Clinical significance of microbiota changes under the influence of psychotropic drugs. An updated narrative review.

Relationship between drugs and microbiota is bilateral. Proper composition thus function of microbiota is a key to some medications used in modern medicine. However, there is also the other side of the coin. Pharmacotherapeutic agents can modify the microbiota significantly, which consequently affects its function. A recently published study showed that nearly 25% of drugs administered to humans have antimicrobial effects. Multiple antidepressants are antimicrobials,. and antibiotics with proven antidepressant effects do exist. On the other hand, antibiotics (e.g., isoniaside, minocycline) confer mental phenotype changes, and adverse effects caused by some antibiotics include neurological and psychological symptoms which further supports the hypothesis that intestinal microbiota may affect the function of the central nervous system. Here we gathered comprehensively data on drugs used in psychiatry regarding their antimicrobial properties. We believe our data has strong implications for the treatment of psychiatric entities. Nevertheless the study of ours highlights the need for more well-designed trials aimed at analysis of gut microbiota function.

Effect of Psychobiotics on Psychometric Tests and Inflammatory Markers in Major Depressive Disorder: Meta-Analysis of Randomized Controlled Trials with Meta-Regression.

Probiotics were shown to act positively on gut-brain axis signaling. We aimed to assess the effect of the administration of a new class of probiotics-psychobiotics-using data from individual psychometric scales, markers of the immune system and neuroactive metabolites. Medical databases were searched from database inception until 22 April 2021 for randomized clinical trials in clinically proven Major Depressive Disorder (MDD) patients treated with either probiotics or placebo reporting any psychometric score (PROSPERO registration number: CRD42021253024). Ten studies with 705 randomized participants and 603 analyzed were included. The mean age of individuals was 38.43 ± 12.1 years, predominantly women (n = 461, 76.45). The mean study duration was 48.8 ± 12.3 (range = 28-62) days. The dosage ranged between 1 × 109 to 2 × 1010 colony forming units (CFU)/day. We found that probiotics might alleviate symptoms of MDD; endpoint data (pooled scores): SMD = -0.292, 95%CI = -0.577 to -0.007, p < 0.044; change scores (BDI): SMD = -0.482, 95%CI = -0.854 to -0.109, p < 0.011; DM = -4.848, 95%CI = -8.559 to -1.137, p < 0.01. The therapy tended to be more effective with time of psychobiotic supplementation (coefficient = -0.12, SE = 0.06, Z = -1.84, p = 0.06) and in men (% of females: coefficient = 0.1, SE = 0.06, Z = 1.78, p = 0.07). Psychobiotics have great potential in the treatment of MDD. However, no specific strain/strains, dosage or duration of treatment can currently be recommended.

Analysis of gut microbiota and intestinal integrity markers of inpatients with major depressive disorder.

Previous studies have reported on the relationship between gut microbiota and major depressive disorder (MDD). However, there remain gaps in literature concerning the role of the intestinal barrier and microflora in the pathogenesis of depression. This study analyzes the potential causative relationship between gut microbiota and inflammatory and gut integrity markers and clinical symptoms in inpatients with depressive episodes. Sixteen inpatients (50% females) being treated with escitalopram (5-20 mg daily) in standardized conditions were included in the study. The composition of fecal microbiota was evaluated at baseline and endpoint using 16S rRNA sequencing. A significant correlation between depression severity was found, as measured with HDRS24 (Hamilton Depression Rating Scale-24 item), and the following abundance in bacteria: positive correlation with Paraprevotella (r = 0.80, q = 0.012), strong, negative correlations with Clostridiales (r = -0.70, q = 0.016), Clostridia (r = -0.71, q = 0.026), Firmicutes (r = -0.67. q = 0.032), and the RF32 order (r = -0.70, p = 0.016) in the Alphaproteobacteria (r = -0.66, q = 0.031). After six weeks of treatment, clinical outcomes were found to have a negative correlation with levels of plasma intestinal fatty acid-binding protein (IFABP) at the beginning of the study. Still they had a positive correlation with changes in fecal calprotectin during hospitalization. In conclusion, gut microbiota was associated with the severity of depressive symptoms. However, these findings do not serve as predictors of symptomatic improvement during antidepressant treatment in inpatient treatment for MDD. In turn, intestinal integrity and inflammation markers were associated with the response to treatment of patients with MDD and symptom severity. Additional studies are needed to confirm and extend these findings.

Major Depressive Disorder and gut microbiota - Association not causation. A scoping review.

