A methionine-choline-deficient diet induces nonalcoholic steatohepatitis and alters the lipidome, metabolome, and gut microbiome profile in the C57BL/6J mouse.

The methionine-choline-deficient (MCD) diet-induced non-alcoholic steatohepatitis (NASH) in mice is a well-established model. Our study aims to elucidate the factors influencing liver pathology in the MCD mouse model by examining physiological, biochemical, and molecular changes using histology, molecular techniques, and OMICS approaches (lipidomics, metabolomics, and metagenomics). Male C57BL/6J mice were fed a standard chow diet, a methionine-choline-sufficient (MCS) diet, or an MCD diet for 10 weeks. The MCD diet resulted in reduced body weight and fat mass, along with decreased plasma triglyceride, cholesterol, glucose, and insulin levels. However, it notably induced steatosis, inflammation, and alterations in gene expression associated with lipogenesis, inflammation, fibrosis, and the synthesis of apolipoproteins, sphingolipids, ceramides, and carboxylesterases. Lipid analysis revealed significant changes in plasma and tissues: most ceramide non-hydroxy-sphingosine lipids significantly decreased in the liver and plasma but increased in the adipose tissue of MCD diet-fed animals. Oxidized glycerophospholipids mostly increased in the liver but decreased in the adipose tissue of the MCD diet-fed group. The gut microbiome of the MCD diet-fed group showed an increase in Firmicutes and a decrease in Bacteroidetes and Actinobacteria. Metabolomic profiling demonstrated that the MCD diet significantly altered amino acid biosynthesis, metabolism, and nucleic acid metabolism pathways in plasma, liver, fecal, and cecal samples. LC-MS data indicated higher total plasma bile acid intensity and reduced fecal glycohyodeoxycholic acid intensity in the MCD diet group. This study demonstrates that although the MCD diet induces hepatic steatosis, the mechanisms underlying NASH in this model differ from those in human NASH pathology.

Mix-match synthesis of nanosynbiotics from probiotics and prebiotics to counter gut dysbiosis via AI integrated formulation profiling.

Antibiotics, improper food, and stress have created a dysbiotic state in the gut and almost 81% of the world's population has been affected due to the pandemic of COVID-19 and the prevalence of dengue virus in the past few years. The main intent of this study is to synthesize nanosynbiotics as nu traceuticals by combining probiotics, and prebiotics with nanoformulation. The effectiveness of the nanosynbiotics was evaluated using a variety of Nutra-pharmacogenetic assays leading to an AI-integrated formulation profiling was assessed by using machine learning methods. Consequently, Acetobacter oryzoeni as a probiotic and inulin as a prebiotic has been chosen and iron-mediated nanoformulation of symbiotic is achieved. Nanosynbiotics possessed 89.4, 96.7, 93.57, 83.53, 88.53% potential powers of Nutra-pharmacogenetic assays. Artificial intelligent solid dispersion formulation of nanosynbiotics has high dissolution, absorption, distribution, and synergism, in addition, they are non-tox, non-allergen and have a docking score of - 10.83 kcal/mol, implying the best interaction with Pregnane X receptor involved in dysbiosis. The potential of nanosynbiotics to revolutionize treatment strategies through precise targeting and modulation of the gut microbiome for improved health outcomes and disease management is promising. Their transformational influence is projected to be powered by integration with modern technology and customized formulas. Further in-vivo studies are required for the validation of nanosynbiotics as nutraceuticals.

Brain-Gut and Microbiota-Gut-Brain Communication in Type-2 Diabetes Linked Alzheimer's Disease.

