Microbiome-targeted Therapies Research Articles

Chronic constipation: focus on microbiome-targeted therapies with prebiotics, probiotics, and synbiotics

Chronic constipation is a global medical, social, and economic problem due to its negative impact on patients’ quality of life and increased risk of colorectal cancer, cardiovascular and cerebrovascular disorders. The gut microbiota plays an important role in the pathophysiology of constipation through its interplay with the immune system, enteral and central nervous system, representing a promising therapeutic target. Gut dysbiosis in patients with constipation is characterized by reduced relative numbers of bacteria producing lactate (Lactobacillaceae, Bifidobacteriaceae) and butyrate (Lachnospiraceae, Oscillospiraceae), as well as with increased numbers of those producing hydrogen sulfide (Desulfovibrionaceae) and methanogenic archaea (Methanobacteriaceae). The leading pathogenetic mechanism related to intestinal dysbiosis in chronic constipation, can be microbial metabolic abnormalities (metabolic dysbiosis) characterized by altered production of short-chain fatty acid, methane, hydrogen sulfide, tryptophan metabolites and by abnormal bile acid biotransformation. It has been proven that dysbiotic abnormalities of the intestinal microbiome play a role in the pathophysiology of constipation, which allows for the use of prebiotics, probiotics, and synbiotics for effective microbiome-modulating therapy in patients with chronic constipation. The proven role of dysbiotic abnormalities of the intestinal microbiome in the pathophysiology of chronic constipation determines the effectiveness of microbiome-modulating therapy (prebiotics, probiotics, synbiotics) in patients with this syndrome. Inulin is the most studied preboitic; it is a soluble food fiber that markedly contributes to the regulation of intestinal microbiota, stimulates the growth of beneficial bacteria, and production of anti-inflammatory metabolites. Inulin normalized the intestinal function in patients with chronic constipation increasing the stool frequency, softening the stool, and reducing the intestinal transit time. In addition, inulin modulates the immune response and impacts the absorption of minerals, appetite, and satiety. Treatment with probiotics is also associated with reduced intestinal transit time, compared to controls. According to a systematic review and meta-analysis of 30 randomized controlled trials, only Bifidobacterium lactis strains (but not other probiotics) significantly increase stool frequencies in chronic constipation in adults. Clinical studies have shown that the targeted probiotic Bifidobacterium lactis HN019 can significantly increase the stool frequencies in patients with low (≤ 3 per week) stool frequency up to 4.7–5.0 per week, reduce the intestinal transit time and the rate of functional gastroenterological symptoms in adults with constipation. Beyond its clinical effects, Bifidobacterium lactis HN019 leads to beneficial changes in intestinal microbiota, significantly increasing the bifidobacteria and decreasing the enterobacteria numbers. The results of trials confirm the importance of synbiotic correction of dysbiotic microbiota in all patients with constipation to increase stool frequencies and improve fecal consistency, as well as to prevent the chronic disorders associated with constipation. Synbiotics, such as a combination of Bifidobacterium lactis HN019 and inulin, with the properties of both complementary and synergic synbiotic, may have the greatest microbiome-modulating and functional potential to significantly improve clinical outcomes in patients with chronic constipation compared to probiotics or prebiotics used alone.

Gut microbiome-targeted therapies as adjuvant treatments in inflammatory bowel diseases: a systematic review and network meta-analysis.

