Gut Microbiota Transplantation Research Articles

Sex differences and testosterone interfere with the structure of the gut microbiota through the bile acid signaling pathway.

The gut microbiome has a significant impact on human wellness, contributing to the emergence and progression of a range of health issues including inflammatory and autoimmune conditions, metabolic disorders, cardiovascular problems, and psychiatric disorders. Notably, clinical observations have revealed that these illnesses can display differences in incidence and presentation between genders. The present study aimed to evaluate whether the composition of gut microbiota is associated with sex-specific differences and to elucidate the mechanism. 16S-rRNA-sequencing technology, hormone analysis, gut microbiota transplantation, gonadectomy, and hormone treatment were employed to investigate the correlation between the gut microbiome and sex or sex hormones. Meanwhile, genes and proteins involved bile acid signaling pathway were analyzed both in the liver and ileum tissues. The composition and diversity of the microbiota from the jejunum and feces and the level of sex hormones in the serum differed between the sexes in young and middle-aged Sprague Dawley (SD) rats. However, no similar phenomenon was found in geriatric rats. Interestingly, whether in young, middle-aged, or old rats, the composition of the microbiota and bacterial diversity differed between the jejunum and feces in rats. Gut microbiota transplantation, gonadectomy, and hormone replacement also suggested that hormones, particularly testosterone (T), influenced the composition of the gut microbiota in rats. Meanwhile, the mRNA and protein level of genes involved bile acid signaling pathway (specifically SHP, FXR, CYP7A1, and ASBT) exhibited gender-specific differences, and T may play a significant role in mediating the expression of this pathway. Sex-specific differences in the structure of the gut microbiota are mediated by T through the bile acid signaling pathway, pointing to potential targets for disease prevention and management techniques by indicating that sex differences and T levels may alter the composition of the gut microbiota via the bile acid signaling pathway.

Paclitaxel chemotherapy disrupts microbiota-enterohepatic bile acid metabolism in mice

ABSTRACT Balanced interactions between the enteric microbiota and enterohepatic organs are essential to bile acid homeostasis, and thus normal gastrointestinal function. Disruption of these interactions by cancer treatment instigates bile acid malabsorption, leading to treatment delays, malnutrition, and decreased quality of life. However, the nature of chemotherapy-induced bile acid malabsorption remains poorly characterized with limited treatment options. Therefore, this study sought to characterize changes in hepatic, enteric, and microbial bile acid metabolism in a mouse model of chemotherapy-induced toxicity. Consistent with clinical bile acid malabsorption, chemotherapy increased fecal excretion of primary bile acids and water, while diminishing microbiome diversity, secondary bile acid formation, and small intestinal bile acid signaling. We identified new contributors to pathology of bile acid malabsorption in the forms of lipopolysaccharide-induced cholestasis and colonic crypt hyperplasia from reduced secondary bile acid signaling. Chemotherapy reduced markers of hepatic bile flow and bile acid synthesis, elevated markers of fibrosis and endotoxemia, and altered transcription of genes at all stages of bile acid metabolism. Primary hepatocytes exposed to lipopolysaccharide (but not chemotherapy) replicated chemotherapy-induced transcriptional differences, while gut microbial transplant into germ-free mice replicated very few differences. In the colon, chemotherapy-altered bile acid profiles (particularly higher tauromuricholic acid and lower hyodeoxycholic acid) coincided with crypt hyperplasia. Exposing primary colonoids to hyodeoxycholic acid reduced proliferation, while gut microbiota transplant enhanced proliferation. Together, these investigations reveal complex involvement of the entire microbiota-enterohepatic axis in chemotherapy-induced bile acid malabsorption. Interventions to reduce hepatic lipopolysaccharide exposure and enhance microbial bile acid metabolism represent promising co-therapies to cancer treatment.

Changes in Type 1 Diabetes-Associated Gut Microbiota Aggravate Brain Ischemia Injury by Affecting Microglial Polarization Via the Butyrate-MyD88 Pathway in Mice.

