Perturbation Of Gut Microbiota Research Articles

Longitudinal study on the effects of a synbiotic supplement to Atlantic salmon diets on performance, gut microbiota and immune responses during antibiotic treatment and subsequent recovery

BackgroundAntibiotic use has undesirable side-effects on the host, including perturbations of gut microbiota, immunity, and health. Mammalian studies have demonstrated that concomitant/post antibiotic use of pro-, pre-, and synbiotics could re-establish gut microbiota and prevent detrimental host effects. However, studies evaluating similar effects in fish are scanty. This study evaluated the effects of dietary supplementation with a synbiotic mixture on the post-smolt Atlantic salmon gut microbiota, growth performance, and health during antibiotic treatment and subsequent recovery. Fish in five tanks each were fed either a commercial control diet or a synbiotic diet containing Pediococcus acidilactici and fructo-oligosaccharides, for 6 weeks (S1). Then, fish in three tanks per treatment were fed with medicated diets, containing 3500 ppm florfenicol coated onto the control or synbiotic diets, for 2 weeks (S2) and refed with the respective nonmedicated diets for another 3 (S3) and 5 (S4) weeks of recovery period. The fish not subjected to medication were fed the control or synbiotic diets throughout the experimental period. Samples were collected at S1-S4 from both the nonmedicated and medicated fish.ResultsFlorfenicol decreased the feed intake in control group. It reduced the growth rate in both control and synbiotic groups with lesser reduction in synbiotic group. Florfenicol did not significantly affect observed taxa and Shannon indexes. Bacterial composition before and after medication clustered distinctly in control and clustered together in synbiotic groups. Lactobacillus dominated in control while Lactobacillus and Pediococcus dominated in synbiotic group during medication and recovery. Florfenicol did not significantly influence the immune or stress response marker gene expressions, though the expression patterns differed between diet groups. Florfenicol did not cause inflammation in the distal intestine or change hepatosomatic index.ConclusionsThis study highlighted the negative impact of a two-week florfenicol treatment on feed intake and growth performance in Atlantic salmon, with moderate effects on gut microbiota and gene expression. Concomitant use of a synbiotic diet helped to maintain the gut microbial composition and influenced the performance positively and immune gene expressions differently during medication. This study indicates the importance of nutritional interventions through synbiotic supplementation as a possible strategy for managing Atlantic salmon during antibiotic treatment.

Host-microbiome determinants of ready-to-use supplemental food efficacy in acute childhood malnutrition.

Ready-to-use supplemental foods (RUSF) are energy-dense meals formulated to prevent and treat moderate and severe childhood acute malnutrition (MAM and SAM) in high-risk settings. Although lifesaving, the degree and durability of weight recovery with RUSF is unpredictable. We examined whether environmental enteric dysfunction (EED) and gut microbiota perturbations are risk factors for RUSF failure in a birth cohort of 416 rural Pakistani children followed for growth, common childhood illnesses, and biomarkers from blood, urine, and stool. Infants who developed wasting (weight-for-length Z score <-2, n=187, 45%) during surveillance received Acha Mum (a chickpea-based RUSF) daily for eight weeks. Machine learning identified seven biomarkers that predicted RUSF response (n=75) vs. non-response (n=112) with 73% accuracy. Remarkably, gut microbiome composition predicted RUSF response with 93% (pre-supplementation) and 98% (post-supplementation) accuracy. Seven outliers whose microbiome falsely predicted positive response experienced extraordinary burdens of inflammation and illness during supplementation. These findings identify gut microbial signatures and biomarkers of gut and systemic inflammation as robust predictors of RUSF response in infants free from intercurrent illness during recovery, setting the stage for predictive models to guide precision use of RUSF and adjunct therapies in undernourished children.

Baseline colitogenicity and acute perturbations of gut microbiota in immunotherapy-related colitis.

Immunotherapy-related colitis (irC) frequently emerges as an immune-related adverse event during immune checkpoint inhibitor therapy and is presumably influenced by the gut microbiota. We longitudinally studied microbiomes from 38 ICI-treated cancer patients. We compared 13 ICI-treated subjects who developed irC against 25 ICI-treated subjects who remained irC-free, along with a validation cohort. Leveraging a preclinical mouse model, predisease stools from irC subjects induced greater colitigenicity upon transfer to mice. The microbiota during the first 10 days of irC closely resembled inflammatory bowel disease microbiomes, with reduced diversity, increased Proteobacteria and Veillonella, and decreased Faecalibacterium, which normalized before irC remission. These findings highlight the irC gut microbiota as functionally distinct but phylogenetically similar to non-irC and healthy microbiomes, with the exception of an acute, transient disruption early in irC. We underscore the significance of longitudinal microbiome profiling in developing clinical avenues to detect, monitor, and mitigate irC in ICI therapy cancer patients.