Gut microbiome-targeted therapies (MTTs), including prebiotics, probiotics, synbiotics, and fecal microbiota transplantation (FMT), have been widely used in inflammatory bowel diseases (IBD), but the best MTTs has not yet been confirmed. We performed a network meta-analysis (NMA) to examine this in ulcerative colitis (UC) and Crohn's disease (CD). We searched for randomized controlled trials (RCTs) on the efficacy and safety of MTTs as adjuvant therapies for IBD until December 10, 2023. Data were pooled using a random effects model, with efficacy reported as pooled relative risks with 95% CIs, and interventions ranked according to means of surfaces under cumulative ranking values. Thirty-eight RCTs met the inclusion criteria. Firstly, we compared the efficacy of MTTs in IBD patients. Only FMT and probiotics were superior to placebo in all outcomes, but FMT ranked best in improving clinical response rate and clinical and endoscopic remission rate, and probiotics ranked second in reducing clinical relapse rate showed significant efficacy, while prebiotics ranked first showed nonsignificant efficacy. Subsequently, we conducted NMA for specific MTT formulations in UC and CD separately, which revealed that FMT, especially combined FMT via colonoscopy and enema, showed significant efficacy and was superior in improving clinical response and remission rate of active UC patients. As for endoscopic remission and clinical relapse, multistrain probiotics based on specific genera of Lactobacillus and Bifidobacterium showed significant efficacy and ranked best in UC. In CD, we found that no MTTs were significantly better than placebo, but synbiotics comprising Bifidobacterium and fructo-oligosaccharide/inulin mix and Saccharomyces ranked best in improving clinical remission and reducing clinical relapse, respectively. Moreover, FMT was safe in both UC and CD. FMT and multistrain probiotics showed superior efficacy in UC. However, the efficacy of MTTs varies among different IBD subtypes and disease stages; thus, the personalized treatment strategies of MTTs are necessary.

Changes in Gut Microbial Composition and DNA Methylation in Obese Patients with NAFLD After Bariatric Surgery

This study investigates the effects of bariatric surgery on non-alcoholic fatty liver disease (NAFLD) by examining the interplay between gut microbiota, epigenetics, and metabolic health. A cohort of 22 patients undergoing sleeve gastrectomy (SG) was analyzed for changes in gut microbial composition and DNA methylation profiles before and six months after surgery. Correlations between gut microbial abundance and clinical markers at baseline revealed that certain genera were associated with worse metabolic health and liver markers. Following SG, significant improvements were observed in the clinical, anthropometric, and biochemical parameters of the NAFLD patients. Although alpha-diversity indices (i.e., Chao1, Simpson, Shannon) did not show significant changes, beta-diversity analysis revealed a slight shift in microbial composition (PERMANOVA, p = 0.036). Differential abundance analysis identified significant changes in specific bacterial taxa, including an increase in beneficial Lactobacillus species such as Lactobacillus crispatus and Lactobacillus iners and a decrease in harmful taxa like Erysipelotrichia. Additionally, DNA methylation analysis revealed 609 significant differentially methylated CpG sites between the baseline values and six months post-surgery, with notable enrichment in genes related to the autophagy pathway, such as IRS4 and ATG4B. The results highlight the individualized responses to bariatric surgery and underscore the potential for personalized treatment strategies. In conclusion, integrating gut microbiota and epigenetic factors into NAFLD management could enhance treatment outcomes, suggesting that future research should explore microbiome-targeted therapies and long-term follow-ups on liver health post-surgery.

Exploring the Frontier: The Human Microbiome’s Role in Rare Childhood Neurological Diseases and Epilepsy

Emerging research into the human microbiome, an intricate ecosystem of microorganisms residing in and on our bodies, reveals that it plays a pivotal role in maintaining our health, highlighting the potential for microbiome-based interventions to prevent, diagnose, treat, and manage a myriad of diseases. The objective of this review is to highlight the importance of microbiome studies in enhancing our understanding of rare genetic epilepsy and related neurological disorders. Studies suggest that the gut microbiome, acting through the gut–brain axis, impacts the development and severity of epileptic conditions in children. Disruptions in microbial composition can affect neurotransmitter systems, inflammatory responses, and immune regulation, which are all critical factors in the pathogenesis of epilepsy. This growing body of evidence points to the potential of microbiome-targeted therapies, such as probiotics or dietary modifications, as innovative approaches to managing epilepsy. By harnessing the power of the microbiome, we stand to develop more effective and personalized treatment strategies for children affected by this disease and other rare neurological diseases.

Functional associations of the gut microbiome with dopamine, serotonin, and BDNF in schizophrenia: a pilot study