People with type 1 diabetes (T1D) have a significantly elevated risk of stroke, but the mechanism through which T1D worsens ischemic stroke remains unclear. This study was aimed at investigating the roles of T1D-associated changes in the gut microbiota in aggravating ischemic stroke and the underlying mechanism. Fecal 16SrRNA sequencing indicated that T1D mice and mice with transplantation of T1D mouse gut microbiota had lower relative abundance of butyric acid producers, f_Erysipelotrichaceae and g_Allobaculum, and lower content of butyric acid in feces. After middle cerebral artery occlusion (MCAO), these mice had poorer neurological outcomes and more severe inflammation, but higher expression of myeloid differentiation factor 88 (MyD88) in the ischemic penumbra; moreover, the microglia were inclined to polarize toward the pro-inflammatory type. Administration of butyrate to T1D mice in the drinking water alleviated the neurological damage after MCAO. Butyrate influenced the response and polarization of BV2 and decreased the production of inflammatory cytokines via MyD88 after oxygen-glucose deprivation/reoxygenation. Knocking down MyD88 in the brain alleviated neurological outcomes and decreased the concentrations of inflammatory cytokines in the brain after stroke in mice with transplantation of T1D mouse gut microbiota. Poor neurological outcomes and aggravated inflammatory responses of T1D mice after ischemic stroke may be partly due to differences in microglial polarization mediated by the gut microbiota-butyrate-MyD88 pathway. These findings provide new ideas and potential intervention targets for alleviating neurological damage after ischemic stroke in T1D.

Litchi Procyanidins Ameliorate DSS-Induced Colitis through Gut Microbiota-Dependent Regulation of Treg/Th17 Balance.

Ulcerative colitis (UC) is a common chronic, relapsing inflammatory bowel condition. Procyanidins (PC) are known for their antiangiogenic, anti-inflammatory, antioxidant, and antimetastatic properties. However, there is comparatively limited information on how PC interacts with UC. In this study, 5 mg/10 mL/kg body weight of PC was administered to mice with dextran sulfate sodium (DSS)-induced colitis mice. PC treatment prolonged the survival period of mice, ameliorated UC symptoms, reduced damage to the intestinal mucosal barrier, and increased the protein expression of ZO-1 and occludin in the DSS-treated mice. Importantly, PC treatment significantly reduced gene expression related to Th17 cell differentiation, including STAT3, SMAD3, TGF-β, and JAK1. The results of the flow cytometry analysis indicated significant increase in the number of Treg cells and a concomitant decrease in the proportion of Th17 cells in the colon following PC treatment. Additionally, PC increased the abundance of gut microbiota such as Bacteroidota, Oscillospiraceae, Muribaculaceae, and Desulfovibrionaceae, as well as the concentrations of acetate acid, propionate acid, and butyrate acid in the feces. PC also activated short-chain fatty acid receptors, such as G-protein coupled receptor 43 in the colon, which promoted the proliferation of Treg cells. The depletion of gut microbiota and subsequent transplantation of fecal microbiota demonstrated that PC's effects on gut microbiota were effective in improving UC and restoring intestinal Th17/Treg homeostasis in a microbiota-dependent manner. This suggests that PC could be a promising functional food for the prevention and treatment of UC in the future.

Tremella aurantialba polysaccharides alleviate ulcerative colitis in mice by improving intestinal barrier via modulating gut microbiota and inhibiting ferroptosis

We aimed to investigate the effect of a polysaccharide from Tremella aurantialba on ulcerative colitis (UC), which targets ferroptosis in epithelial cells. TA 2-1 (127 kDa) was isolated from T. aurantialba and consisted of Man, Xyl, GlcA, Glc, Fuc and Rha with a molar ratio of 59.2: 23.2: 13.9: 1.6: 1.7: 0.4, exhibited a 1, 3-Man structure with branch chains of T-Xylp, 1,3-Xylp, 1,4-GlcAp, and T-Manp at its O-2 position. TA 2-1 (100 μg/mL) inhibited the cell viability of ferroptosis (19.8 %) in RLS3-induced Caco-2 cells and significantly ameliorated symptoms in the colons of mice with dextran sodium sulfate (DSS)-induced UC. TA 2-1 remarkably repaired the intestinal barrier by upregulating claudin-1 and zonula occludens-1 levels. Further analysis found TA 2-1 significantly suppressed lipid peroxidation by regulating ferroptosis-related proteins in UC mice, suggesting that its protective effects are partially mediated by inhibiting ferroptosis. Further analysis of the gut microbiota and fecal microbiota transplantation revealed TA 2-1 might relieve UC symptoms or inhibit ferroptosis by modulating the gut microbiota's composition or metabolites. Results suggest the protective effects of TA 2-1 on the intestinal barrier by inhibiting ferroptosis of epithelial cells, at least by regulating the gut microbiota, highlighting the potential of TA 2-1 in UC treatment.

