Gut Microbiome and Plasma Metabolome Signatures in Middle-Aged Mice With Cognitive Dysfunction Induced by Chronic Neuropathic Pain.
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SUBMITTER: Hua D
PROVIDER: S-EPMC8763791 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Gut dysbiosis, defined as pathogenic alterations in the distribution and abundance of different microbial species, is associated with neuropathic pain in a variety of clinical conditions, but this has not been explored in the context of neuropathy in people with HIV (PWH). We assessed gut microbial diversity and dysbiosis in PWH and people without HIV (PWoH), some of whom reported distal neuropathic pain (DNP). DNP was graded on a standardized, validated severity scale. The gut microbiome was characterized using 16S rRNA sequencing and diversity was assessed using phylogenetic tree construction. Songbird analysis (https://github.com/mortonjt/songbird) was used to produce a multinomial regression model predicting counts of specific microbial taxa through metadata covariate columns. Participants were 226 PWH and 101 PWoH, mean (SD) age 52.0 (13.5), 21.1% female, 54.7% men who have sex with men, 44.7% non-white. Among PWH, median (interquartile range, IQR) nadir and current CD4 were 174 (21, 302) and 618 (448, 822), respectively; 90% were virally suppressed on antiretroviral therapy. PWH and PWoH did not differ with respect to microbiome diversity as indexed by Faith's phylogenetic diversity (PD). More severe DNP was associated with lower alpha diversity as indexed by Faith's phylogenetic diversity in PWH (Spearman's ρ = .224, P = 0.0007), but not in PWoH (Spearman's ρ = .032, P = .748). These relationships were not confounded by demographics or disease factors. In addition, the log-ratio of features identified at the genus level as Blautia to Lachnospira was statistically significantly higher in PWH with DNP than in PWH without DNP (t-test, P = 1.01e-3). Furthermore, the log-ratio of Clostridium features to Lachnospira features also was higher in PWH with DNP than in those without (t-test, P = 6.24e-5). Our results, in combination with previous findings in other neuropathic pain conditions, suggest that gut dysbiosis, particularly reductions in diversity and relative increases in the ratios of Blautia and Clostridium to Lachnospira, may contribute to prevalent DNP in PWH. Two candidate pathways for these associations, involving microbial pro-inflammatory components and microbially-produced anti-inflammatory short chain fatty acids, are discussed. Future studies might test interventions to re-establish a healthy gut microbiota and determine if this prevents or improves DNP. PERSPECTIVE: The association of neuropathic pain in people with HIV with reduced gut microbial diversity and dysbiosis raises the possibility that re-establishing a healthy gut microbiota might ameliorate neuropathic pain in HIV by reducing proinflammatory and increasing anti-inflammatory microbial products.
| S-EPMC9854399 | biostudies-literature
Project description:ABSTARCT:The dorsal root ganglia (DRG) are key structures in nociception and chronic pain disorders. Several gene expression studies of DRG in preclinical pain models have been performed, but it is unclear if consistent gene changes are identifiable. We, therefore, compared several recent RNA-Seq data sets on the whole DRG in rodent models of nerve injury. Contrary to previous findings, we show hundreds of common differentially expressed genes and high positive correlation between studies, despite model and species differences. We also find, in contrast to previous studies, that 60% of the common rodent gene response after injury is likely to occur in nociceptors of the DRG. Substantial expression changes are observed at a 1-week time-point, with smaller changes in the same genes at a later 3- to 4-week time-point. However, a subset of genes shows a similar magnitude of changes at both early and late time-points, suggesting their potential involvement in the maintenance of chronic pain. These genes are centred around suppression of endogenous opioid signalling. Reversal of this suppression could allow endogenous and exogenous opioids to exert their analgesic functions and may be an important strategy for treating chronic pain disorders. Currently used drugs, such as amitriptyline and duloxetine, do not seem to appropriately modulate many of the critical pain genes and indeed may transcriptionally suppress endogenous opioid signalling further.
| S-EPMC7302324 | biostudies-literature
Project description:Stress negatively impacts gut and brain health. Individual differences in response to stress have been linked to genetic and environmental factors and more recently, a role for the gut microbiota in the regulation of stress-related changes has been demonstrated. However, the mechanisms by which these factors influence each other are poorly understood, and there are currently no established robust biomarkers of stress susceptibility. To determine the metabolic and microbial signatures underpinning physiological stress responses, we compared stress-sensitive Wistar Kyoto (WKY) rats to the normo-anxious Sprague Dawley (SD) strain. Here we report that acute stress-induced strain-specific changes in brain lipid metabolites were a prominent feature in WKY rats. The relative abundance of Lactococcus correlated with the relative proportions of many brain lipids. In contrast, plasma lipids were significantly elevated in response to stress in SD rats, but not in WKY rats. Supporting these findings, we found that the greatest difference between the SD and WKY microbiomes were the predicted relative abundance of microbial genes involved in lipid and energy metabolism. Our results provide potential insights for developing novel biomarkers of stress vulnerability, some of which appear genotype specific.