BackgroundSchizophrenia is a complex neuropsychiatric disorder with various etiologic factors. Aberrant levels of neurotransmitters or growth factors such as dopamine, serotonin, and BDNF have been shown to cause cognitive impairment in schizophrenia. Recently, the gut microbiome has also been suggested as a factor in the development of the disorder. To explore this potential link, we conducted a pilot study to examine the relationship between the gut microbiome and plasma levels of neurotransmitters and growth factors in schizophrenia. Shotgun metagenome sequencing of total RNA from fecal samples were used to profile the gut microbiome of schizophrenia patients (SCZ) and healthy controls (HC). The MetaPhlAn2 and HUMaN2 pipelines were used for bioinformatic analyses. ELISA was used to measure the plasma levels of dopamine, serotonin, and BDNF. Spearman’s rank correlation coefficient was used for correlation analysis.ResultsWe found that butyrate-producing bacteria were enriched in HC, whereas succinate-producing bacteria, namely Phascolarctobacterium succinatutens and Paraprevotella clara, were enriched in SCZ. The gut microbiota of SCZ was enriched in lipid biosynthesis pathways related to bile-resistant bacteria, whereas phospholipid pathways linked with butyrate-producing bacteria were enriched in HC. Alistipes indistinctus, Dorea longicatena, and Roseburia inulinivorans were negatively correlated with dopamine levels. Roseburia intestinalis and Parabacteroides goldsteini were negatively correlated with serotonin and BDNF levels, respectively. We found a significant correlation between dopamine and serotonin levels, and the super-pathway of purine deoxyribonucleoside degradation.ConclusionsThis study provides further support that gut microbiota could modulate neurotransmitter levels. The results suggest that gut microbiome-targeted therapies may help to rebalance neurotransmitter levels, offering new hope for the treatment of schizophrenia.

Sugar-rich foods exacerbate antibiotic-induced microbiome injury.

Intestinal microbiota composition is implicated in several diseases; understanding the factors that influence it are key to elucidating host-commensal interactions and to designing microbiome-targeted therapies. We quantified how diet influences microbiome dynamics in hospitalized patients. We recorded 9,419 meals consumed by 173 patients undergoing hematopoietic cell transplantation and profiled the microbiome in 1,009 longitudinally collected stool samples from 158 of them. Caloric intake was correlated with fecal microbiota diversity. Bayesian inference revealed associations between intake of sweets or sugars during antibiotic exposure with microbiome disruption, as assessed by low diversity or expansion of the pathobiont Enterococcus. We validated this observation experimentally, finding that sucrose exacerbated antibiotic-induced Enterococcus expansion in mice. Taken together, our results suggest that avoiding sugar-rich foods during antibiotic treatment may reduce microbiome injury.

The Role of Gut Microbiome Alterations in the Pathogenesis and Management of Sjögren's Syndrome

Sjögren’s syndrome (SS) is a systemic autoimmune disorder characterized by inflammation and damage to the exocrine glands, leading to symptoms such as ocular and oral dryness, and a range of extraglandular manifestations including polyneuropathies, lung and kidney dysfunction, and systemic vasculitis. Although the exact etiology of SS remains unclear, recent research has highlighted the significant role of gut microbiota in its pathogenesis. Alterations in the gut microbiome, known as dysbiosis, have been implicated in the onset and progression of autoimmune diseases, including SS. This review synthesizes current research on the impact of microbiota on SS, focusing on microbial dysbiosis, its impact on disease severity, and potential therapeutic interventions. Evidence indicates that specific microbial changes, such as reductions in beneficial bacteria and alterations in short-chain fatty acid (SCFA) production, correlate with increased disease activity and systemic inflammation. Microbiome-targeted therapies, including probiotics, prebiotics, and fecal microbiota transplantation, have shown promise in improving SS symptoms and modulating immune responses. Notably, butyrate and specific probiotic strains have demonstrated potential in reducing inflammation and enhancing salivary flow in preclinical studies. However, further research is needed to validate these findings and assess long-term efficacy. This review underscores the importance of gut microbiota in SS and suggests that microbiome-focused treatments could offer new avenues for managing this condition, improving patient outcomes, and potentially preventing disease onset.

Lactobacillus johnsonii is a dominant Lactobacillus in the murine oral mucosa and has chitinase activity that compromises fungal cell wall integrity.

The interactions between the opportunistic pathogen Candida albicans and resident oral bacteria are particularly crucial in maintaining oral health. Emerging antifungal drug-resistant strains, slow-paced drug discovery, and the risk of side effects can compromise the effectiveness of current treatments available for oropharyngeal candidiasis. This study advances the search for alternative microbiome-targeted therapies in oral fungal infections. We report that Lactobacillus johnsonii strain MT4 prevents the Candida-induced bloom of dysbiotic oral enterococci and reduces oral mucosal lesions in an oropharyngeal candidiasis murine model. We also show that this strain directly compromises the cell wall and reduces fungal metabolic activity, partly due to its chitinase activity.