The gastrointestinal (GI) tract, home to the largest microbial population in the human body, plays a crucial role in overall health through various mechanisms. Recent advancements in research have revealed the potential implications of gut-brain and vice-versa communication mediated by gut-microbiota and their microbial products in various diseases including type-2 diabetes and Alzheimer's disease (AD). AD is the most common type of dementia where most of cases are sporadic with no clearly identified cause. However, multiple factors are implicated in the progression of sporadic AD which can be classified as non-modifiable (e.g., genetic) and modifiable (e.g. Type-2 diabetes, diet etc.). Present review focusses on key players particularly the modifiable factors such as Type-2 diabetes (T2D) and diet and their implications in microbiota-gut-brain (MGB) and brain-gut (BG) communication and cognitive functions of healthy brain and their dysfunction in Alzheimer's Disease. Special emphasis has been given on elucidation of the mechanistic aspects of the impact of diet on gut-microbiota and the implications of some of the gut-microbial products in T2D and AD pathology. For example, mechanistically, HFD induces gut dysbiosis with driven metabolites that in turn cause loss of integrity of intestinal barrier with concomitant colonic and systemic chronic low-grade inflammation, associated with obesity and T2D. HFD-induced obesity and T2D parallel neuroinflammation, deposition of Amyloid ß (Aß), and ultimately cognitive impairment. The review also provides a new perspective of the impact of diet on brain-gut and microbiota-gut-brain communication in terms of transcription factors as a commonly spoken language that may facilitates the interaction between gut and brain of obese diabetic patients who are at a higher risk of developing cognitive impairment and AD. Other commonality such as tyrosine kinase expression and functions maintaining intestinal integrity on one hand and the phagocytic clarence by migratory microglial functions in brain are also discussed. Lastly, the characterization of the key players future research that might shed lights on novel potential pharmacological target to impede AD progression are also discussed.

Pathogenesis of Sarcopenia in Chronic Kidney Disease-The Role of Inflammation, Metabolic Dysregulation, Gut Dysbiosis, and microRNA.

Chronic kidney disease (CKD) is a progressive disorder associated with a decline in kidney function. Consequently, patients with advanced stages of CKD require renal replacement therapies, such as dialysis and kidney transplantation. Various conditions lead to the development of CKD, including diabetes mellitus, hypertension, and glomerulonephritis, among others. The disease is associated with metabolic and hormonal dysregulation, including uraemia and hyperparathyroidism, as well as with low-grade systemic inflammation. Altered homeostasis increases the risk of developing severe comorbidities, such as cardiovascular diseases or sarcopenia, which increase mortality. Sarcopenia is defined as a progressive decline in muscle mass and function. However, the precise mechanisms that link CKD and the development of sarcopenia are poorly understood. Knowledge about these linking mechanisms might lead to the introduction of precise treatment strategies that could prevent muscle wasting. This review discusses inflammatory mediators, metabolic and hormonal dysregulation, gut microbiota dysbiosis, and non-coding RNA alterations that could link CKD and sarcopenia.

Probiotics in Traumatic Brain Injury: New Insights into Mechanisms and Future Perspectives.

Traumatic brain injury (TBI) is a serious global public health issue, recognized as a chronic and progressive disease that can affect multiple organs, including the gastrointestinal (GI) tract. Research shows that there is a specific link between the GI tract and the central nervous system, termed the gut-brain axis, which consists of bidirectional exchange between these two. Several preclinical and clinical studies have demonstrated intestinal barrier dysfunction, intestinal inflammation and gut dysbiosis in patients with TBI. It is proven that probiotics can modulate the inflammatory process and modify gut microbiota. Numerous animal studies and human clinical trials have proven the effectiveness of selected bacterial strains as an adjuvant treatment in reducing inflammation, infection rates and time spent in intensive care of hospitalized patients suffering from brain injury. Thus, this review summarizes the current evidence regarding the beneficial effects of probiotic administration in patients suffering from TBI-related complications. This review will help identify novel therapeutic strategies in the future as probiotics have an extensive history of apparently safe use.

Altered gut microbiota and systemic immunity in Chinese patients with schizophrenia comorbid with metabolic syndrome.

BACKGROUND: Metabolic syndrome (MetS) is highly prevalent in individuals with schizophrenia (SZ), leading to negative consequences like premature mortality. Gut dysbiosis, which refers to an imbalance of the microbiota, and chronic inflammation are associated with both SZ and MetS. However, the relationship between gut dysbiosis, host immunological dysfunction, and SZ comorbid with MetS (SZ-MetS) remains unclear. This study aims to explore alterations in gut microbiota and their correlation with immune dysfunction in SZ-MetS, offering new insights into its pathogenesis. METHODS AND RESULTS: We enrolled 114 Chinese patients with SZ-MetS and 111 age-matched healthy controls from Zhejiang, China, to investigate fecal microbiota using Illumina MiSeq sequencing targeting 16 S rRNA gene V3-V4 hypervariable regions. Host immune responses were assessed using the Bio-Plex Pro Human Cytokine 27-Plex Assay to examine cytokine profiles. In SZ-MetS, we observed decreased bacterial α-diversity and significant differences in ß-diversity. LEfSe analysis identified enriched acetate-producing genera (Megamonas and Lactobacillus), and decreased butyrate-producing bacteria (Subdoligranulum, and Faecalibacterium) in SZ-MetS. These altered genera correlated with body mass index, the severity of symptoms (as measured by the Scale for Assessment of Positive Symptoms and Scale for Assessment of Negative Symptoms), and triglyceride levels. Altered bacterial metabolic pathways related to lipopolysaccharide biosynthesis, lipid metabolism, and various amino acid metabolism were also found. Additionally, SZ-MetS exhibited immunological dysfunction with increased pro-inflammatory cytokines, which correlated with the differential genera. CONCLUSION: These findings suggested that gut microbiota dysbiosis and immune dysfunction play a vital role in SZ-MetS development, highlighting potential therapeutic approaches targeting the gut microbiota. While these therapies show promise, further mechanistic studies are needed to fully understand their efficacy and safety before clinical implementation.