Toralactone alleviates cisplatin-induced acute kidney injury by modulating the gut microbiota-renal axis

BackgroundGut microbiota has been reported to be perturbed by cisplatin and to modulate the nephrotoxicity of chemotherapeutic agents. However, the critical role of toralactone, a bioactive components of Cassia obtusifolia L. seeds, in modulating the gut microbiota in the pathogenesis of cisplatin-induced nephrotoxicity remains to be elucidated. Methods: In this study, we verified the reno-protective effects of toralactone and compared the composition and function of the gut microbiota in the normal, cisplatin-treated and low or high dose of toralactone-treated mice using 16S rDNA gene sequencing. We also investigated the gut microbiota related LPS/TLR4/NF-κB/TNF-α pathway in renal tissue. To elucidate the causal relationship between gut dysbiosis and cisplatin nephrotoxicity, an antibiotic cocktail was administered to deplete the gut microbiota and fecal microbiota transplantation (FMT) was performed prior to cisplatin treatment. Results: The renal histopathology showed that toralactone significantly alleviated cisplatin-induced renal injury. 16S rDNA gene sequencing analysis demonstrated that toralactone treatment effectively reversed cisplatin-induced gut microbiota dysbiosis in mice. FMT from toralactone-treated mice to cisplatin-induced kidney injury mice was observed to have the reno-protective effects, and deletion of gut microbiota by antibiotics was found to negate the reno-protective effect of toralactone. Interestingly, the renal tissue of cisplatin-associated kidney injury mice showed activation of the LPS/TLR4/NF-κB pathway and increase in TNF-α within the renal tissue, whereas toralactone treatment was observed to inhibit the LPS/TLR4/NF-κB/TNF-α pathway. Conclusion: This study elucidated the reno-protective effects for the first time, demonstrating that it exerts its beneficial effects through the gut microbiota, which mediate the LPS/TLR4/NF-κB/TNF-α inflammatory pathway. It may help to develop therapeutic approaches using toralactone and targeted restoration of the gut microbiota.

Gut microbiota mediates anxiety-like behaviors induced by chronic infection of Toxoplasma gondii in mice

ABSTRACT Background Chronic infection with the neurotropic parasite Toxoplasma gondii (T. gondii) can cause anxiety and gut microbiota dysbiosis in hosts. However, the potential role of gut microbiota in anxiety induced by the parasite remains unclear. Methods C57BL/6J mice were infected with 10 cysts of T. gondii. Antibiotic depletion of gut microbiota and fecal microbiota transplantation experiments were utilized to investigate the causal relationship between gut microbiota and anxiety. Anxiety-like behaviors were examined by the elevated plus maze test and the open field test; blood, feces, colon and amygdala were collected to evaluate the profiles of serum endotoxin (Lipopolysaccharide, LPS) and serotonin (5-hydroxytryptamine, 5-HT), gut microbiota composition, metabolomics, global transcriptome and neuroinflammation in the amygdala. Furthermore, the effects of Diethyl butylmalonate (DBM, an inhibitor of mitochondrial succinate transporter, which causes the accumulation of endogenous succinate) on the disorders of the gut-brain axis were evaluated. Results Here, we found that T. gondii chronic infection induced anxiety-like behaviors and disturbed the composition of the gut microbiota in mice. In the amygdala, T. gondii infection triggered the microglial activation and neuroinflammation. In the colon, T. gondii infection caused the intestinal dyshomeostasis including elevated colonic inflammation, enhanced bacterial endotoxin translocation to blood and compromised intestinal barrier. In the serum, T. gondii infection increased the LPS levels and decreased the 5-HT levels. Interestingly, antibiotics ablation of gut microbiota alleviated the anxiety-like behaviors induced by T. gondii infection. More importantly, transplantation of the fecal microbiota from T. gondii-infected mice resulted in anxiety and the transcriptomic alteration in the amygdala of the antibiotic-pretreated mice. Notably, the decreased abundance of succinate-producing bacteria and the decreased production of succinate were observed in the feces of the T. gondii-infected mice. Moreover, DBM administration ameliorated the anxiety and gut barrier impairment induced by T. gondii infection. Conclusions The present study uncovers a novel role of gut microbiota in mediating the anxiety-like behaviors induced by chronic T. gondii infection. Moreover, we show that DBM supplementation has a beneficial effect on anxiety. Overall, these findings provide new insights into the treatment of T. gondii-related mental disorders.

Intestinal IL-33 promotes microbiota-derived trimethylamine N -oxide synthesis and drives metabolic dysfunction-associated steatotic liver disease progression by exerting dual regulation on HIF-1α.