Gut microbiota perturbation and subsequent oxidative stress in gut and kidney tissues of zebrafish after individual and combined exposure to inorganic arsenic and fluoride.

Chronic exposure to inorganic arsenic (iAs) and fluoride (F) affect gut health and potentially damage organs. The present study investigates the interplay between gut bacteria and oxidative stress (measured by MDA level, GSH level, catalase activity, Nrf2 translocation and expression) in zebrafish exposed to F (NaF 15ppm) and As (As2O3 50ppb) alone or in combination. Combined exposure to As and F reduced gut bacterial alteration and imposed less oxidative stress compared to F- exposure alone. V3-V4 metagenomic sequencing revealed Pseudomonas, Aeromonas and Plesiomonas genera dominated in As or F treated groups while As+F treated group was enriched in beneficial Lactococcus and Streptococcus genera. Functional KEGG analysis demonstrated treatment-specific changes in bacterial metabolism, host organismal systems, human diseases, as well as cellular processes of microbial community were significantly affected. When Aeromonas sp. isolated from F-treated fish gut, tagged with GFP-vector and fed (~3.2×106 CFU/mL) to untreated fish, induced oxidative stress in gut and kidney. Gut bacteria were found to both increase and mitigate iAs or F-toxicity, whereas As+F treatment promoted a protective response. Correlation analysis between gut microbial community at genus level and oxidative stress parameters of gut and kidney, showed Aeromonas and Plesiomonas genera are strongly correlated with oxidative stress (r=0.5-0.9, p˂0.05). This study identifies microbiome biomarkers of iAs and F toxicity on gut-kidney axis.

Profiling the gut and oral microbiota of hormone receptor-positive, HER2-negative metastatic breast cancer patients receiving pembrolizumab and eribulin

Aim: Changes in host-associated microbial communities (i.e., the microbiota) may modulate responses to checkpoint blockade immunotherapy. In the KELLY phase II study (NCT03222856), we previously demonstrated that pembrolizumab [anti-programmed cell death protein 1 (PD-1)] combined with eribulin (plus microtubule-targeting chemotherapy) showed encouraging antitumor activity in patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC) who had received prior treatments. Methods: A total of 58 fecal and 67 saliva samples were prospectively collected from a subset of 28 patients at baseline (BL), after three treatment cycles, and end of treatment. Shotgun metagenomics, 16S rRNA gene amplicon sequencing, and bioinformatics and statistical approaches were used to characterize fecal and oral microbiota profiles. Results: Treatment caused no substantial perturbations in gut or oral microbiota, suggesting minimal drug-related microbial toxicity. Bacteroides and Faecalibacterium were the dominant gut microbiota genera, while Prevotella and Streptococcus were present in both oral and gut samples, highlighting potential gut-oral microbial interactions. Additionally, clinical benefit (CB) appeared to be associated with gut-associated Bacteroides fragilis (B. fragilis ) and a BL oral abundance of Streptococcus ≥ 30%. Notably, B. fragilis NCTC 9343 supernatant induced dose-dependent lactate dehydrogenase (LDH) release from the MCF-7 (HR-positive/HER2-negative) BC cell line. Conclusion: These findings suggest that specific gut and oral microbiota may modulate the effectiveness of combinatory anti-BC therapies, potentially through the action of microbial metabolites.

Trace antibiotic exposure affects murine gut microbiota and metabolism

Gut microbiota is important for host metabolism regulation. Antibiotic exposure disturbs this regulation by affecting the microbiome. Trace levels of antibiotics in water have been widely reported and the impact on gut microbiota remains understudied. We provide evidence of trace antibiotic exposure affecting the host's gut microbiota using a mouse model exposed to trace amounts of azithromycin (AZI) or ciprofloxacin (CIP) in drinking water. AZI exposure in males changed the distribution of gram-positive (Firmicutes and Bacteroidetes) and gram-negative (Proteobacteria, Fusobacteria, and Verrucomicrobia) bacteria at an early age. Both AZI and CIP resulted in abnormal microbiota maturation. Additionally, the production of short-chain fatty acids (SCFAs), including acetate, butyrate, and propionate, in females is affected. Serum hormone and metabolome levels shifted after trace antibiotic exposure. AZI and CIP exposure broadly disrupted original host-microbe interaction relationships between the gut microbiota and SCFAs or serum metabolites. In this study, we demonstrated that trace antibiotic exposure was associated with extensive gut microbiota and metabolism perturbation in mice and that the potential health risks in susceptible populations should be considered.