One very promising hypothesis of Major Depressive Disorder (MDD) pathogenesis is the gut-brain axis (GBA) dysfunction, which can lead to subclinical inflammation, hypothalamic-pituitary (HPA) axis dysregulation, and altered neural, metabolic and endocrine pathways. One of the most important parts of GBA is gut microbiota, which was shown to regulate different functions in the central nervous system (CNS). The purpose of this scoping review was to present the current state of research on the relationship between MDD and gut microbiota and extract causal relationships. Further, we presented the relationship between the use of probiotics and antidepressants, and the microbiota changes. We evaluated the data from 27 studies aimed to investigate microbial fingerprints associated with depression phenotype. We abstracted data from 16 and 11 observational and clinical studies, respectively; the latter was divided into trials evaluating the effects of psychiatric treatment (n = 3) and probiotic intervention (n = 9) on the microbiome composition and function. In total, the data of 1187 individuals from observational studies were assessed. In clinical studies, there were 490 individuals analysed. In probiotic studies, 220 and 218 patients with MDD received the intervention and non-active study comparator, respectively. It was concluded that in MDD, the microbiota is altered. Although the mechanism of this relationship is unknown, we hypothesise that the taxonomic changes observed in patients with MDD are associated with bacterial proinflammatory activity, reduced Schort Chain Fatty Acids (SCFAs) production, impaired intestinal barrier integrity and neurotransmitter production, impaired carbohydrates, tryptophane and glutamate metabolic pathways. However, only in few publications this effect was confirmed by metagenomic, metabolomic analysis, or by assessment of immunological parameters or intestinal permeability markers. Future research requires standardisation process starting from patient selection, material collection, DNA sequencing, and bioinformatic analysis. We did not observe whether antidepressive medications influence on gut microbiota, but the use of psychobiotics in patients with MDD has great prospects; however, this procedure requires also standardisation and thorough mechanistic research. The microbiota should be treated as an environmental element, which considers the aetiopathogenesis of the disease and provides new possibilities for monitoring and treating patients with MDD.

Heartburn-Related Internet Searches and Trends of Interest across Six Western Countries: A Four-Year Retrospective Analysis Using Google Ads Keyword Planner.

The internet is becoming the main source of health-related information. We aimed to investigate data regarding heartburn-related searches made by Google users from Australia, Canada, Germany, Poland, the United Kingdom, and the United States. We retrospectively analyzed data from Google Ads Keywords Planner. We extracted search volumes of keywords associated with "heartburn" for June 2015 to May 2019. The data were generated in the respective primary language. The number of searches per 1,000 Google-user years was as follows: 177.4 (Australia), 178.1 (Canada), 123.8 (Germany), 199.7 (Poland), 152.5 (United Kingdom), and 194.5 (United States). The users were particularly interested in treatment (19.0 to 41.3%), diet (4.8 to 10.7%), symptoms (2.6 to 13.1%), and causes (3.7 to 10.0%). In all countries except Germany, the number of heartburn-related queries significantly increased over the analyzed period. For Canada, Germany, Poland, and the United Kingdom, query numbers were significantly lowest in summer; there was no significant seasonal trend for Australia and the United States. The number of heartburn-related queries has increased over the past four years, and a seasonal pattern may exist in certain regions. The trends in heartburn-related searches may reflect the scale of the complaint, and should be verified through future epidemiological studies.

Second-generation antipsychotics and metabolism alterations: a systematic review of the role of the gut microbiome.

RATIONALE: Multiple drugs are known to induce metabolic malfunctions, among them second-generation antipsychotics (SGAs). The pathogenesis of such adverse effects is of multifactorial origin. OBJECTIVES: We investigated whether SGAs drive dysbiosis, assessed whether gut microbiota alterations affect body weight and metabolic outcomes, and looked for the possible mechanism of metabolic disturbances secondary to SGA treatment in animal and human studies. METHODS: A systematic literature search (PubMed/Medline/Embase/ClinicalTrials.gov/PsychInfo) was conducted from database inception until 03 July 2018 for studies that reported the microbiome and weight alterations in SGA-treated subjects. RESULTS: Seven articles reporting studies in mice (experiments = 8) and rats (experiments = 3) were included. Olanzapine was used in five and risperidone in six experiments. Only three articles (experiments = 4) in humans fit our criteria of using risperidone and mixed SGAs. The results confirmed microbiome alterations directly (rodent experiments = 5, human experiments = 4) or indirectly (rodent experiments = 4) with predominantly increased Firmicutes abundance relative to Bacteroidetes, as well as weight gain in rodents (experiments = 8) and humans (experiments = 4). Additionally, olanzapine administration was found to induce both metabolic alterations (adiposity, lipogenesis, plasma free fatty acid, and acetate levels increase) (experiments = 3) and inflammation (experiments = 2) in rodents, whereas risperidone suppressed the resting metabolic rate in rodents (experiments = 5) and elevated fasting blood glucose, triglycerides, LDL, hs-CRP, antioxidant superoxide dismutase, and HOMA-IR in humans (experiment = 1). One rodent study suggested a gender-dependent effect of dysbiosis on body weight. CONCLUSIONS: Antipsychotic treatment-related microbiome alterations potentially result in body weight gain and metabolic disturbances. Inflammation and resting metabolic rate suppression seem to play crucial roles in the development of metabolic disorders.