Gut microbiota plays a prominent role in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). IL-33 is highly expressed at mucosal barrier sites and regulates intestinal homeostasis. Herein, we aimed to investigate the role and mechanism of intestinal IL-33 in MASLD. In both humans and mice with MASLD, hepatic expression of IL-33 and its receptor suppression of tumorigenicity 2 (ST2) showed no significant change compared to controls, while serum soluble ST2 levels in humans, as well as intestinal IL-33 and ST2 expression in mice were significantly increased in MASLD. Deletion of global or intestinal IL-33 in mice alleviated metabolic disorders, inflammation, and fibrosis associated with MASLD by reducing intestinal barrier permeability and rectifying gut microbiota dysbiosis. Transplantation of gut microbiota from IL-33 deficiency mice prevented MASLD progression in wild-type mice. Moreover, IL-33 deficiency resulted in a decrease in the abundance of trimethylamine N -oxide-producing bacteria. Inhibition of trimethylamine N -oxide synthesis by 3,3-dimethyl-1-butanol mitigated hepatic oxidative stress in mice with MASLD. Nuclear IL-33 bound to hypoxia-inducible factor-1α and suppressed its activation, directly damaging the integrity of the intestinal barrier. Extracellular IL-33 destroyed the balance of intestinal Th1/Th17 and facilitated Th1 differentiation through the ST2- Hif1a - Tbx21 axis. Knockout of ST2 resulted in a diminished MASLD phenotype resembling that observed in IL-33 deficiency mice. Intestinal IL-33 enhanced gut microbiota-derived trimethylamine N -oxide synthesis and aggravated MASLD progression through dual regulation on hypoxia-inducible factor-1α. Targeting IL-33 and its associated microbiota may provide a potential therapeutic strategy for managing MASLD.

Intestinal microbiota dysbiosis contributes to the liver damage in subchronic arsenic-exposed mice.

There is an extensive amount of evidence that links changes in the intestinal microbiota structure to the progression and pathophysiology of many liver diseases. However, comprehensive analysis of gut flora dysbiosis in arsenic-induced hepatotoxicity is lacking. Herein, C57BL/6 mice are exposed to arsenic (1, 2, or 4 mg/kg) for 12 weeks, after which fecal microbiota transplantation (FMT) study is conducted to confirm the roles of the intestinal microbiome in pathology. Treatment with arsenic results in pathological and histological changes in the liver, such as inflammatory cell infiltration and decreased levels of TP and CHE but increased levels of ALP, GGT, TBA, AST, and ALT. Arsenic causes an increase in the relative abundance of Escherichia-Shigella, Klebsiella and Blautia, but a decrease in the relative abundance of Muribaculum and Lactobacillus. In arsenic-exposed mice, protein expressions of Occludin, ZO-1, and MUC2 are significantly decreased, but the level of FITC in serum is increased, and FITC fluorescence is extensively dispersed in the intestinal tract. Importantly, FMT experiments show that mice gavaged with stool from arsenic-treated mice exhibit severe inflammatory cell infiltration in liver tissues. Arsenic-manipulated gut microbiota transplantation markedly facilitates gut flora dysbiosis in the recipient mice, including an up-regulation in Escherichia-Shigella and Bacteroides, and a down-regulation in Lactobacillus and Desulfovibrio. In parallel with the intestinal microbiota wreck, protein expressions of Occludin, ZO-1, and MUC2 are decreased. Our findings suggest that subchronic exposure to arsenic can affect the homeostasis of the intestinal microbiota, induce intestinal barrier dysfunction, increase intestinal permeability, and cause damage to liver tissues in mice.