L. acidophilus/L. johnsonii ratio affects slow transit constipation in rats

Slow Transit Constipation (STC) is characterized by impaired colonic motility, but its relationship with gut microbiota remains unclear. This study investigated the correlation between specific gut microbial populations and STC, focusing on the Lactobacillus acidophilus to Lactobacillus johnsonii (A/J) ratio. We used four rat groups: Control (CON), Loperamide-induced STC (LOP), antibiotic-treated (ABX), and antibiotic plus Loperamide (ABX + LOP). Fecal samples were analyzed using 16S rRNA gene sequencing, and serum metabolites were examined through LC–MS. The LOP group showed an increased A/J ratio, while ABX and ABX + LOP groups had decreased ratios. Notably, the ABX + LOP group did not develop STC symptoms. Metabolomic analysis revealed alterations in key metabolites across groups, including changes in levels of guanidinoacetate, glycine, l-glutamine, nicotine, and nicotinate d-ribonucleotide in the LOP group, and variations in l-glutamine, l-phenylalanine, l-tyrosine, histamine, d-ornithine, and lecithin in the ABX and ABX + LOP groups. Our findings suggest a correlation between the A/J ratio and STC development, offering insights into STC pathophysiology and potential microbiome-targeted therapies.

Gender-specific microbial signatures in saliva: Unveiling the association between the oral microbiome and the pathogenesis of glioma

The intricate interplay between the human oral microbiome and systemic health is increasingly being recognized, particularly in the context of central nervous system pathologies such as glioblastoma. In this study, we aimed to elucidate gender-specific differences in the salivary microbiome of glioma patients by utilizing 16S rRNA sequencing data from publicly available salivary microbiome datasets. We conducted comprehensive bioinformatics analysis, encompassing quality control, noise reduction, species classification, and microbial community composition analysis at various taxonomic levels. Machine learning algorithms were employed to identify microbial signatures associated with glioma. When compared to healthy controls, our analysis revealed distinct differences in the salivary microbiota of glioma patients. Notably, the genera Leptotrichia and Atopobium exhibited significant variations in abundance between genders. Leptotrichia was prevalent in healthy females but exhibited a reduced abundance in female glioma patients. In contrast, Atopobium was more abundant in male glioma patients. These findings suggest that hormonal influences might play a role in shaping the salivary microbiome and its association with glioma. We utilized a combination of LASSO-logistic regression and random forest models for feature selection, and identified key microbial features that differentiated glioma patients from healthy controls. We developed a diagnostic model with high predictive accuracy and area under the curve and principal component analysis metrics confirmed its robustness. The analysis of microbial markers, including Atopobium and Leptotrichia, highlighted the potential of the salivary microbiota as a non-invasive biomarker for the diagnosis and prognosis of glioma. Our findings highlight significant gender-specific disparities in the salivary microbiome of patients with glioma, offering new insights into the pathogenesis of glioma and paving the way for innovative diagnostic and therapeutic strategies. The use of saliva as a diagnostic fluid, given its ease of collection and non-invasive nature, holds immense promise for monitoring systemic health and the trajectory of disease. Future research should focus on investigating the underlying mechanisms by which the salivary microbiome influences the development of glioma and identifying potential microbiome-targeted therapies to enhance the management of glioma.

Machine learning based identification potential feature genes for prediction of drug efficacy in nonalcoholic steatohepatitis animal model