Oral supplementation with Bifidobacterium infantis and 2′-fucosyllactose revives gut microbiota perturbation and intestinal and immune developmental delay following early-life antibiotic challenge in BALB/c mice

Probiotics and synbiotics can mitigate the negative health consequences of early-life antibiotic exposure. This study aimed to determine whether supplementation with Bifidobacterium longum ssp. infantis 79 (B79) or synbiotics composed of B79 and 2'-fucosyllactose (2'-FL) could mitigate the negative impact of ceftriaxone exposure in early-life. We found that antibiotic-treated mice exhibited lower body weight, crypt depth, short-chain fatty acid content, and α-diversity indices at weaning, while they increased the relative abundance of opportunistic pathogens (such as Enterococcus and Staphylococcus) and decreased the relative abundance of intestinal commensal bacteria. Supplementation with B79 and 2'-FL revived these antibiotic-induced negative effects and reduced the mRNA expression of IL-6, IL-12p40, and TNF-α in the spleen at weaning. Moreover, B79 and 2'-FL supplementation persistently improved crypt depth, propionic acid synthesis, and IgG and sIgA production and revived the gut microbiota structure and composition in adulthood. In conclusion, our study suggests that early-life supplementation with B79 alone or in combination with 2'-FL can mitigate ceftriaxone-induced negative effects on the gut microbiota and intestinal and immune development of mice, and these improvements can partially last into adulthood.

Assessing Diagnostic Performance of Molecular Culture for Neonatal Sepsis: Protocol of the CHAMPIONS Study.

Managing neonatal sepsis is challenging due to nonspecific clinical signs, hematological markers with poor accuracy, and a lengthy turnaround time for the identification of microorganisms. Delaying the initiation of antibiotics in truly infected infants can lead to severe morbidity and mortality. Therefore, decisions regarding empiric antibiotic treatment are risk stratified, which exposes many uninfected infants to antibiotics. This causes gut microbiota perturbation, unnecessary hospital admissions, and the generation of multi-resistant organisms. High-speed diagnostic assays could expedite discontinuation or avert the initiation of antibiotics in uninfected infants. This study will evaluate the diagnostic performance of molecular culture (MC), a rapid broad-range PCR-based bacterial profiling technique, for diagnosing neonatal sepsis in infants below 90 days old. A multi-center prospective observational cohort study will include infants evaluated for early and late-onset sepsis. Routine evaluation for suspected sepsis includes microbiological cultures of blood. Additionally, blood for MC will be collected. For early-onset sepsis, umbilical cord blood may be used alternatively. Primary outcome is the agreement between MC and conventional blood culture results. Secondary outcome is the agreement of both assays with clinical sepsis using four different, commonly used definitions. Faster diagnostic pathways for sepsis may reduce antibiotic exposure time. Broad-range molecular assays may identify pathogens undetectable by conventional methods. Employment of umbilical cord blood samples for early-onset sepsis diagnosis can resolve challenges in collecting adequate blood volume and could further expedite treatment decisions.

Prevalence of perturbed gut microbiota in pathophysiology of arsenic-induced anxiety- and depression-like behaviour in mice