The main factors that improve gut microbiota composition

The aim is to observe and compare the main factors that can improve gut microbiota composition. Materials and methods. The literature study research was performed in PubMed and Google Scholar electronic databases. We assessed more than 300 studies, data from 65 of which were included in this review. They are presented in three tables: nonpharmacological influence on gut microbiota composition, drugs impact on gut microbiota, and medicines prescribed for gut microbiota correction. Results. On the one hand, non-pharmacological methods of gut microbiota improvement are the safest and the most traditional: healthy diet and physical activity, good sleep, avoiding stress and bad habits, but they are the most difficult for patients’ fulfillment and doctors’ observation. All listed are the components of a healthy way of life and should be followed by everybody. The most prescribed drugs have a significant influence on gut microbiota composition, so physicians should consider their effects in prescriptions. They are antibiotics, steroids and non-steroids, proton pump inhibitors, laxatives, antidepressants, etc. On the other hand, despite the diversity of available medicines (prebiotics, probiotics, paraprobiotics, postbiotics, synbiotics, and antibiotics) that can be used for gut microbiota improvement, all of them are under investigation and need further evaluation. The trendiest medicines for today are paraprobiotics and postbiotics. Paraprobiotics are represented by heat / ultraviolet / sonication Lactobacillus spp., Bifidobacterium spp., and Saccharomyces strains. Postbiotics are performed by short-chain fatty acids, secreted biosurfactants, secreted proteins, organic acids, amino acids, bacteriocins, vitamins, and peptides. Most of the data on their pharmacodynamics is based on animal studies or experimental research, so they need further investigations. Fecal gut microbiota transplantation is also an up-to-date method for multiple disease correction but is approved only for the treatment of recurrent and refractory infections caused by Clostridium difficile. Conclusions. Gut microbiota composition improvement methods are an up-to-date topic for practical medicine because gut microbiota changes are closely linked with host health status. Gut microbiota violations lead to metabolic, cardiovascular, neurological, inflammatory disorders, etc. Nowadays the healthy way of life is the best gut microbiota composition improvement method, but prebiotics, probiotics, paraprobiotics, postbiotics, synbiotics, antibiotics supplementation, and fecal microbiota transplantation also take place and have their indisputable advantages in special cases. Unfortunately, most pharmacological methods of gut microbiota modulation have a weak evidence base. Therefore, this question needs further research in appropriate patient groups with long-term monitoring.

Transplantation of gut microbiota derived from patients with schizophrenia induces schizophrenia-like behaviors and dysregulated brain transcript response in mice

Schizophrenia (SCZ), as a neurodevelopmental disorder and devastating disease, affects approximately 1% of the world population. Although numerous studies have attempted to elucidate the causes of SCZ occurrence, it is not clearly understood. Recently, the emerging roles of the gut microbiota in a range of brain disorders, including SCZ, have attracted much attention. While the molecular mechanism of gut microbiota in regulating the pathogenesis of SCZ is still lacking. Here, we first confirmed the difference of gut microbiome between SCZ patients and healthy controls, and then, we performed fecal microbiota transplantation (FMT) to clarify the roles of SCZ patients-derived microbiota in a specific pathogen free (SPF) mice model. 16 S rDNA sequencing confirmed that a significant difference of gut microbiome was present between two groups of FMT mice, which has a similar trend with the above human gut microbiome. Furthermore, we found that transplantation of fecal microbiota from SCZ patients into SPF mice was sufficient to induce schizophrenia-like (SCZ-like) symptoms, such as deficits in sociability and hyperactivity. Furthermore, the brains of mice colonized with SCZ microbiota displayed dysregulated transcript response and alternative splicing of SCZ-relevant genes. Moreover, 10 key genes were identified to be correlated with SCZ by an integrative transcriptome data analysis. Finally, 4 key genes were identified to be correlated with the 12 differential genera between two groups of FMT mice. Our results thus demonstrated that the gut microbiome might modify the transcriptomic profile in the brain, thereby modulating social behavior, and our present study can help better understand the link between gut microbiota and SCZ pathogenesis through the gut-brain axis.

Queen bee gut microbiota extends honeybee lifespan by inhibiting insulin signaling.

Queen and worker bees share the same genetic background but have vastly different lifespans. The gut microbiome regulates host health, suggesting that differences in lifespan between queen and worker bees could be related to gut bacteria. Herein, we used an innovative method to transplant gut microbiota from adult queen or worker bees to microbiota-free bees. The transplantation of queen gut microbiota to microbiota-free bees extended their lifespan. Insulin/insulin-like growth factor signaling, a highly conserved metabolic pathway related to lifespan, displayed identical expression profiles in natural queen bees and microbiota-free bees transplanted with queen microbiota. This finding significantly expands our understanding of the relationships between intestinal bacteria, host health, and the biology of aging.

Exploring the Role of Inulin in Targeting the Gut Microbiota: An Innovative Strategy for Alleviating Colonic Fibrosis Induced By Irradiation.