NAFLD/MASLD and the Gut-Liver Axis: From Pathogenesis to Treatment Options.

Nonalcoholic fatty liver disease (NAFLD) poses an emerging threat topublic health. Nonalcoholic steatohepatitis (NASH) is reported to be the most rapidly rising cause of hepatocellular carcinoma in the western world. Recently, a new term has been proposed: metabolic dysfunction-associated steatotic liver disease (MASLD). The introduction of this new terminology has sparked a debate about the interchangeability of these terms. The pathogenesis of NAFLD/MASLD is thought to be multifactorial, involving both genetic and environmental factors. Among these factors, alterations in gut microbiota and gut dysbiosis have recently garnered significant attention. In this context, this review will further discuss the gut-liver axis, which refers to the bidirectional interaction between the human gut microbiota and the liver. Additionally, the therapeutic potential of probiotics, particularly next-generation probiotics and genetically engineered bacteria, will be explored. Moreover, the role of prebiotics, synbiotics, postbiotics, and phages as well as fecal microbiota transplantation will be analyzed. Particularly for lean patients with NAFLD/MASLD, who have limited treatment options, approaches that modify the diversity and composition of the gut microbiota may hold promise. However, due to ongoing safety concerns with approaches that modulate gut microbiota, further large-scale studies are necessary to better assess their efficacy and safety in treating NAFLD/MASLD.

The Relationship between Canine Behavioral Disorders and Gut Microbiome and Future Therapeutic Perspectives.

Canine behavioral disorders have become one of the most common concerns and challenging issues among dog owners. Thus, there is a great demand for knowledge about various factors affecting dogs' emotions and well-being. Among them, the gut-brain axis seems to be particularly interesting, especially since in many instances the standard treatment or behavioral therapies insufficiently improve animal behavior. Therefore, to face this challenge, the search for novel therapeutic methods is highly required. Existing data show that mammals' gut microbiome, immune system, and nervous system are in continuous communication and influence animal physiology and behavior. This review aimed to summarize and discuss the most important scientific evidence on the relationship between mental disorders and gut microbiota in dogs, simultaneously presenting comparable outcomes in humans and rodent models. A comprehensive overview of crucial mechanisms of the gut-brain axis is included. This refers especially to the neurotransmitters crucial for animal behavior, which are regulated by the gut microbiome, and to the main microbial metabolites-short-chain fatty acids (SCFAs). This review presents summarized data on gut dysbiosis in relation to the inflammation process within the organism, as well as the activation of the hypothalamic-pituitary-adrenal (HPA) axis. All of the above mechanisms are presented in this review in strict correlation with brain and/or behavioral changes in the animal. Additionally, according to human and laboratory animal studies, the gut microbiome appears to be altered in individuals with mental disorders; thus, various strategies to manipulate the gut microbiota are implemented. This refers also to the fecal microbiome transplantation (FMT) method, based on transferring the fecal matter from a donor into the gastrointestinal tract of a recipient in order to modulate the gut microbiota. In this review, the possible effects of the FMT procedure on animal behavioral disorders are discussed.

Opioid Use and Gut Dysbiosis in Cancer Pain Patients.