A Systematic Review, Meta-Analysis, and Meta-Regression Evaluating the Efficacy and Mechanisms of Action of Probiotics and Synbiotics in the Prevention of Surgical Site Infections and Surgery-Related Complications.

Intestinal microbiota play an important role in the pathogenesis of surgical site infections (SSIs) and other surgery-related complications (SRCs). Probiotics and synbiotics were found to lower the risk of surgical infections and other surgery-related adverse events. We systematically reviewed the approach based on the administration of probiotics and synbiotics to diminish SSIs/SRCs rates in patients undergoing various surgical treatments and to determine the mechanisms responsible for their effectiveness. A systematic literature search in PubMed/MEDLINE/Cochrane Central Register of Controlled Trials from the inception of databases to June 2018 for trials in patients undergoing surgery supplemented with pre/pro/synbiotics and randomized to the intervention versus placebo/no treatment and reporting on primarily: (i) putative mechanisms of probiotic/symbiotic action, and secondarily (ii) SSIs and SRCs outcomes. Random-effect model meta-analysis and meta-regression analysis of outcomes was done. Thirty-five trials comprising 3028 adult patients were included; interventions were probiotics (n = 16) and synbiotics (n = 19 trials). We found that C-reactive protein (CRP) and Interleukin-6 (IL-6) were significantly decreased (SMD: -0.40, 95% CI [-0.79, -0.02], p = 0.041; SMD: -0.41, 95% CI [-0.70, -0.02], p = 0.006, respectively) while concentration of acetic, butyric, and propionic acids were elevated in patients supplemented with probiotics (SMD: 1.78, 95% CI [0.80, 2.76], p = 0.0004; SMD: 0.67, 95% CI [0.37, -0.97], p = 0.00001; SMD: 0.46, 95% CI [0.18, 0.73], p = 0.001, respectively). Meta-analysis confirmed that pro- and synbiotics supplementation was associated with significant reduction in the incidence of SRCs including abdominal distention, diarrhea, pneumonia, sepsis, surgery site infection (including superficial incisional), and urinary tract infection, as well as the duration of antibiotic therapy, duration of postoperative pyrexia, time of fluid introduction, solid diet, and duration of hospital stay (p < 0.05). Probiotics and synbiotics administration counteract SSIs/SRCs via modulating gut-immune response and production of short chain fatty acids.

Microbiome-The Missing Link in the Gut-Brain Axis: Focus on Its Role in Gastrointestinal and Mental Health.

The central nervous system (CNS) and the human gastrointestinal (GI) tract communicate through the gut-brain axis (GBA). Such communication is bi-directional and involves neuronal, endocrine, and immunological mechanisms. There is mounting data that gut microbiota is the source of a number of neuroactive and immunocompetent substances, which shape the structure and function of brain regions involved in the control of emotions, cognition, and physical activity. Most GI diseases are associated with altered transmission within the GBA that are influenced by both genetic and environmental factors. Current treatment protocols for GI and non-GI disorders may positively or adversely affect the composition of intestinal microbiota with a diverse impact on therapeutic outcome(s). Alterations of gut microbiota have been associated with mood and depressive disorders. Moreover, mental health is frequently affected in GI and non-GI diseases. Deregulation of the GBA may constitute a grip point for the development of diagnostic tools and personalized microbiota-based therapy. For example, next generation sequencing (NGS) offers detailed analysis of microbiome footprints in patients with mental and GI disorders. Elucidating the role of stem cell⁻host microbiome cross talks in tissues in GBA disorders might lead to the development of next generation diagnostics and therapeutics. Psychobiotics are a new class of beneficial bacteria with documented efficacy for the treatment of GBA disorders. Novel therapies interfering with small molecules involved in adult stem cell trafficking are on the horizon.