Severe toxic effects of arsenic on human physiology have been of immense concern worldwide. Arsenic causes irrevocable structural and functional disruption of tissues, leading to major diseases in chronically exposed individuals. However, it is yet to be resolved whether the effects result from direct deposition and persistence of arsenic in tissues, or via activation of indirect signaling components. Emerging evidences suggest that gut inhabitants play an active role in orchestrating various aspects of brain physiology, as the gut-brain axis maintains cognitive health, emotions, learning and memory skills. Arsenic-induced dysbiosis may consequentially evoke neurotoxicity, eventually leading to anxiety and depression. To delineate the mechanism of action, mice were exposed to different concentrations of arsenic. Enrichment of Gram-negative bacteria and compromised barrier integrity of the gut enhanced lipopolysaccharide (LPS) level in the bloodstream, which in turn elicited systemic inflammation. Subsequent alterations in neurotransmitter levels, microglial activation and histoarchitectural disruption in brain triggered onset of anxiety- and depression-like behaviour in a dose-dependent manner. Finally, to confirm whether the neurotoxic effects are specifically a consequence of modulation of gut microbiota (GM) by arsenic and not arsenic accumulation in the brain, fecal microbiota transplantations (FMT) were performed from arsenic-exposed mice to healthy recipients. 16S rRNA gene sequencing indicated major alterations in GM population in FMT mice, leading to severe structural, functional and behavioural alterations. Moreover, suppression of Toll-like receptor 4 (TLR4) using vivo-morpholino oligomers (VMO) indicated restoration of the altered parameters towards normalcy in FMT mice, confirming direct involvement of the GM in inducing neurotoxicity through the arsenic-gut-brain axis. This study accentuates the potential role of the gut microbiota in promoting neurotoxicity in arsenic-exposed mice, and has immense relevance in predicting neurotoxicity under altered conditions of the gut for designing therapeutic interventions that will target gut dysbiosis to attenuate arsenic-mediated neurotoxicity.

Research progress on pathogenesis of chronic fatigue syndrome and treatment of traditional Chinese and Western medicine

Chronic Fatigue Syndrome (CFS) is a complex and perplexing medical disorder primarily characterized by persistent and debilitating fatigue, often accompanied by a constellation of symptoms, including weakness, dyspnea, arthromyalgia, sore throat, and disrupted sleep patterns. CFS is defined by its persistent or recurrent manifestation for a minimum duration of six months, marked by an enduring and unrelenting fatigue that remains refractory to rest. In recent decades, this condition has garnered significant attention within the medical community. While the precise etiology of CFS remains elusive, it is postulated to be multifactorial. CFS is potentially associated with various contributory factors such as infections, chronic stress, genetic predisposition, immune dysregulation, and psychosocial influences. The pathophysiological underpinnings of CFS encompass viral infections, immune system dysregulation, neuroendocrine aberrations, heightened oxidative stress, and perturbations in gut microbiota. Presently, clinical management predominantly relies on pharmaceutical interventions or singular therapeutic modalities, offering alleviation of specific symptoms but exhibiting inherent limitations. Traditional Chinese Medicine (TCM) interventions have emerged as a promising paradigm, demonstrating notable efficacy through their multimodal, multi-target, multi-pathway approach, and holistic regulatory mechanisms. These interventions effectively address the lacunae in contemporary medical interventions. This comprehensive review synthesizes recent advancements in the understanding of the etiological factors, pathophysiological mechanisms, and interventional strategies for CFS, drawing from a corpus of domestic and international literature. Its aim is to furnish valuable insights for clinicians actively involved in diagnosing and treating CFS, as well as for pharmaceutical researchers delving into innovative drug development pathways. Moreover, it seeks to address the intricate challenges confronted by clinical practitioners in managing this incapacitating condition.

Modulation of mercaptopurine intestinal toxicity and pharmacokinetics by gut microbiota

The interaction between the gut microbiota and mercaptopurine (6-MP), a crucial drug used in pediatric acute lymphoblastic leukemia (ALL) treatment, has not been extensively studied. Here we reveal the significant perturbation of gut microbiota after 2-week 6-MP treatment in beagles and mice followed by the functional prediction that showed impairment of SCFAs production and altered amino acid synthesis. And the targeted metabolomics in plasma also showed changes in amino acids. Additionally, targeted metabolomics analysis of feces showed changes in amino acids and SCFAs. Furthermore, ablating the intestinal microbiota by broad-spectrum antibiotics exacerbated the imbalance of amino acids, particularly leading to a significant decrease in the concentration of S-adenosylmethionine (SAM). Importantly, the depletion of gut microbiota worsened the damage of small intestine caused by 6-MP, resulting in increased intestinal permeability. Considering the relationship between toxicity and 6-MP metabolites, we conducted a pharmacokinetic study in pseudo germ-free rats to confirm that gut microbiota depletion altered the methylation metabolites of 6-MP. Specifically, the concentration of MeTINs, a secondary methylation metabolite, showed a negative correlation with SAM, the pivotal methyl donor. Additionally, we observed a strong correlation between Alistipes and SAM levels in both feces and plasma. In conclusion, our study demonstrates that 6-MP disrupts the gut microbiota, and depleting the gut microbiota exacerbates 6-MP-induced intestinal toxicity. Moreover, SAM derived from microbiota plays a crucial role in influencing plasma SAM and the methylation of 6-MP. These findings underscore the importance of comprehending the role of the gut microbiota in 6-MP metabolism and toxicity.