Opioids are commonly used for the management of severe chronic cancer pain. Their well-known pharmacological effects on the gastrointestinal system, particularly opioid-induced constipation (OIC), are the most common limiting factors in the optimization of analgesia, and have led to the wide use of laxatives and/or peripherally acting mu-opioid receptor antagonists (PAMORAs). A growing interest has been recently recorded in the possible effects of opioid treatment on the gut microbiota. Preclinical and clinical data, as presented in this review, showed that alterations of the gut microbiota play a role in modulating opioid-mediated analgesia and tolerability, including constipation. Moreover, due to the bidirectional crosstalk between gut bacteria and the central nervous system, gut dysbiosis may be crucial in modulating opioid reward and addictive behavior. The microbiota may also modulate pain regulation and tolerance, by activating microglial cells and inducing the release of inflammatory cytokines and chemokines, which sustain neuroinflammation. In the subset of cancer patients, the clinical meaning of opioid-induced gut dysbiosis, particularly its possible interference with the efficacy of chemotherapy and immunotherapy, is still unclear. Gut dysbiosis could be a new target for treatment in cancer patients. Restoring the physiological amount of specific gut bacteria may represent a promising therapeutic option for managing gastrointestinal symptoms and optimizing analgesia for cancer patients using opioids.

Role of gut microbiota and immune cells in metabolic-associated fatty liver disease: clinical impact.

In 2020, a revised definition of fatty liver disease associated with metabolic dysfunction (MAFLD) was proposed to replace non-alcoholic fatty liver (NAFLD). Liver steatosis and at least one of the three metabolic risk factors, including type 2 diabetes, obesity, or signs of metabolic dysregulation, are used to diagnose MAFLD. MAFLD, similarly to NAFLD, is characterized by a spectrum of disease ranging from simple steatosis to advanced metabolic steatohepatitis with or without fibrosis, and may progress to cirrhosis and liver cancer, including increased risk of other critical extrahepatic diseases. Even though the pathophysiology of MAFLD and potential therapeutic targets have been explored in great detail, there is yet no Food and Drug Administration approved treatment. Recently, gut microbiome-derived products (e.g., endotoxins and metabolites) involved in intestinal barrier disruption, systemic inflammation, and modification of intrahepatic immunity have been associated with MAFLD development and progression. Therefore, different strategies could be adopted to modify the gut microbiome to improve outcomes in early and progressive MAFLD. Here, we provide an overview of mechanisms that may link the gut microbiome and immune response during the onset of liver steatosis and progression to steatohepatitis and fibrosis in patients with MAFLD. Finally, gut microbiota-based approaches are discussed as potential personalized treatments against MAFLD.

Toll-like receptor 4 mutation mitigates gut microbiota-mediated hypertensive kidney injury.

Hypertension-associated dysbiosis is linked to several clinical complications, including inflammation and possible kidney dysfunction. Inflammation and TLR4 activation during hypertension result from gut dysbiosis-related impairment of intestinal integrity. However, the contribution of TLR4 in kidney dysfunction during hypertension-induced gut dysbiosis is unclear. We designed this study to address this knowledge gap by utilizing TLR4 normal (TLR4N) and TLR4 mutant (TLR4M) mice. These mice were infused with high doses of Angiotensin-II for four weeks to induce hypertension. Results suggest that Ang-II significantly increased renal arterial resistive index (RI), decreased renal vascularity, and renal function (GFR) in TLR4N mice compared to TLR4M. 16 S rRNA sequencing analysis of gut microbiome revealed that Ang-II-induced hypertension resulted in alteration of Firmicutes: Bacteroidetes ratio in the gut of both TLR4N and TLR4M mice; however, it was not comparably rather differentially. Additionally, Ang-II-hypertension decreased the expression of tight junction proteins and increased gut permeability, which were more prominent in TLR4N mice than in TLR4M mice. Concomitant with gut hyperpermeability, an increased bacterial component translocation to the kidney was observed in TLR4N mice treated with Ang-II compared to TLR4N plus saline. Interestingly, microbiota translocation was mitigated in Ang-II-hypertensive TLR4M mice. Furthermore, Ang-II altered the expression of inflammatory (IL-1ß, IL-6) and anti-inflammatory IL-10) markers, and extracellular matrix proteins, including MMP-2, -9, -14, and TIMP-2 in the kidney of TLR4N mice, which were blunted in TLR4M mice. Our data demonstrate that ablation of TLR4 attenuates hypertension-induced gut dysbiosis resulting in preventing gut hyperpermeability, bacterial translocation, mitigation of renal inflammation and alleviation of kidney dysfunction.

Impact of high-salt diet in health and diseases and its role in pursuit of cancer immunotherapy by modulating gut microbiome.