BackgroundNonalcoholic Steatohepatitis (NASH) results from complex liver conditions involving metabolic, inflammatory, and fibrogenic processes. Despite its burden, there has been a lack of any approved food-and-drug administration therapy up till now.PurposeUtilizing machine learning (ML) algorithms, the study aims to identify reliable potential genes to accurately predict the treatment response in the NASH animal model using biochemical and molecular markers retrieved using bioinformatics techniques.MethodsThe NASH-induced rat models were administered various microbiome-targeted therapies and herbal drugs for 12 weeks, these drugs resulted in reducing hepatic lipid accumulation, liver inflammation, and histopathological changes. The ML model was trained and tested based on the Histopathological NASH score (HPS); while (0–4) HPS considered Improved NASH and (5–8) considered non-improved, confirmed through rats’ liver histopathological examination, incorporates 34 features comprising 20 molecular markers (mRNAs-microRNAs-Long non-coding-RNAs) and 14 biochemical markers that are highly enriched in NASH pathogenesis. Six different ML models were used in the proposed model for the prediction of NASH improvement, with Gradient Boosting demonstrating the highest accuracy of 98% in predicting NASH drug response.FindingsFollowing a gradual reduction in features, the outcomes demonstrated superior performance when employing the Random Forest classifier, yielding an accuracy of 98.4%. The principal selected molecular features included YAP1, LATS1, NF2, SRD5A3-AS1, FOXA2, TEAD2, miR-650, MMP14, ITGB1, and miR-6881-5P, while the biochemical markers comprised triglycerides (TG), ALT, ALP, total bilirubin (T. Bilirubin), alpha-fetoprotein (AFP), and low-density lipoprotein cholesterol (LDL-C).ConclusionThis study introduced an ML model incorporating 16 noninvasive features, including molecular and biochemical signatures, which achieved high performance and accuracy in detecting NASH improvement. This model could potentially be used as diagnostic tools and to identify target therapies.

In situ targeted base editing of bacteria in the mouse gut

Microbiome research is now demonstrating a growing number of bacterial strains and genes that affect our health1. Although CRISPR-derived tools have shown great success in editing disease-driving genes in human cells2, we currently lack the tools to achieve comparable success for bacterial targets in situ. Here we engineer a phage-derived particle to deliver a base editor and modify Escherichia coli colonizing the mouse gut. Editing of a β-lactamase gene in a model E. coli strain resulted in a median editing efficiency of 93% of the target bacterial population with a single dose. Edited bacteria were stably maintained in the mouse gut for at least 42 days following treatment. This was achieved using a non-replicative DNA vector, preventing maintenance and dissemination of the payload. We then leveraged this approach to edit several genes of therapeutic relevance in E. coli and Klebsiella pneumoniae strains in vitro and demonstrate in situ editing of a gene involved in the production of curli in a pathogenic E. coli strain. Our work demonstrates the feasibility of modifying bacteria directly in the gut, offering a new avenue to investigate the function of bacterial genes and opening the door to the design of new microbiome-targeted therapies.

Dynamic Human Gut Microbiome and Immune Shifts During an Immersive Psychosocial Therapeutic Program.

Depression is a leading cause of disability worldwide yet its underlying factors, particularly microbial associations, are poorly understood. We examined the longitudinal interplay between the microbiome and immune system in the context of depression during an immersive psychosocial intervention. 142 multi-omics samples were collected from 52 well-characterized participants before, during, and three months after a nine-day inquiry-based stress reduction program. We found that depression was associated with both an increased presence of putatively pathogenic bacteria and reduced microbial beta-diversity. Following the intervention, we observed reductions in neuroinflammatory cytokines and improvements in several mental health indicators. Interestingly, participants with a Prevotella-dominant microbiome showed milder symptoms when depressed, along with a more resilient microbiome and more favorable inflammatory cytokine profile, including reduced levels of CXCL-1. Our findings reveal a protective link between the Prevotella-dominant microbiome and depression, associated with a less inflammatory environment and moderated symptoms. These insights, coupled with observed improvements in neuroinflammatory markers and mental health from the intervention, highlight potential avenues for microbiome-targeted therapies in depression management.

Current landscape of fecal microbiota transplantation in treating depression.

Depression, projected to be the predominant contributor to the global disease burden, is a complex condition with diverse symptoms including mood disturbances and cognitive impairments. Traditional treatments such as medication and psychotherapy often fall short, prompting the pursuit of alternative interventions. Recent research has highlighted the significant role of gut microbiota in mental health, influencing emotional and neural regulation. Fecal microbiota transplantation (FMT), the infusion of fecal matter from a healthy donor into the gut of a patient, emerges as a promising strategy to ameliorate depressive symptoms by restoring gut microbial balance. The microbial-gut-brain (MGB) axis represents a critical pathway through which to potentially rectify dysbiosis and modulate neuropsychiatric outcomes. Preclinical studies reveal that FMT can enhance neurochemicals and reduce inflammatory markers, thereby alleviating depressive behaviors. Moreover, FMT has shown promise in clinical settings, improving gastrointestinal symptoms and overall quality of life in patients with depression. The review highlights the role of the gut-brain axis in depression and the need for further research to validate the long-term safety and efficacy of FMT, identify specific therapeutic microbial strains, and develop targeted microbial modulation strategies. Advancing our understanding of FMT could revolutionize depression treatment, shifting the paradigm toward microbiome-targeting therapies.