Environmental concentrations of microplastic-induced gut microbiota and metabolite disruption in silkworm, Bombyx mori

Microplastics (MPs) existing extensively in various ecosystems can be ingested by marine organisms and enter the food chain, resulting the health risks from the presence of MPs in aquatic and terrestrial ecosystems. In the present study, an ideal model for Lepidoptera, the silkworm, Bombyx mori, was exposed to environmental concentrations (0.125 μg, 0.25 μg or 0.5 μg/diet) of MPs for 5 days, and the global changes in gut microbes and metabolites were subsequently examined via 16S rDNA sequencing and GC‒MS-based metabolomics. The results showed that MPs exposure did not seriously threaten survival but may regulate signaling pathways involved in development and cocoon production. MPs exposure induced gut microbiota perturbation according to the indices of α-diversity and β-diversity, and the functional prediction of the altered microbiome and associated metabolites demonstrated the potential roles of the altered microbiome following MPs exposure in the metabolic and physiological states of silkworm. The metabolites markedly altered following MPs exposure may play vital biological roles in energy metabolism, lipid metabolism, xenobiotic detoxification and the immune system by directly or indirectly affecting the physiological state of silkworms. These findings contribute to assessing the health risks of MPs exposure in model insects and provide novel insight into the toxicity mechanism of MPs.

Food additive emulsifiers and the risk of type 2 diabetes: analysis of data from the NutriNet-Santé prospective cohort study

Experimental studies have suggested potential detrimental effects of emulsifiers on gut microbiota, inflammation, and metabolic perturbations. We aimed to investigate the associations between exposures to food additive emulsifiers and the risk of type 2 diabetes in a large prospective cohort of French adults. We analysed data from 104 139 adults enrolled in the French NutriNet-Santé prospective cohort study from May 1, 2009, to April 26, 2023; 82 456 (79·2%) were female and the mean age was 42·7 years (SD 14·5). Dietary intakes were assessed with three 24 h dietary records collected over three non-consecutive days, every 6 months. Exposure to additive emulsifiers was evaluated through multiple food composition databases and ad-hoc laboratory assays. Associations between cumulative time-dependent exposures to food additive emulsifiers and the risk of type 2 diabetes were characterised with multivariable proportional hazards Cox models adjusted for known risk factors. The NutriNet-Santé study is registered at ClinicalTrials.gov (NCT03335644). Of 104 139 participants, 1056 were diagnosed with type 2 diabetes during follow-up (mean follow-up duration 6·8 years [SD 3·7]). Intakes of the following emulsifiers were associated with an increased risk of type 2 diabetes: total carrageenans (hazard ratio [HR] 1·03 [95% CI 1·01-1·05] per increment of 100 mg per day, p<0·0001), carrageenans gum (E407; HR 1·03 [1·01-1·05] per increment of 100 mg per day, p<0·0001), tripotassium phosphate (E340; HR 1·15 [1·02-1·31] per increment of 500 mg per day, p=0·023), acetyl tartaric acid esters of monoglycerides and diglycerides of fatty acids (E472e; HR 1·04 [1·00-1·08] per increment of 100 mg per day, p=0·042), sodium citrate (E331; HR 1·04 [1·01-1·07] per increment of 500 mg per day, p=0·0080), guar gum (E412; HR 1·11 [1·06-1·17] per increment of 500 mg per day, p<0·0001), gum arabic (E414; HR 1·03 [1·01-1·05] per increment of 1000 mg per day, p=0·013), and xanthan gum (E415, HR 1·08 [1·02-1·14] per increment of 500 mg per day, p=0·013). We found direct associations between the risk of type 2 diabetes and exposures to various food additive emulsifiers widely used in industrial foods, in a large prospective cohort of French adults. Further research is needed to prompt re-evaluation of regulations governing the use of additive emulsifiers in the food industry for better consumer protection. European Research Council, French National Cancer Institute, French Ministry of Health, IdEx Université de Paris, and Bettencourt-Schueller Foundation.

