Agata Misera

Bio: Agata Misera is an academic researcher from Pomeranian Medical University. The author has contributed to research in topics: Gut flora & Microbiome. The author has an hindex of 6, co-authored 7 publications receiving 138 citations. Previous affiliations of Agata Misera include Charité.

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

Abstract: 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.

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

Abstract: Multiple drugs are known to induce metabolic malfunctions, among them second-generation antipsychotics (SGAs). The pathogenesis of such adverse effects is of multifactorial origin. 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. 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. 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. 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

Abstract: 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.

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

Abstract: 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

Abstract: 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.

The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of synbiotics

Abstract: In May 2019, the International Scientific Association for Probiotics and Prebiotics (ISAPP) convened a panel of nutritionists, physiologists and microbiologists to review the definition and scope of synbiotics. The panel updated the definition of a synbiotic to “a mixture comprising live microorganisms and substrate(s) selectively utilized by host microorganisms that confers a health benefit on the host”. The panel concluded that defining synbiotics as simply a mixture of probiotics and prebiotics could suppress the innovation of synbiotics that are designed to function cooperatively. Requiring that each component must meet the evidence and dose requirements for probiotics and prebiotics individually could also present an obstacle. Rather, the panel clarified that a complementary synbiotic, which has not been designed so that its component parts function cooperatively, must be composed of a probiotic plus a prebiotic, whereas a synergistic synbiotic does not need to be so. A synergistic synbiotic is a synbiotic for which the substrate is designed to be selectively utilized by the co-administered microorganisms. This Consensus Statement further explores the levels of evidence (existing and required), safety, effects upon targets and implications for stakeholders of the synbiotic concept. Gut microbiota can be manipulated to benefit host health, including the use of probiotics, prebiotics and synbiotics. This Consensus Statement outlines the definition and scope of the term ‘synbiotics’ as determined by an expert panel convened by the International Scientific Association for Probiotics and Prebiotics in May 2019.

Gut Microbiome: Profound Implications for Diet and Disease

Abstract: The gut microbiome plays an important role in human health and influences the development of chronic diseases ranging from metabolic disease to gastrointestinal disorders and colorectal cancer. Of increasing prevalence in Western societies, these conditions carry a high burden of care. Dietary patterns and environmental factors have a profound effect on shaping gut microbiota in real time. Diverse populations of intestinal bacteria mediate their beneficial effects through the fermentation of dietary fiber to produce short-chain fatty acids, endogenous signals with important roles in lipid homeostasis and reducing inflammation. Recent progress shows that an individual’s starting microbial profile is a key determinant in predicting their response to intervention with live probiotics. The gut microbiota is complex and challenging to characterize. Enterotypes have been proposed using metrics such as alpha species diversity, the ratio of Firmicutes to Bacteroidetes phyla, and the relative abundance of beneficial genera (e.g., Bifidobacterium, Akkermansia) versus facultative anaerobes (E. coli), pro-inflammatory Ruminococcus, or nonbacterial microbes. Microbiota composition and relative populations of bacterial species are linked to physiologic health along different axes. We review the role of diet quality, carbohydrate intake, fermentable FODMAPs, and prebiotic fiber in maintaining healthy gut flora. The implications are discussed for various conditions including obesity, diabetes, irritable bowel syndrome, inflammatory bowel disease, depression, and cardiovascular disease.

The Gut-Brain Axis: How Microbiota and Host Inflammasome Influence Brain Physiology and Pathology.

