual abilities, and use of medication. However, previous studies have not considered these relationships comprehensively. We conducted a cross-sectional study of 6-12-year-old children with diagnoses of ASD and/or ADHD at two hospitals in Japan. Scores for the aberrant behavior checklist (ABC), autism-spectrum quotient (AQ), and Conners 3, as well as information on daily sleep and exercise, GI symptoms, and Short Sensory Profile, were collected. Each factor was subjected to a correlation analysis to investigate its effect on ABC scores. A stepwise multiple linear regression analysis for the factors with p < 0.05 was performed. Data were obtained from 60 patients with a mean age of 8.3 years; 21 had ASD alone, 18 had ADHD alone, and 21 had ASD + ADHD. The correlation analyses identified six factors associated with ABC severity: (a) methylphenidate use, (b) Conners hyperactivity score, (c) Conners inattention score, (d) AQ score, (e) SSP score, and (f) GI symptom score. The multiple regression showed that "GI symptoms" and "sensory abnormalities" were independently associated with ABC severity. Although further studies are needed to show a causal relationship, appropriate assessment of GI symptoms and sensory abnormalities may help alleviate some problematic behaviors and improve the quality of life of children with neurodevelopmental disorders and their families. LAY SUMMARY: Behavioral problems in children with neurodevelopmental disorders are known to be associated with many factors. This study aimed to comprehensively investigate the known factors. We have discovered that "gastrointestinal symptoms" and "sensory abnormalities" were independently associated with Behavioral problems. Our results suggest that it is important for clinicians and caregivers to pay more attention to children's GI symptoms and sensory abnormalities that may not present as obvious symptoms or complaints.

Fecal Microbial and Metabolomic Change during treatment course for depression: An Observational Study.

BACKGROUND: There is growing evidence regarding the connection between alterations in gut microbiota and their metabolites in patients with depressive disorders, suggesting a potential role in pathophysiology. Our study aimed to investigate the relationship between microbial, metabolomic features and the course of treatment for depression in a real-world clinical setting. METHODS: Patients diagnosed with depressive disorders were recruited, and their stool was collected at three time points during their depression treatments. Patients were divided into three groups: non-responders, responders, and stable remitters. Gut microbiomes were analyzed using 16S rRNA gene sequencing, and gut metabolomes were analyzed by a mass spectrometry approach. Microbiomes/metabolomes were compared between groups cross-sectionally and longitudinally. RESULTS: A total of 33 patients were recruited and divided into non-responders (n = 16), responders (n = 11), and stable remitters (n = 6). Non-responders presented lower alpha diversity in the Phylogenic Diversity index compared to responders during the treatment course (p = 0.003). Non-responders presented increased estimated glutamate synthesis functions by the microbiota compared to responders and stable remitters (p = 0.035). There were no specific microbiota or metabolome that differentiated the three groups. LIMITATIONS: Small sample size with no healthy controls. CONCLUSIONS: Our results indicate that both cross-sectional microbial features and longitudinal microbial transitions are different depending on the treatment course of depression. Controlled studies, as well as animal studies, are needed in the future to elucidate the causal relationship between microbiota and depression.

Effects of Psychotropics on the Microbiome in Patients With Depression and Anxiety: Considerations in a Naturalistic Clinical Setting.

BACKGROUND: The antibacterial effects of psychotropics may be part of their pharmacological effects when treating depression. However, limited studies have focused on gut microbiota in relation to prescribed medication. METHOD: We longitudinally investigated the relationship between patients' prescribed medications and intestinal bacterial diversity in a naturalistic treatment course for patients with major depressive disorders and anxiety disorders. Patients were recruited and their stool was collected at 3 time points during their usual psychiatric treatments. Gut microbiota were analyzed using 16S rRNA gene sequencing. We examined the impact of psychotropics (i.e., antidepressants, anxiolytics, antipsychotics) on their gut microbial diversity and functions. RESULTS: We collected 246 stool samples from 40 patients. Despite no differences in microbial diversity between medication groups at the baseline, over the course of treatment, phylogenic diversity whole-tree diversity decreased in patients on antipsychotics compared with patients without (P = .027), and beta diversity followed this trend. Based on a fixed-effect model, antipsychotics predicted microbial diversity; the higher doses correlated with less diversity based on the Shannon index and phylogenic diversity whole tree (estimate = -0.00254, SE = 0.000595, P < .0001; estimate = -0.02644, SE = 0.00833, P = .002, respectively). CONCLUSION: Antipsychotics may play a role in decreasing the alpha diversity of the gut microbiome among patients with depression and anxiety, and our results indicate a relationship with medication dosage. Future studies are warranted and should consider patients' types and doses of antipsychotics in order to further elucidate the mechanisms of gut-brain interactions in psychiatric disorders.