Cancer chemotherapy remains an area of concern, as many of the therapies are uncomfortable involving side effects and unpleasant experiences. These factors could further reduce patient's quality of life, and even endanger their life. Many therapeutic strategies have been tried to reduce the unpleasant side effects and increase the treatment effectiveness; however, none have shown to have promising effects. One of the main hindrances to cancer therapy is the escape strategies by tumor cells to the immune attack. Promoting inflammation in the tumor microenvironment is the cornerstone and key therapeutic target in cancer chemotherapy. High-salt diet (HSD) intake, though it has deleterious effects on human health by promoting chronic inflammation, is found to be advantageous in the tumor microenvironment. Studies identified HSD favors an increased abundance of Bifidobacterium species in the tumor environment due to gut barrier alteration, which, in turn, promotes inflammation and favors improved response to cancer chemotherapy. A review of the literature was carried out to find out the effects of an HSD on health and diseases, with special mention of its effect on cancer chemotherapy. Studies emphasized HSD would block the myeloid-derived suppressor cells which will enhance the tumor immunity. Exploration of the precise mechanism of simple HSD regime/ingestion of specific bacterial species as probiotics will be effective and essential to formulate the game-changing cancer chemotherapy. With the modern era of healthcare moving toward precision medicine where the physician can choose the treatment option suitable for the individual, HSD regime/ingestion of specific bacterial species can be considered.

Role of Claudin- 3 as a biomarker of gut-skin axis integrity in patients with psoriasis.

Increased intestinal permeability and gut dysbiosis are important factors in the pathophysiology of psoriasis and its associated conditions. Claudin-3 is a protein that is found in tight junctions and may be used to assess the integrity of the gut barrier. The aim of this study was to investigate serum concentration of Claudin- 3 (CLDN3) in patients with psoriasis. Exploring its possible relations with patients' demographic, clinical and laboratory findings was another objective. Fifty psoriatic patients and thirty-five age- and sex-matched healthy volunteers served as the study's control group in this case-control, hospital-based research. The amount of serum CLDN3 was determined by means of an enzyme-linked immunosorbent test (ELISA). Concentration of serum CLDN3 was found to be significantly higher in patients with psoriasis. (p = 0.002). There was no statistically significant correlation between CLDN3 and patient's clinical & laboratory variables. We demonstrated that gut permeability is dysfunctional in patients with psoriasis as indicated by reduction of serum CLDN3. Further investigations are needed to determine whether modulation of gut barrier may represent a new therapeutic approach for psoriasis.

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.

How aging influences the gut-bone marrow axis and alters hematopoietic stem cell regulation.

The gut microbiome has come to prominence across research disciplines, due to its influence on major biological systems within humans. Recently, a relationship between the gut microbiome and hematopoietic system has been identified and coined the gut-bone marrow axis. It is well established that the hematopoietic system and gut microbiome separately alter with age; however, the relationship between these changes and how these systems influence each other demands investigation. Since the hematopoietic system produces immune cells that help govern commensal bacteria, it is important to identify how the microbiome interacts with hematopoietic stem cells (HSCs). The gut microbiota has been shown to influence the development and outcomes of hematologic disorders, suggesting dysbiosis may influence the maintenance of HSCs with age. Short chain fatty acids (SCFAs), lactate, iron availability, tryptophan metabolites, bacterial extracellular vesicles, microbe associated molecular patterns (MAMPs), and toll-like receptor (TLR) signalling have been proposed as key mediators of communication across the gut-bone marrow axis and will be reviewed in this article within the context of aging.

Immunological mechanisms in steatotic liver diseases: An overview and clinical perspectives.

Steatotic liver diseases (SLD) are the principal worldwide cause of cirrhosis and end-stage liver cancer, affecting nearly a quarter of the global population. SLD includes metabolic dysfunction-associated alcoholic liver disease (MetALD) and metabolic dysfunction-associated steatotic liver disease (MASLD), resulting in asymptomatic liver steatosis, fibrosis, cirrhosis and associated complications. The immune processes include gut dysbiosis, adipose-liver organ crosstalk, hepatocyte death and immune cell-mediated inflammatory processes. Notably, various immune cells such as B cells, plasma cells, dendritic cells, conventional CD4+ and CD8+ T cells, innate-like T cells, platelets, neutrophils and macrophages play vital roles in the development of MetALD and MASLD. Immunological modulations targeting hepatocyte death, inflammatory reactions and gut microbiome include N-acetylcysteine, selonsertib, F-652, prednisone, pentoxifylline, anakinra, JKB-121, HA35, obeticholic acid, probiotics, prebiotics, antibiotics and FMT. Understanding the immunological mechanisms underlying in SLD is crucial for advancing clinical therapeutic strategies.