The use of radiation therapy to treat pelvic and abdominal cancers can lead to the development of either acute or chronic radiation enteropathy. Radiation-induced chronic colonic fibrosis is a common gastrointestinal disorder resulting from the above radiation therapy. In this study, we establish the efficacy of inulin supplements in safeguarding against colonic fibrosis caused by irradiation therapy. Studies have demonstrated that inulin supplements enhance the proliferation of bacteria responsible to produce short-chain fatty acids (SCFAs) and elevate the levels of SCFAs in feces. In a mouse model of chronic radiation enteropathy, the transplantation of gut microbiota and its metabolites from feces of inulin-treated mice were found to reduce colonic fibrosis in validation experiments. Administering inulin-derived metabolites from gut microbiota led to a notable decrease in the expression of genes linked to fibrosis and collagen production in mouse embryonic fibroblast cell line NIH/3T3. In the cell line, inulin-derived metabolites also suppressed the expression of genes linked to the extracellular matrix synthesis pathway. The results indicate a novel and practical approach to safeguarding against chronic radiation-induced colonic fibrosis.

Analysis on the change of gut microbiota and metabolome in lung transplant patients.

This study has profound implications for lung transplantation as it uncovers the important role of gut microbiota and metabolome in shaping transplantation outcomes. The identification of dominant bacterial genera, such as Enterococcus and Streptococcus, within the lung transplant cohort, along with the significant decrease in Bacteroides, Epulopiscium, Faecalibacterium, and Prevotella abundance, reveals potential microbial imbalances associated with lung transplantation. In addition, a significant reduction in ATRA (all-trans retinoic acid) levels and suppression of IgA production were observed in lung transplant recipients, which were found to be closely associated with the Enterococcus genus. It was speculated that the association might have implications for the prognosis of lung transplant patients. These findings hold immense clinical significance as they lay the groundwork for future research and targeted therapeutic interventions. Understanding the impact of the gut microbiota and metabolome on lung transplantation outcomes offers promising avenues for improving transplantation patient prognosis.

Gut dysbiosis induces the development of depression-like behavior through abnormal synapse pruning in microglia-mediated by complement C3

BackgroundRemodeling eubiosis of the gut microenvironment may contribute to preventing the occurrence and development of depression. Mounting experimental evidence has shown that complement C3 signaling is associated with the pathogenesis of depression, and disruption of the gut microbiota may be an underlying cause of complement system activation. However, the mechanism by which complement C3 participates in gut-brain crosstalk in the pathogenesis of depression remains unknown.ResultsIn the present study, we found that chronic unpredictable mild stress (CUMS)-induced mice exhibited obvious depression-like behavior as well as cognitive impairment, which was associated with significant gut dysbiosis, especially enrichment of Proteobacteria and elevation of microbiota-derived lipopolysaccharides (LPS). In addition, peripheral and central complement C3 activation and central C3/CR3-mediated aberrant synaptic pruning in microglia have also been observed. Transplantation of gut microbiota from CUMS-induced depression model mice into specific pathogen-free and germ-free mice induced depression-like behavior and concomitant cognitive impairment in the recipient mice, accompanied by increased activation of the complement C3/CR3 pathway in the prefrontal cortex and abnormalities in microglia-mediated synaptic pruning. Conversely, antidepressants and fecal microbiota transplantation from antidepressant-treated donors improved depression-like behaviors and restored gut microbiome disturbances in depressed mice. Concurrently, inhibition of the complement C3/CR3 pathway, amelioration of abnormal microglia-mediated synaptic pruning, and increased expression of the synapsin and postsynaptic density protein 95 were observed. Collectively, our results revealed that gut dysbiosis induces the development of depression-like behaviors through abnormal synapse pruning in microglia-mediated by complement C3, and the inhibition of abnormal synaptic pruning is the key to targeting microbes to treat depression.ConclusionsOur findings provide novel insights into the involvement of complement C3/CR3 signaling and aberrant synaptic pruning of chemotactic microglia in gut-brain crosstalk in the pathogenesis of depression.7Y-kpmDzT5DuysQHRM1-uuVideo

Gut microbiota contributes to bisphenol A-induced maternal intestinal and placental apoptosis, oxidative stress, and fetal growth restriction in pregnant ewe model by regulating gut-placental axis