| S-EPMC6773725 | biostudies-literature
Project description:Exercise can directly alter the gut microbiome at the compositional and functional metabolic levels, which in turn may beneficially influence physical performance. However, data how the gut microbiome and fecal metabolome change, and how they interact in soldiers who commonly undergo sustained military training are limited. To address this issue, we first performed 16S rRNA sequencing to assess the gut microbial community patterns in a cohort of 80 soldiers separated into elite soldiers (ES, n = 40) and non-elite soldiers (N-ES, n = 40). We observed that the α-diversities of the ES group were higher than those of the N-ES group. As for both taxonomical structure and phenotypic compositions, elite soldiers were mainly characterized by an increased abundance of bacteria producing short-chain fatty acids (SCFAs), including Ruminococcaceae_UCG-005, Prevotella_9, and Veillonella, as well as a higher proportion of oxidative stress tolerant microbiota. The taxonomical signatures of the gut microbiome were significantly correlated with soldier performance. To further investigate the metabolic activities of the gut microbiome, using an untargeted metabolomic method, we found that the ES and N-ES groups displayed significantly different metabolic profiles and differential metabolites were primarily involved in the metabolic network of carbohydrates, energy, and amino acids, which might contribute to an enhanced exercise phenotype. Furthermore, these differences in metabolites were strongly correlated with the altered abundance of specific microbes. Finally, by integrating multi-omics data, we identified a shortlist of bacteria-metabolites associated with physical performance, following which a random forest classifier was established based on the combinatorial biomarkers capable of distinguishing between elite and non-elite soldiers with high accuracy. Our findings suggest possible future modalities for improving physical performance through targeting specific bacteria associated with more energetically efficient metabolic patterns.
| S-EPMC8990768 | biostudies-literature
Project description:The gut microbiome plays an important role in the mammalian host and when in proper balance helps protect health and prevent disease. Host environmental stress and its influence on the gut microbiome, health, and disease is an emerging area of research. Exposures to unnatural light cycles are becoming increasingly common due to travel and shift work. However, much remains unknown about how these changes influence the microbiome and host health. This information is needed to understand and predict the relationship between the microbiome and host response to altered sleep cycles. In the present study, we exposed three cohorts of mice to different light cycle regimens for 12 consecutive weeks; including continuous light, continuous dark, and a standard light dark regimen consisting of 12 h light followed by 12 h of dark. After exposure, motor and memory behavior, and the composition of the fecal microbiome and plasma metabolome were measured. Memory potential was significantly reduced in mice exposed to continuous light, whereas rotarod performance was minimally affected. The overall composition of the microbiome was relatively constant over time. However, Bacteroidales Rikenellaceae was relatively more abundant in mice exposed to continuous dark, while Bacteroidales S24-7 was relatively more abundant in mice exposed to continuous light. The plasma metabolome after the continuous dark exposure differed from the other exposure conditions. Several plasma metabolites, including glycolic acid, tryptophan, pyruvate, and several unidentified metabolites, were correlated to continuous dark and light exposure conditions. Networking analyses showed that serotonin was positively correlated with three microbial families (Rikenellaceae, Ruminococcaceae, and Turicibacteraceae), while tryptophan was negatively correlated with abundance of Bacteroidales S24-7 based on light exposure. This study provides the foundation for future studies into the mechanisms underlying the role of the gut microbiome on the murine host during light-dark stress.