Polycystic ovary syndrome: Insights into its prevalence, diagnosis, and management with special reference to gut microbial dysbiosis.

Polycystic ovary syndrome (PCOS) represents major endocrine and metabolic disorder among women largely characterized by hyperandrogenism and oligomenorrhea precipitates serious complications such as type 2 diabetes, early atherosclerosis, infertility, and endometrial cancer. Several etiological theories were proposed to define the exact cause of the PCOS, which is characterized, by the hypothalamic-pituitary axis, ovarian morphology, and release of adrenal steroid hormones, metabolic syndrome, and hereditary factors. The review explored the role of dysbiosis and the mechanisms through which microbial dysbiosis can affect PCOS development. In recent time, various research groups highlighted the role of microbial gut dysbiosis associated with obesity as potential etiological factor for the PCOS. In the present review, we reviewed the mechanisms attributed to the microbial dysbiosis and treatment approaches to deal with the situation.

Antibiotic-induced gut microbe dysbiosis alters neurobehavior in mice through modulation of BDNF and gut integrity.

Gut microbiota is essential for intestinal integrity and brain functions. Herein we aimed to investigate the effects of alteration of gut microbiome using broad-spectrum antibiotics on CD 1 male mice (germ-modified group (GM). Moreover, we co-administrated probiotics with or without antibiotics for four weeks and evaluated if probiotics could reverse these behavioral and intestinal effects. GM, co-administered antibiotics and probiotics, and probiotics-only groups were compared to control mice of the same sex, age, and weight that did not receive either drug (n=12 in all groups). Cultivation of aerobic and anaerobic bacteria was evaluated by fecal culture of all groups. We tested exploratory behavior, anxiety, memory, depression-like behavior, and hippocampal and frontal lobe BDNF protein level alterations in response to antibiotics and its downstream effect on the PI3K/Akt1/Bcl2 pathway. Intestinal integrity was evaluated using gene expression analysis of ZO-1, claudin, and occludin genes. Additionally, the inflammatory TLR4 and p-p38 MAPK pathways in the intestines were investigated. Twice-daily administration of oral antibiotics for four weeks significantly reduced total bacterial count and upregulated TLR4 and p-p38.GM mice showed a significant reduction in BDNF(P =0.04), impaired spatial memory, and long-term memory as evidenced by decreased T maze correct alternation trails and shortened retention time in the passive avoidance test in GM(P =0.01). Passive avoidance showed significantly increased latency after probiotics intake. Depressive-like behavior was more pronounced in GM mice as assessed by the tail suspension test (P =0.01). GM showed significant upregulation(p<0.001) of the TLR4 and p-p38 MAPK pathway. Co-administration of probiotics with antibiotics showed an increase in BDNF levels, and upregulation of the cell survival PI3K/Akt1/Bcl2 pathway, significantly higher relative abundance in the firmucutes members, a significant decrease in the Firmicutes/Bacteroidetes ratio and downregulation of TLR4 and p-p38 MAPK. The tight junction proteins ZO-1, claudin and occludin were downregulated by antibiotic administration for four weeks and restored by probiotics. Collectively, the data suggest that long-term use of antibiotics appears to disrupt the intestinal epithelial barrier and alter neurobehavioral qualities specifically, long-term memory and exploratory drive, possibly through the reduction of BDNF, and probiotics partially reverse these effects. Our study emphasizes the effect of prolonged intake of antibiotics on production of dysbiosis as well as the impact of the antibiotic induced intestinal inflammation on neurobehavioral aspects in mice as the memory and anxiety-like behavior. We also reveal that co-administration of probiotics can reverse these changes.

Gut Dysbiosis Shaped by Cocoa Butter-Based Sucrose-Free HFD Leads to Steatohepatitis, and Insulin Resistance in Mice.