Melatonin-mediated corrective changes in gut microbiota of experimentally chronodisrupted C57BL/6J mice

ABSTRACT Chronic consumption of a high-calorie diet coupled with an altered sleep-wake cycle causes disruption of circadian clock that can impact the gut microbiome leading to metabolic syndrome and associated diseases. Herein, we investigate the effects of a high fat high fructose diet (H) alone or in combination with photoperiodic shifts induced chronodisruption (CD) on gut microbiota of C57BL/6J male mice. Further, the merits of daily evening intraperitoneal administration of melatonin in restoring gut microbiota are studied herein. Experimental groups viz. H, CD and HCD mice recorded higher levels of serum pro-inflammatory cytokines (TNF-α and IL-6) and lower levels of the anti-inflammatory cytokine, IL-10. These findings correlate with a concomitant increase in the transcripts of TLR4, TNF-α, and IL-6 in small intestine of the said groups. A decrement in mRNA levels of Ocln, ZO-1 and Vdr in these groups implied towards an altered gut permeability. These results were in agreement with the observed decrement in percentage abundance of total gut microflora and Firmicutes: Bacteroidetes (F/B) ratio. Melatonin administration accounted for lower-level inflammation (serum and gut) along with an improvement in gut permeability markers. The total abundance of gut microflora and F/B ratio showed an improvement in all the melatonin-treated groups and the same is the highlight of this study. Taken together, our study is the first to report perturbations in gut microbiota resulting due to a combination of photoperiodic shifts induced CD and a high fat high calorie diet-induced lifestyle disorder. Further, melatonin-mediated rejuvenation of gut microbiome provides prima facie evidence of its role in improving gut dysbiosis that needs a detailed scrutiny.

Sodium oligomannate alters gut microbiota, reduces cerebral amyloidosis and reactive microglia in a sex-specific manner

It has recently become well-established that there is a connection between Alzheimer’s disease pathology and gut microbiome dysbiosis. We have previously demonstrated that antibiotic-mediated gut microbiota perturbations lead to attenuation of Aβ deposition, phosphorylated tau accumulation, and disease-associated glial cell phenotypes in a sex-dependent manner. In this regard, we were intrigued by the finding that a marine-derived oligosaccharide, GV-971, was reported to alter gut microbiota and reduce Aβ amyloidosis in the 5XFAD mouse model that were treated at a point when Aβ burden was near plateau levels. Utilizing comparable methodologies, but with distinct technical and temporal features, we now report on the impact of GV-971 on gut microbiota, Aβ amyloidosis and microglial phenotypes in the APPPS1-21 model, studies performed at the University of Chicago, and independently in the 5X FAD model, studies performed at Washington University, St. Louis.Methods To comprehensively characterize the effects of GV-971 on the microbiota-microglia-amyloid axis, we conducted two separate investigations at independent institutions. There was no coordination of the experimental design or execution between the two laboratories. Indeed, the two laboratories were not aware of each other’s experiments until the studies were completed. Male and female APPPS1-21 mice were treated daily with 40, 80, or 160 mg/kg of GV-971 from 8, when Aβ burden was detectable upto 12 weeks of age when Aβ burden was near maximal levels. In parallel, and to corroborate existing published studies and further investigate sex-related differences, male and female 5XFAD mice were treated daily with 100 mg/kg of GV-971 from 7 to 9 months of age when Aβ burden was near peak levels. Subsequently, the two laboratories independently assessed amyloid-β deposition, metagenomic, and neuroinflammatory profiles. Finally, studies were initiated at the University of Chicago to evaluate the metabolites in cecal tissue from vehicle and GV-971-treated 5XFAD mice.Results These studies showed that independent of the procedural differences (dosage, timing and duration of treatment) between the two laboratories, cerebral amyloidosis was reduced primarily in male mice, independent of strain. We also observed sex-specific microbiota differences following GV-971 treatment. Interestingly, GV-971 significantly altered multiple overlapping bacterial species at both institutions. Moreover, we discovered that GV-971 significantly impacted microbiome metabolism, particularly by elevating amino acid production and influencing the tryptophan pathway. The metagenomics and metabolomics changes correspond with notable reductions in peripheral pro-inflammatory cytokine and chemokine profiles. Furthermore, GV-971 treatment dampened astrocyte and microglia activation, significantly decreasing plaque-associated reactive microglia while concurrently increasing homeostatic microglia only in male mice. Bulk RNAseq analysis unveiled sex-specific changes in cerebral cortex transcriptome profiles, but most importantly, the transcriptome changes in the GV-971-treated male group revealed the involvement of microglia and inflammatory responses.Conclusions In conclusion, these studies demonstrate the connection between the gut microbiome, neuroinflammation, and Alzheimer’s disease pathology while highlighting the potential therapeutic effect of GV-971. GV-971 targets the microbiota-microglia-amyloid axis, leading to the lowering of plaque pathology and neuroinflammatory signatures in a sex-dependent manner when given at the onset of Aβ deposition or when given after Aβ deposition is already at higher levels.