| S-EPMC6813214 | biostudies-literature
Project description:Submerged cultivation using low-value agro-industrial side streams allows large-scale and efficient production of fungal mycelia, which has a high nutritional value. As the dietary properties of fungal mycelia in poultry are largely unknown, the present study aimed to investigate the effect of feeding a Pleurotus sapidus (PSA) mycelium as a feed supplement on growth performance, composition of the cecal microbiota and several physiological traits including gut integrity, nutrient digestibility, liver lipids, liver transcriptome and plasma metabolome in broilers. 72 male, 1-day-old Cobb 500 broilers were randomly assigned to three different groups and fed three different adequate diets containing either 0% (PSA-0), 2.5% (PSA-2.5) and 5% (PSA-5.0) P. sapidus mycelium in a three-phase feeding system for 35 days. Each group consisted of 6 cages (replicates) with 4 broilers/cage. Body weight gain, feed intake and feed:gain ratio and apparent ileal digestibility of crude protein, ether extract and amino acids were not different between groups. Metagenomic analysis of the cecal microbiota revealed no differences between groups, except that one α-diversity metric (Shannon index) and the abundance of two low-abundance bacterial taxa (Clostridia UCG 014, Eubacteriales) differed between groups (P < 0.05). Concentrations of total and individual short-chain fatty acids in the cecal digesta and concentrations of plasma lipopolysaccharide and mRNA levels of proinflammatory genes, tight-junction proteins, and mucins in the cecum mucosa did not differ between groups. None of the plasma metabolites analyzed using targeted-metabolomics differed across the groups. Hepatic transcript profiling revealed a total of 144 transcripts to be differentially expressed between group PSA-5.0 and group PSA-0 but none of these genes was regulated greater 2-fold. Considering either the lack of effects or the very weak effects of feeding the P. sapidus mycelium in the broilers it can be concluded that inclusion of a sustainably produced fungal mycelium in broiler diets at the expense of other feed components has no negative consequences on broilers´ performance and metabolism.
2024-06-06 | GSE269154 | GEO
Project description:BackgroundCeliac disease (CD) is an autoimmune disorder triggered by gluten consumption. Almost all CD patients possess human leukocyte antigen (HLA) DQ2/DQ8 haplotypes; however, only a small subset of individuals carrying these alleles develop CD, indicating the role of environmental factors in CD pathogenesis. The main objective of this study was to determine the contributory role of gut microbiota and microbial metabolites in CD onset. To this end, we obtained fecal samples from a prospective cohort study (ABIS) at ages 2.5 and 5 years. Samples were collected from children who developed CD after the final sample collection (CD progressors) and healthy children matched by age, HLA genotype, breastfeeding duration, and gluten-exposure time (n=15-16). We first used 16S sequencing and immunoglobulin-A sequencing (IgA-seq) using fecal samples obtained from the same children (i) 16 controls and 15 CD progressors at age 2.5 and (ii) 13 controls and 9 CD progressors at age 5. We completed the cytokine profiling, and plasma metabolomics using plasma samples obtained at age 5 (n=7-9). We also determined the effects of one microbiota-derived metabolite, taurodeoxycholic acid (TDCA), on the small intestines and immune cell composition in vivo.ResultsCD progressors have a distinct gut microbiota composition, an increased IgA response, and unique IgA targets compared to healthy subjects. Notably, 26 plasma metabolites, five cytokines, and one chemokine were significantly altered in CD progressors at age 5. Among 26 metabolites, we identified a 2-fold increase in TDCA. TDCA treatment alone caused villous atrophy, increased CD4+ T cells, Natural Killer cells, and two important immunoregulatory proteins, Qa-1 and NKG2D expression on T cells while decreasing T-regulatory cells in intraepithelial lymphocytes (IELs) in C57BL/6J mice.ConclusionsPediatric CD progressors have a distinct gut microbiota composition, plasma metabolome, and cytokine profile before diagnosis. Furthermore, CD progressors have more IgA-coated bacteria and unique targets of IgA in their gut microbiota. TDCA feeding alone stimulates an inflammatory immune response in the small intestines of C57BJ/6 mice and causes villous atrophy, the hallmark of CD. Thus, a microbiota-derived metabolite, TDCA, enriched in CD progressors' plasma, has the potential to drive inflammation in the small intestines and enhance CD pathogenesis. Video Abstract.
| S-EPMC9840338 | biostudies-literature
Project description:A combinatory approach using metabolomics and gut microbiome analysis techniques was performed to unravel the nature and specificity of metabolic profiles related to gut ecology in obesity. This study focused on gut and liver metabolomics of two different mouse strains, the C57BL/6J (C57J) and the C57BL/6N (C57N) fed with high-fat diet (HFD) for 3 weeks, causing diet-induced obesity in C57N, but not in C57J mice. Furthermore, a 16S-ribosomal RNA comparative sequence analysis using 454 pyrosequencing detected significant differences between the microbiome of the two strains on phylum level for Firmicutes, Deferribacteres and Proteobacteria that propose an essential role of the microbiome in obesity susceptibility. Gut microbial and liver metabolomics were followed by a combinatory approach using Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) and ultra performance liquid chromatography time of tlight MS/MS with subsequent multivariate statistical analysis, revealing distinctive host and microbial metabolome patterns between the C57J and the C57N strain. Many taurine-conjugated bile acids (TBAs) were significantly elevated in the cecum and decreased in liver samples from the C57J phenotype likely displaying different energy utilization behavior by the bacterial community and the host. Furthermore, several metabolite groups could specifically be associated with the C57N phenotype involving fatty acids, eicosanoids and urobilinoids. The mass differences based metabolite network approach enabled to extend the range of known metabolites to important bile acids (BAs) and novel taurine conjugates specific for both strains. In summary, our study showed clear alterations of the metabolome in the gastrointestinal tract and liver within a HFD-induced obesity mouse model in relation to the host-microbial nutritional adaptation.