BackgroundBisphenol A (BPA) is an environmental contaminant with endocrine-disrupting properties that induce fetal growth restriction (FGR). Previous studies on pregnant ewes revealed that BPA exposure causes placental apoptosis and oxidative stress (OS) and decreases placental efficiency, consequently leading to FGR. Nonetheless, the response of gut microbiota to BPA exposure and its role in aggravating BPA-mediated apoptosis, autophagy, mitochondrial dysfunction, endoplasmic reticulum stress (ERS), and OS of the maternal placenta and intestine are unclear in an ovine model of gestation.ResultsTwo pregnant ewe groups (n = 8/group) were given either a subcutaneous (sc) injection of corn oil (CON group) or BPA (5 mg/kg/day) dissolved in corn oil (BPA group) once daily, from day 40 to day 110 of gestation. The maternal colonic digesta and the ileum and placental tissue samples were collected to measure the biomarkers of autophagy, apoptosis, mitochondrial dysfunction, ERS, and OS. To investigate the link between gut microbiota and the BPA-induced FGR in pregnant ewes, gut microbiota transplantation (GMT) was conducted in two pregnant mice groups (n = 10/group) from day 0 to day 18 of gestation after removing their intestinal microbiota by antibiotics. The results indicated that BPA aggravates apoptosis, ERS and autophagy, mitochondrial function injury of the placenta and ileum, and gut microbiota dysbiosis in pregnant ewes. GMT indicated that BPA-induced ERS, autophagy, and apoptosis in the ileum and placenta are attributed to gut microbiota dysbiosis resulting from BPA exposure.ConclusionsOur findings indicate the underlying role of gut microbiota dysbiosis and gut-placental axis behind the BPA-mediated maternal intestinal and placental apoptosis, OS, and FGR. The findings further provide novel insights into modulating the balance of gut microbiota through medication or probiotics, functioning via the gut-placental axis, to alleviate gut-derived placental impairment or FGR.DorkkcsjvJM4thb48aSHyrVideo

Age-Related Gut Microbiota Transplantation Disrupts Myocardial Energy Homeostasis and Induces Oxidative Damage

BackgroundAging-related energy homeostasis significantly affects normal heart function and disease development. The relationship between the gut microbiota and host energy metabolism has been well established. However, the influence of an aged microbiota on energy metabolism in the heart remains unclear. ObjectiveThe objective of this was to explore the effects of age-related microbiota composition on energy metabolism in the heart. MethodsIn this study, we used the fecal microbiota transplantation (FMT) method. The fecal microbiota from young (2–3 mo) and aged (18–22 mo) donor mice were transplanted into separate groups of young (2–3 mo) recipient mice. The analysis utilized whole 16S rRNA sequencing and plasma metabolomics to assess changes in the gut microbiota composition and metabolic potential. Energy changes were monitored by performing an oral glucose tolerance test, biochemical testing, body composition analysis, and metabolic cage measurements. Metabolic markers and markers of DNA damage were assessed in heart samples. ResultsFMT of an aged microbiota changed the composition of the recipient’s gut microbiota, leading to an elevated Firmicutes-to-Bacteroidetes ratio. It also affected overall energy metabolism, resulting in elevated plasma glucose concentrations, impaired glucose tolerance, and epididymal fat accumulation. Notably, FMT of an aged microbiota increased the heart weight and promoted cardiac hypertrophy. Furthermore, there were significant associations between heart weight and cardiac hypertrophy indicators, epididymal fat weight, and fasting glucose concentrations. Mechanistically, FMT of an aged microbiota modulated the glucose metabolic pathway and induced myocardial oxidative damage. ConclusionsOur findings suggested that an aged microbiota can modulate metabolism and induce cardiac injury. This highlights the possible role of the gut microbiota in age-related metabolic disorders and cardiac dysfunction.

Gut microbiota regulates hepatic ischemia-reperfusion injury-induced cognitive dysfunction via the HDAC2-ACSS2 axis in mice.

Hepatic ischemia-reperfusion injury (HIRI) resulting from hepatic inflow occlusion, which is a common procedure in liver surgery is inevitable. Previous research has confirmed that the cognitive dysfunction induced by HIRI is closely related to dysbiosis of the gut microbiota. This research aims to investigate the mechanisms underlying this complication. C57BL/6 mice underwent hepatic ischemia experimentally through the occlusion of the left hepatic artery and portal vein. To assess the HDAC2-ACSS2 axis, gut microbiota transplantation. Enzyme-linked immunosorbent assay and LC/MS short-chain fatty acid detection were utilized. The findings indicated a notable decline in ACSS2 expression in the hippocampus of mice experiencing hepatic ischemia-reperfusion injury, emphasizing the compromised acetate metabolism in this particular area. Furthermore, the cognitive impairment phenotype and the dysregulation of the HDAC2-ACSS2 axis could also be transmitted to germ-free mice via fecal microbial transplantation. Enzyme-linked immunosorbent assay revealed reduced Acetyl-coenzyme A (acetyl-CoA) and Acetylated lysine levels in the hippocampus. These findings suggest that acetate metabolism is impaired in the hippocampus of HIRI-induced cognitive impairment mice and related to dysbiosis, leading to compromised histone acetylation.