Fecal microbiota transplantation unveils sex-specific differences in a controlled cortical impact injury mouse model.

Contusion type of traumatic brain injury (TBI) is a major cause of locomotor disability and mortality worldwide. While post-TBI deleterious consequences are influenced by gender and gut dysbiosis, the sex-specific importance of commensal gut microbiota is underexplored after TBI. In this study, we investigated the impact of controlled cortical impact (CCI) injury on gut microbiota signature in a sex-specific manner in mice. We depleted the gut microflora of male and female C57BL/6 mice using antibiotic treatment. Thereafter, male mice were colonized by the gut microbiota of female mice and vice versa, employing the fecal microbiota transplantation (FMT) method. CCI surgery was executed using a stereotaxic impactor (Impact One™). For the 16S rRNA gene amplicon study, fecal boli of mice were collected at 3 days post-CCI (dpi). CCI-operated male and female mice exhibited a significant alteration in the genera of Akkermansia, Alistipes, Bacteroides, Clostridium, Lactobacillus, Prevotella, and Ruminococcus. At the species level, less abundance of Lactobacillus helveticus and Lactobacillus hamsteri was observed in female mice, implicating the importance of sex-specific bacteriotherapy in CCI-induced neurological deficits. FMT from female donor mice to male mice displayed an increase in genera of Alistipes, Lactobacillus, and Ruminococcus and species of Bacteroides acidifaciens and Ruminococcus gnavus. Female FMT-recipient mice from male donors showed an upsurge in the genus Lactobacillus and species of Lactobacillus helveticus, Lactobacillus hamsteri, and Prevotella copri. These results suggest that the post-CCI neurological complications may be influenced by the differential gut microbiota perturbation in male and female mice.

Gut flora metagenomic analysis coupled with metabolic and deep immune profiling in chronic kidney disease.

Perturbation of gut microbiota has been linked to chronic kidney disease (CKD), which was correlated with a sophisticated milieu of metabolic and immune dysregulation. To clarify the underlying host-microbe interaction in CKD, we performed multi-omics measurements, including systems-level gut microbiome, targeted serum metabolome and deep immunotyping, in a cohort of patients and non-CKD controls. Our analyses on functional profiles of the gut microbiome showed a decrease in the diversity and abundance of carbohydrate-active enzyme (CAZyme) genes but an increase in the abundance of antibiotic resistance, nitrogen cycling enzyme and virulence factor genes in CKD. Moreover, models generated using measurements of serum metabolites (amino acids, bile acids and short-chain fatty acids) or immunotypes were predictive of renal impairment but less so than many of the functional profiles derived from gut microbiota, with the CAZyme genes being the top-performing model to accurately predict the early stage of diseases. In addition, co-occurrence analyses revealed coordinated host-microbe relationships in CKD. Specifically, the highest fractions of significant correlations were identified with circulating metabolites by several taxonomic and functional profiles of gut microbiome, while immunotype features were moderately associated with the abundance of microbiome-encoded metabolic pathways and serum levels of amino acids (e.g. B cell cluster tryptophan and B cell cluster tryptophan metabolism). Overall, our multi-omics integration revealed several signatures of systems-level gut microbiome in robust associations with host-microbe co-metabolites and renal function, which may have aetiological and diagnostic implications in CKD.

Gut microbiota dysbiosis contributes to α-synuclein-related pathology associated with C/EBPβ/AEP signaling activation in a mouse model of Parkinson's disease.