Understanding Gut Health: Probiotics, Dysbiosis, and their Connection to Type 2 Diabetes - A Review

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder characterized by hyperglycaemia resulting from defects in insulin secretion, insulin action, or both. The pathophysiology of T2DM involves a multifaceted interplay of genetic, behavioural, and environmental factors. Beta cells play a central role in regulating blood glucose levels through intricate mechanisms involving insulin secretion triggered by elevated glucose concentrations and other factors. Dysfunction of beta cells in T2DM encompasses various molecular pathways influenced by factors such as hyperglycaemia, hyperlipidaemia, chronic inflammation, and genetic susceptibility, leading to impaired insulin secretion and insulin resistance. Recent research has highlighted the role of gut dysbiosis in the pathogenesis of T2DM, with alterations in gut microbiome composition impacting glucose metabolism. Dysbiosis-induced intestinal permeability can lead to systemic inflammation, contributing to insulin resistance and diabetes progression. Conversely, a diverse and rich gut microbiome has been associated with protection against obesity, diabetes, and metabolic syndrome. Probiotics, defined as live bacteria conferring health benefits when administered in adequate amounts, hold promise in mitigating T2DM-related metabolic derangements through various mechanisms, including modulation of gut microbiota, regulation of the gut-brain axis, and reduction of chronic low-grade inflammation. This provides a comprehensive overview of the mechanisms through which probiotics may positively impact glucose metabolism and discusses current evidence on the efficacy of probiotic supplementation in improving glycemic parameters and highlights the need for further research to elucidate strain-specific effects, optimal dosages, and long-term outcomes. Additionally, the translation of research findings into clinical practice and the potential of microbiome-targeted therapies for precision management of T2DM are explored, underscoring the importance of evidence-based guidelines for healthcare practitioners.

Modulation of Gut Microbial Biomarkers and Metabolites in Cancer Management by Tea Compounds.

Cancers are causing millions of deaths and leaving a huge clinical and economic burden. High costs of cancer drugs are limiting their access to the growing number of cancer cases. The development of more affordable alternative therapy could reach more patients. As gut microbiota plays a significant role in the development and treatment of cancer, microbiome-targeted therapy has gained more attention in recent years. Dietary and natural compounds can modulate gut microbiota composition while providing broader and more accessible access to medicine. Tea compounds have been shown to have anti-cancer properties as well as modulate the gut microbiota and their related metabolites. However, there is no comprehensive review that focuses on the gut modulatory effects of tea compounds and their impact on reshaping the metabolic profiles, particularly in cancer models. In this review, the effects of different tea compounds on gut microbiota in cancer settings are discussed. Furthermore, the relationship between these modulated bacteria and their related metabolites, along with the mechanisms of how these changes led to cancer intervention are summarized.

Probiotics, prebiotics, synbiotics and other microbiome-based innovative therapeutics to mitigate obesity and enhance longevity via the gut-brain axis.

The global prevalence of obesity currently exceeds 1 billion people and is accompanied by an increase in the aging population. Obesity and aging share many hallmarks and are leading risk factors for cardiometabolic disease and premature death. Current anti-obesity and pro-longevity pharmacotherapies are limited by side effects, warranting the development of novel therapies. The gut microbiota plays a major role in human health and disease, with a dysbiotic composition evident in obese and aged individuals. The bidirectional communication system between the gut and the central nervous system, known as the gut-brain axis, may link obesity to unhealthy aging. Modulating the gut with microbiome-targeted therapies, such as biotics, is a novel strategy to treat and/or manage obesity and promote longevity. Biotics represent material derived from living or once-living organisms, many of which have therapeutic effects. Pre-, pro-, syn- and post-biotics may beneficially modulate gut microbial composition and function to improve obesity and the aging process. However, the investigation of biotics as next-generation therapeutics has only just begun. Further research is needed to identify therapeutic biotics and understand their mechanisms of action. Investigating the function of the gut-brain axis in obesity and aging may lead to novel therapeutic strategies for obese, aged and comorbid (e.g., sarcopenic obese) patient populations. This review discusses the interrelationship between obesity and aging, with a particular emphasis on the gut microbiome, and presents biotics as novel therapeutic agents for obesity, aging and related disease states.