| S-EPMC4260703 | biostudies-literature
Project description:The pathogenesis of gut microbiota and their metabolites in the development of metabolic syndrome (MS) remains unclear. This study aimed to evaluate the signatures of gut microbiota and metabolites as well as their functions in obese children with MS. A case-control study was conducted based on 23 MS children and 31 obese controls. The gut microbiome and metabolome were measured using 16S rRNA gene amplicon sequencing and liquid chromatography-mass spectrometry. An integrative analysis was conducted, combining the results of the gut microbiome and metabolome with extensive clinical indicators. The biological functions of the candidate microbial metabolites were validated in vitro. We identified 9 microbiota and 26 metabolites that were significantly different from the MS and the control group. The clinical indicators of MS were correlated with the altered microbiota Lachnoclostridium, Dialister, and Bacteroides, as well as with the altered metabolites all-trans-13,14-dihydroretinol, DL-dipalmitoylphosphatidylcholine (DPPC), LPC 24: 1, PC (14:1e/10:0), and 4-phenyl-3-buten-2-one, etc. The association network analysis further identified three MS-linked metabolites, including all-trans-13,14-dihydroretinol, DPPC, and 4-phenyl-3-buten-2-one, that were significantly correlated with the altered microbiota. Bio-functional validation showed that all-trans-13, 14-dihydroretinol could significantly upregulate the expression of lipid synthesis genes and inflammatory genes. This study identified a new biomarker that may contribute to MS development. These findings provided new insights regarding the development of efficient therapeutic strategies for MS. IMPORTANCE Metabolic syndrome (MS) has become a health concern worldwide. Gut microbiota and metabolites play an important role in human health. We first endeavored to comprehensively analyze the microbiome and metabolome signatures in obese children and found the novel microbial metabolites in MS. We further validated the biological functions of the metabolites in vitro and illustrated the effects of the microbial metabolites on lipid synthesis and inflammation. The microbial metabolite all-trans-13, 14-dihydroretinol may be a new biomarker in the pathogenesis of MS, especially in obese children. These findings were not available in previous studies, and they provide new insights regarding the management of metabolic syndrome.
| S-EPMC10101147 | biostudies-literature
Project description:BackgroundChronic granulomatous disease (CGD) is caused by defects in any 1 of the 6 subunits forming the nicotinamide adenine dinucleotide phosphate oxidase complex 2 (NOX2), leading to severely reduced or absent phagocyte-derived reactive oxygen species production. Almost 50% of patients with CGD have inflammatory bowel disease (CGD-IBD). While conventional IBD therapies can treat CGD-IBD, their benefits must be weighed against the risk of infection. Understanding the impact of NOX2 defects on the intestinal microbiota may lead to the identification of novel CGD-IBD treatments.ObjectiveWe sought to identify microbiome and metabolome signatures that can distinguish individuals with CGD and CGD-IBD.MethodsWe conducted a cross-sectional observational study of 79 patients with CGD, 8 pathogenic variant carriers, and 19 healthy controls followed at the National Institutes of Health Clinical Center. We profiled the intestinal microbiome (amplicon sequencing) and stool metabolome, and validated our findings in a second cohort of 36 patients with CGD recruited through the Primary Immune Deficiency Treatment Consortium.ResultsWe identified distinct intestinal microbiome and metabolome profiles in patients with CGD compared to healthy individuals. We observed enrichment for Erysipelatoclostridium spp, Sellimonas spp, and Lachnoclostridium spp in CGD stool samples. Despite differences in bacterial alpha and beta diversity between the 2 cohorts, several taxa correlated significantly between both cohorts. We further demonstrated that patients with CGD-IBD have a distinct microbiome and metabolome profile compared to patients without CGD-IBD.ConclusionIntestinal microbiome and metabolome signatures distinguished patients with CGD and CGD-IBD, and identified potential biomarkers and therapeutic targets.
| S-EPMC11279821 | biostudies-literature