JOURNAL/nrgr/04.03/01300535-202409000-00042/figure1/v/2024-01-16T170235Z/r/image-tiff Parkinson's disease is a neurodegenerative disease characterized by motor and gastrointestinal dysfunction. Gastrointestinal dysfunction can precede the onset of motor symptoms by several years. Gut microbiota dysbiosis is involved in the pathogenesis of Parkinson's disease, whether it plays a causal role in motor dysfunction, and the mechanism underlying this potential effect, remain unknown. CCAAT/enhancer binding protein β/asparagine endopeptidase (C/EBPβ/AEP) signaling, activated by bacterial endotoxin, can promote α-synuclein transcription, thereby contributing to Parkinson's disease pathology. In this study, we aimed to investigate the role of the gut microbiota in C/EBPβ/AEP signaling, α-synuclein-related pathology, and motor symptoms using a rotenone-induced mouse model of Parkinson's disease combined with antibiotic-induced microbiome depletion and fecal microbiota transplantation. We found that rotenone administration resulted in gut microbiota dysbiosis and perturbation of the intestinal barrier, as well as activation of the C/EBP/AEP pathway, α-synuclein aggregation, and tyrosine hydroxylase-positive neuron loss in the substantia nigra in mice with motor deficits. However, treatment with rotenone did not have any of these adverse effects in mice whose gut microbiota was depleted by pretreatment with antibiotics. Importantly, we found that transplanting gut microbiota derived from mice treated with rotenone induced motor deficits, intestinal inflammation, and endotoxemia. Transplantation of fecal microbiota from healthy control mice alleviated rotenone-induced motor deficits, intestinal inflammation, endotoxemia, and intestinal barrier impairment. These results highlight the vital role that gut microbiota dysbiosis plays in inducing motor deficits, C/EBPβ/AEP signaling activation, and α-synuclein-related pathology in a rotenone-induced mouse model of Parkinson's disease. Additionally, our findings suggest that supplementing with healthy microbiota may be a safe and effective treatment that could help ameliorate the progression of motor deficits in patients with Parkinson's disease.

Integrated metagenomic and metabonomic mechanisms for the therapeutic effects of Duhuo Jisheng decoction on intervertebral disc degeneration.

Intervertebral disc degeneration (IVDD) is a prevalent orthopedic condition with lower back pain as the predominant clinical presentation that challenges clinical treatment with few therapeutic options. Duhuo Jisheng Decoction (DHJSD) has been proven effective in the therapy of IVDD, but the precise underlying mechanisms remain not fully elucidated. The current study was designed to test our hypothesis that DHJSD may systematically correct the phenotypic disruption of the gut microbiota and changes in the serum metabolome linked to IVDD. Analysis of the active ingredients of DHJSD by ultra high performance liquid chromatography. An integrated metagenomic and metabonomic approach was used to analyze feces and blood samples from normal and IVDD rats. Compared to the control group, fiber ring pinning on the caudal 3 to caudal 5 segments of the rats caused IVDD and significantly altered the compositions of the intestinal microbiota and serum metabolites. Integrated analysis revealed commonly-altered metabolic pathways shared by both intestinal microbiota and serum metabolome of the IVDD rats. DHJSD inhibited the degenerative process and restored the compositions of the perturbed gut microbiota, particularly the relative abundance of commensal microbes of the Prevotellaceae family. DHJSD also corrected the altered metabolic pathways involved in the metabolism of glycine, serine, threonine, valine, the citric acid cycle, and biosynthesis of leucine and isoleucine. DHJSD inhibited the disc degeneration process by an integrated metagenomic and metabonomic mechanism to restore the microbiome profile and normalize the metabonomic pathways.

Novel approach for ameliorating high-fat diet-induced syndromes via probiotic-fermented oyster mushroom: from metabolites and microbiota to regulation mechanisms.

The potential effects of probiotics on lowering lipid accumulation and alleviating gut microbiota perturbation have been extensively substantiated, but whether Lactobacillus rhamnoses-fermented oyster mushroom (FOM) could more pronouncedly attenuate obesity remains unclear. In this study, the anti-obesity effect of FOM was estimated based on the gut microbiota profile and analysis of hepatic lipid metabolic characteristics. The results revealed that FOM intervention dramatically improved hepatic lipid accumulation, characterized by reduction in fat-related factor metabolism levels and liver lesion enzymatic activities and down-regulation of the expression of genes associated with glycolipid metabolism (Foxo1, Gck, G6pd, Il6r and IL-β). Metabolomics analysis indicated HFD-induced dysglycaemia and disturbed amino acid metabolism, characterized by significant enrichment of pathways (butanoate metabolism, arginine biosynthesis, etc.) and elevated levels of D-mannose, succinate and β-D-fructose, followed by a decreased galactitol content. Furthermore, FOM intervention showed significant enrichment of specific pathways, particularly transcriptional misregulation in cancer and FoxO signaling pathways, while the MAPK signaling pathway demonstrated consistent enrichment across all experimental groups. FOM intervention reshaped the gut microbiota structure by facilitating the proliferation of SCFA producers (Romboutsia, Ruminococcaceae and Allobaculum), together with the depletion of Lachnospiraceae population. The current study strengthened our understanding of FOM prebiotic activities and obesity alleviation mechanisms.