The Potential Impact of the Gut Microbiota on Neonatal Brain Development and Adverse Health Outcomes.

Over the past decade, microbiome research has significantly expanded in both scope and volume, leading to the development of new models and treatments targeting the gut-brain axis to mitigate the effects of various disorders. Related research suggests that interventions during the critical period from birth to three years old may yield the greatest benefits. Investigating the substantial link between the gut and brain during this crucial developmental phase raises fundamental issues about the role of microorganisms in human health and brain development. This underscores the importance of focusing on the prevention rather than the treatment of neurodevelopmental and neuropsychiatric disorders. The present review examines the gut microbiota from birth to age 3, with a particular focus on its potential relationship with neurodevelopment. This review emphasizes the immunological mechanisms underlying this relationship. Additionally, the study investigates the impact of the microbiome on cognitive development and neurobehavioral issues such as anxiety and autism. Importantly, it highlights the need to integrate mechanistic studies of animal models with epidemiological research across diverse cultures to better understand the role of a healthy microbiome in early life and the implications of dysbiosis. Furthermore, this review summarizes factors contributing to the transmission of gut microbiome-targeted therapies and their effects on neurodevelopment. Recent studies on environmental toxins known to impact neurodevelopment are also reviewed, exploring whether the microbiota may mitigate or modulate these effects.

Roles of Traditional and Next-Generation Probiotics on Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH): A Systematic Review and Network Meta-Analysis.

Non-alcoholic fatty liver disease (NAFLD) and its progressive stage, non-alcoholic steatohepatitis (NASH), are becoming one of the most common chronic liver diseases globally. Lifestyle interventions such as weight reduction, increased physical activity, and maintaining healthy diets play a pivotal role in managing NAFLD/NASH. Recent studies suggest that the gut microbiome is associated with the pathogenesis of NAFLD/NASH, prompting microbiome-targeted therapy to emerge as a new therapeutic option for NAFLD/NASH. We conducted a systematic review based on the PRISMA statement and employed network meta-analysis to investigate the effects of traditional probiotics and next-generation probiotics (NGPs) on NAFLD/NASH. Comparative analysis reveals that traditional probiotics primarily reduce liver fat deposition and inflammation by improving gut microbiota composition, enhancing intestinal barrier function, and modulating immune responses. In contrast, NGPs demonstrate a more significant therapeutic potential, attributed to their direct effects on inhibiting oxidative stress and their ability to enhance the production of short-chain fatty acids (SCFAs), NGPs appear as a new potential strategy for the management of NAFLD/NASH through their dual action of directly inhibiting oxidative stress and enhancing SCFA production, highlighting the importance of understanding and utilizing the direct and indirect regulatory mechanisms of oxidative stress in the management of NAFLD/NASH.

Longitudinal gut microbiome changes in immune checkpoint blockade-treated advanced melanoma

Multiple clinical trials targeting the gut microbiome are being conducted to optimize treatment outcomes for immune checkpoint blockade (ICB). To improve the success of these interventions, understanding gut microbiome changes during ICB is urgently needed. Here through longitudinal microbiome profiling of 175 patients treated with ICB for advanced melanoma, we show that several microbial species-level genome bins (SGBs) and pathways exhibit distinct patterns from baseline in patients achieving progression-free survival (PFS) of 12 months or longer (PFS ≥12) versus patients with PFS shorter than 12 months (PFS <12). Out of 99 SGBs that could discriminate between these two groups, 20 were differentially abundant only at baseline, while 42 were differentially abundant only after treatment initiation. We identify five and four SGBs that had consistently higher abundances in patients with PFS ≥12 and <12 months, respectively. Constructing a log ratio of these SGBs, we find an association with overall survival. Finally, we find different microbial dynamics in different clinical contexts including the type of ICB regimen, development of immune-related adverse events and concomitant medication use. Insights into the longitudinal dynamics of the gut microbiome in association with host factors and treatment regimens will be critical for guiding rational microbiome-targeted therapies aimed at enhancing ICB efficacy.