Faecal Microbiota Transplantation Alleviates Ferroptosis after Ischaemic Stroke

Ischaemic stroke can induce changes in the abundance of gut microbiota constituents, and the outcome of stroke may also be influenced by the gut microbiota. This study aimed to determine whether gut microbiota transplantation could rescue changes in the gut microbiota and reduce ferroptosis after stroke in rats. Male Sprague-Dawley rats (6 weeks of age) were subjected to ischaemic stroke by middle cerebral artery occlusion (MCAO). Fecal samples were collected for 16S ribosomal RNA (rRNA) sequencing to analyze the effects of FMT on the gut microbiota. Neurological deficits were evaluated using the Longa score. triphenyl tetrazolium chloride (TTC) staining was performed in the brain, and kits were used to measure malondialdehyde (MDA), iron, and glutathione (GSH) levels in the ipsilateral brain of rats. Western blotting was used to detect the protein expression levels of glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), and the transferrin receptor 2 (TFR2) in the ipsilateral brain of rats. Stroke induced significant changes in the gut microbiota, and FMT ameliorated these changes. TTC staining results showed that FMT reduced cerebral infarct volume. In addition, FMT diminished MDA and iron levels and elevated GSH levels in the ipsilateral brain. Western blot analysis showed that FMT increased GPX4 and SLC7A11 protein expression and decreased TFR2 protein expression in the ipsilateral brain after stroke. FMT can reverse gut microbiota dysbiosis, reduce cerebellar infarct volume, and decrease ferroptosis after stroke.

Gut microbiota dysbiosis and decreased levels of acetic and propionic acid participate in glucocorticoid-induced glycolipid metabolism disorder.

Long-term/high-dose glucocorticoid (GC) use results in glycolipid metabolism disorder, which severely limits its clinical application. The role of the gut microbiota and its metabolites in GC-induced glycolipid metabolism disorder remains unclear. Our previous human study found that obvious gut microbiota dysbiosis characterized by an increasing abundance of Proteobacteria and a decreased abundance of Lachnospiraceae and Faecalibacterium were observed in patients with endogenous hypercortisolism. In this study, we established a mouse model of GC-induced glycolipid metabolism disorder (Dex group) and found that the relative abundances of Proteobacteria and Parasuttrerella were increased, while the abundances of Lachnospiraceae, Faecalibacterium, and Lachnospiraceae_NK4A136_group were decreased significantly in the Dex group. Compared with the control group, serum total short-chain fatty acids (SCFAs), acetic acid, propionic acid, and GLP-1 levels were all decreased in the Dex group. The mRNA expression of the GPR41 receptor and Pcsk1 in the colon was significantly decreased in the Dex group. Furthermore, GC-induced glycolipid metabolism disorder could be alleviated by depletion of the gut microbiota or fecal bacteria transplantation with control bacteria. The abundances of Lachnospiraceae_NK4A136_group and the serum GLP-1 levels were significantly increased, while the abundances of Proteobacteria and Parasutterella were significantly decreased after fecal bacteria transplantation with control bacteria. Our work indicates that gut microbiota dysbiosis and decreased levels of serum acetic acid and propionic acid may participate in GC-induced glycolipid metabolism disorder. These findings may provide novel insights into the prevention and treatment of GC-induced metabolic disorders.IMPORTANCEThe role of the gut microbiota in glucocorticoid (GC)-induced glycolipid metabolism disorder remains unclear. In our study, gut microbiota dysbiosis characterized by an increased abundance of Proteobacteria/Parasuttrerella and a decreased abundance of Lachnospiraceae_NK4A136_group was observed in mice with GC-induced glycolipid metabolism disorder. Some bacteria were shared in our previous study in patients with endogenous hypercortisolism and the mouse model used in the study. Furthermore, the depletion of the gut microbiota and fecal bacteria transplantation with control bacteria could alleviate GC-induced glycolipid metabolism disorder. Plasma acetic acid, propionic acid, and GLP-1 and the mRNA expression of the GPR41 receptor and Pcsk1 in the colon were decreased significantly in mice with GC-induced glycolipid metabolism disorder, which indicated that the gut microbiota/SCFA/GPR41/GLP-1 axis may participate in GC-induced glycolipid metabolism disorder. Our findings indicate that the gut microbiota may serve as a novel therapeutic target for GC-related metabolic disorders.