BACKGROUND: High-fat diets cause gut dysbiosis and promote triglyceride accumulation, obesity, gut permeability changes, inflammation, and insulin resistance. Both cocoa butter and fish oil are considered to be a part of healthy diets. However, their differential effects on gut microbiome perturbations in mice fed high concentrations of these fats, in the absence of sucrose, remains to be elucidated. The aim of the study was to test whether the sucrose-free cocoa butter-based high-fat diet (C-HFD) feeding in mice leads to gut dysbiosis that associates with a pathologic phenotype marked by hepatic steatosis, low-grade inflammation, perturbed glucose homeostasis, and insulin resistance, compared with control mice fed the fish oil based high-fat diet (F-HFD). RESULTS: C57BL/6 mice (5-6 mice/group) were fed two types of high fat diets (C-HFD and F-HFD) for 24 weeks. No significant difference was found in the liver weight or total body weight between the two groups. The 16S rRNA sequencing of gut bacterial samples displayed gut dysbiosis in C-HFD group, with differentially-altered microbial diversity or relative abundances. Bacteroidetes, Firmicutes, and Proteobacteria were highly abundant in C-HFD group, while the Verrucomicrobia, Saccharibacteria (TM7), Actinobacteria, and Tenericutes were more abundant in F-HFD group. Other taxa in C-HFD group included the Bacteroides, Odoribacter, Sutterella, Firmicutes bacterium (AF12), Anaeroplasma, Roseburia, and Parabacteroides distasonis. An increased Firmicutes/Bacteroidetes (F/B) ratio in C-HFD group, compared with F-HFD group, indicated the gut dysbiosis. These gut bacterial changes in C-HFD group had predicted associations with fatty liver disease and with lipogenic, inflammatory, glucose metabolic, and insulin signaling pathways. Consistent with its microbiome shift, the C-HFD group showed hepatic inflammation and steatosis, high fasting blood glucose, insulin resistance, increased hepatic de novo lipogenesis (Acetyl CoA carboxylases 1 (Acaca), Fatty acid synthase (Fasn), Stearoyl-CoA desaturase-1 (Scd1), Elongation of long-chain fatty acids family member 6 (Elovl6), Peroxisome proliferator-activated receptor-gamma (Pparg) and cholesterol synthesis (ß-(hydroxy ß-methylglutaryl-CoA reductase (Hmgcr). Non-significant differences were observed regarding fatty acid uptake (Cluster of differentiation 36 (CD36), Fatty acid binding protein-1 (Fabp1) and efflux (ATP-binding cassette G1 (Abcg1), Microsomal TG transfer protein (Mttp) in C-HFD group, compared with F-HFD group. The C-HFD group also displayed increased gene expression of inflammatory markers including Tumor necrosis factor alpha (Tnfa), C-C motif chemokine ligand 2 (Ccl2), and Interleukin-12 (Il12), as well as a tendency for liver fibrosis. CONCLUSION: These findings suggest that the sucrose-free C-HFD feeding in mice induces gut dysbiosis which associates with liver inflammation, steatosis, glucose intolerance and insulin resistance.

Akkermansia muciniphila-derived pentadecanoic acid enhances oxaliplatin sensitivity in gastric cancer by modulating glycolysis.

Accumulating evidence has proved the close association between alterations in gut microbiota and resistance to chemotherapeutic drugs. However, the potential roles of gut microbiota in regulating oxaliplatin sensitivity in gastric cancer (GC) have not been investigated before. We first found that antibiotic treatment diminished the therapeutic efficacy of oxaliplatin in a GC mouse model. Importantly, this effect could be transmitted to germ-free mice via fecal microbiota transplantation, indicating a potential role of gut microbiota modulation in oxaliplatin efficacy. Further, metagenomics data showed that Akkermansia muciniphila (A. muciniphila) ranked first among the bacterial species with decreased relative abundances after antibiotic treatment. Metabolically active A. muciniphila promotes oxaliplatin efficacy. As shown by metabolomics analysis, the metabolic pattern of gut microbiota was disrupted with significantly downregulated levels of pentadecanoic acid (PEA), and the use of PEA significantly promoted oxaliplatin efficacy. Mechanistically, FUBP1 positively regulated aerobic glycolysis of GC cells to hinder the therapeutic efficacy of oxaliplatin. A. muciniphila-derived PEA functioned as an inhibitory factor of glycolysis by directly antagonizing the activity of FUBP1, which potentiated GC responses to oxaliplatin. Our research suggested a key role for intestinal A. muciniphila and its metabolite PEA in promoting oxaliplatin efficacy, thus providing a new perspective for probiotic and prebiotic intervention in GC patients during chemotherapy.