Abstract: The human microbiota has a fundamental role in host physiology and pathology. Gut microbial alteration, also known as dysbiosis, is a condition associated not only with gastrointestinal disorders but also with diseases affecting other distal organs. Recently it became evident that the intestinal bacteria can affect the central nervous system (CNS) physiology and inflammation. The nervous system and the gastrointestinal tract are communicating through a bidirectional network of signaling pathways called the gut-brain axis, which consists of multiple connections, including the vagus nerve, the immune system, and bacterial metabolites and products. During dysbiosis, these pathways are dysregulated and associated with altered permeability of the blood-brain barrier (BBB) and neuroinflammation. However, numerous mechanisms behind the impact of the gut microbiota in neuro-development and -pathogenesis remain poorly understood. There are several immune pathways involved in CNS homeostasis and inflammation. Among those, the inflammasome pathway has been linked to neuroinflammatory conditions such as multiple sclerosis, Alzheimer's and Parkinson's diseases, but also anxiety and depressive-like disorders. The inflammasome complex assembles upon cell activation due to exposure to microbes, danger signals, or stress and lead to the production of pro-inflammatory cytokines (interleukin-1β and interleukin-18) and to pyroptosis. Evidences suggest that there is a reciprocal influence of microbiota and inflammasome activation in the brain. However, how this influence is precisely working is yet to be discovered. Herein, we discuss the status of the knowledge and the open questions in the field focusing on the function of intestinal microbial metabolites or products on CNS cells during healthy and inflammatory conditions, such as multiple sclerosis, Alzheimer's and Parkinson's diseases, and also neuropsychiatric disorders. In particular, we focus on the innate inflammasome pathway as immune mechanism that can be involved in several of these conditions, upon exposure to certain microbes.

The HPA axis dysregulation in severe mental illness: Can we shift the blame to gut microbiota?

Abstract: Accumulating evidence indicates that patients with severe mental disorders, including major depression, bipolar disorder and schizophrenia present with various alterations of the gut microbiota and increased intestinal permeability. In addition, the hypothalamic-pituitary-adrenal (HPA) axis dysregulation and subclinical inflammation have been reported in this group of patients. Although it has been found that the HPA axis dysregulation appears as a consequence of psychosocial stress, especially traumatic life events, the exact mechanisms of this observation remain unclear. Animal model studies have unraveled several mechanisms linking the gut microbiota with the HPA axis dysfunction. Indeed, the gut microbiota can activate the HPA axis through several mediators that cross the blood-brain barrier and include microbial antigens, cytokines and prostaglandins. There is also evidence that various microbial species can affect ileal corticosterone production that may impact the activity of the HPA axis. However, some metabolites released by various microbes, e.g., short-chain fatty acids, can attenuate the HPA axis response. Moreover, several bacteria release neurotransmitters that can directly interact with vagal afferents. It has been postulated that the HPA axis activation can impact the gut microbiota and intestinal permeability. In this article, we discuss various mechanisms linking the gut microbiota with the HPA axis activity and summarize current evidence for a cross-talk between the gut-brain axis and the HPA axis from studies of patients with mood and psychotic disorders. Finally, we show potential clinical implications that can arise from future studies investigating the HPA axis activity with respect to the gut microbiota in severe mental disorders.

A systematic review of gut microbiota composition in observational studies of major depressive disorder, bipolar disorder and schizophrenia

Abstract: Abstract The emerging understanding of gut microbiota as ‘metabolic machinery’ influencing many aspects of physiology has gained substantial attention in the field of psychiatry. This is largely due to the many overlapping pathophysiological mechanisms associated with both the potential functionality of the gut microbiota and the biological mechanisms thought to be underpinning mental disorders. In this systematic review, we synthesised the current literature investigating differences in gut microbiota composition in people with the major psychiatric disorders, major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SZ), compared to ‘healthy’ controls. We also explored gut microbiota composition across disorders in an attempt to elucidate potential commonalities in the microbial signatures associated with these mental disorders. Following the PRISMA guidelines, databases were searched from inception through to December 2021. We identified 44 studies (including a total of 2510 psychiatric cases and 2407 controls) that met inclusion criteria, of which 24 investigated gut microbiota composition in MDD, seven investigated gut microbiota composition in BD, and 15 investigated gut microbiota composition in SZ. Our syntheses provide no strong evidence for a difference in the number or distribution (α-diversity) of bacteria in those with a mental disorder compared to controls. However, studies were relatively consistent in reporting differences in overall community composition (β-diversity) in people with and without mental disorders. Our syntheses also identified specific bacterial taxa commonly associated with mental disorders, including lower levels of bacterial genera that produce short-chain fatty acids (e.g. butyrate), higher levels of lactic acid-producing bacteria, and higher levels of bacteria associated with glutamate and GABA metabolism. We also observed substantial heterogeneity across studies with regards to methodologies and reporting. Further prospective and experimental research using new tools and robust guidelines hold promise for improving our understanding of the role of the gut microbiota in mental and brain health and the development of interventions based on modification of gut microbiota.