-
IScience Nov 2021The gut microbiome has emerged as a key regulator of obesity; however, its role in brown adipose tissue (BAT) metabolism and association with obesity remain to be...
The gut microbiome has emerged as a key regulator of obesity; however, its role in brown adipose tissue (BAT) metabolism and association with obesity remain to be elucidated. We found that the levels of circulating branched-chain amino acids (BCAA) and their cognate α-ketoacids (BCKA) were significantly correlated with the body weight in humans and mice and that BCAA catabolic defects in BAT were associated with obesity in diet-induced obesity (DIO) mice. Pharmacological systemic enhancement of BCAA catabolic activity reduced plasma BCAA and BCKA levels and protected against obesity; these effects were reduced in BATectomized mice. DIO mice gavaged with and exhibited improved BAT BCAA catabolism and attenuated body weight gain, which were not observed in BATectomized DIO mice. Our data have highlighted a possible link between the gut microbiota and BAT BCAA catabolism and suggest that probiotics could be used for treating obesity.
PubMed: 34805797
DOI: 10.1016/j.isci.2021.103342 -
Journal of Advanced Research Feb 2022The roles of species in alleviating inflammation and intestinal injury has been widely demonstrated, but few studies have focused on the roles of .
INTRODUCTION
The roles of species in alleviating inflammation and intestinal injury has been widely demonstrated, but few studies have focused on the roles of .
OBJECTIVES
In this study, four strains were selected, based on their genomic characteristics, to assess their ability to alleviate lipopolysaccharide (LPS)-induced acute intestinal injury in C57BL/6J mice.
METHODS
Alterations in the intestinal microbiota, intestinal epithelial permeability, cytokine level, short-chain fatty acid (SCFA) concentration, and immune responses were investigated following LPS-induced acute intestinal injury in C57BL/6J mice.
RESULTS
Severe histological damage and a significant change in cytokine expression was observed in the mouse colon tissues 24 h after LPS administration. Oral administration of different strains showed different effects on the assessed parameters of the mice; particularly, only the administration of FTJS7K1 was able to protect the architectural integrity of the intestinal epithelium. FTJS7K1 also negated the LPS-induced changes in cytokine mRNA expression in the colon tissues, and in the proportion of regulatory T cells in the mesenteric lymph node. Compared with the LPS group, the FTJS7K1 group showed significantly increased abundance of , , and , and decreased abundance of . The FTJS7K1 group also showed significantly increased concentration of SCFAs in fecal samples. The results of genomic analysis showed that these protective roles of FTJS7K1 may be mediated through specific genes associated with defense mechanisms and metabolism (e.g., the secretion of SCFAs).
CONCLUSIONS
Our findings suggest that the protective role of FTJS7K1 appear to be via modulation of cytokine production in the colon tissue and regulation of the structure of the gut microbiota. These results provide support for the screening of the genus for next-generation probiotics.
Topics: Animals; Bacteroides; Gastrointestinal Microbiome; Lipopolysaccharides; Mice; Mice, Inbred C57BL
PubMed: 35127162
DOI: 10.1016/j.jare.2021.06.012 -
Genome Medicine Oct 2021Immune checkpoint blockade (ICB) shows lasting benefits in advanced melanoma; however, not all patients respond to this treatment and many develop potentially...
BACKGROUND
Immune checkpoint blockade (ICB) shows lasting benefits in advanced melanoma; however, not all patients respond to this treatment and many develop potentially life-threatening immune-related adverse events (irAEs). Identifying individuals who will develop irAEs is critical in order to improve the quality of care. Here, we prospectively demonstrate that the gut microbiome predicts irAEs in melanoma patients undergoing ICB.
METHODS
Pre-, during, and post-treatment stool samples were collected from 27 patients with advanced stage melanoma treated with IPI (anti-CTLA-4) and NIVO (anti-PD1) ICB inhibitors at NYU Langone Health. We completed 16S rRNA gene amplicon sequencing, DNA deep shotgun metagenomic, and RNA-seq metatranscriptomic sequencing. The divisive amplicon denoising algorithm (DADA2) was used to process 16S data. Taxonomy for shotgun sequencing data was assigned using MetaPhlAn2, and gene pathways were assigned using HUMAnN 2.0. Compositionally aware differential expression analysis was performed using ANCOM. The Cox-proportional hazard model was used to assess the prospective role of the gut microbiome (GMB) in irAES, with adjustment for age, sex, BMI, immune ICB treatment type, and sequencing batch.
RESULTS
Two natural GMB clusters with distinct community compositions were identified from the analysis of 16S rRNA data (R = 0.16, p < 0.001). In Cox-proportional hazard modeling, these two clusters showed a near 7-fold differential risk for developing irAEs within 1 year of initiating treatment (HR = 6.89 [95% CI: 1.33-35.58]). Using shotgun metagenomics, we further identified 37 bacterial strains differentially expressed between the risk groups, with specific dominance of Bacteroides dorei within the high-risk GMB cluster and Bacteroides vulgatus in the low-risk cluster. The high-risk cluster also appeared to have elevated expression of several functional pathways, including those associated with adenosine metabolism (all FDR < 0.05). A sub-analysis of samples (n = 10 participants) at baseline and 6 and 12 weeks after the start of treatment revealed that the microbiome remained stable over the course of treatment (R = 0.88, p < 0.001).
CONCLUSIONS
We identified two distinct fecal bacterial community clusters which are associated differentially with irAEs in ICB-treated advanced melanoma patients.
Topics: Algorithms; Bacteroides; Biomarkers, Tumor; Feces; Gastrointestinal Microbiome; Humans; Immune Checkpoint Inhibitors; Melanoma; Metagenome; Metagenomics; Prospective Studies; RNA, Ribosomal, 16S
PubMed: 34641962
DOI: 10.1186/s13073-021-00974-z -
Cellular and Molecular Life Sciences :... Dec 2022Gut microbes are associated with the development of depression based on extensive evidence. However, previous studies have led to conflicting reports on this... (Meta-Analysis)
Meta-Analysis
Gut microbes are associated with the development of depression based on extensive evidence. However, previous studies have led to conflicting reports on this association, posing challenges to the application of gut bacteria in the diagnostics and treatment of depression. To minimise heterogenicity in data analysis, the present meta-analysis adopted a standardised bioinformatics and statistical pipeline to analyse 16S rRNA sequences of 1827 samples from eight different cohorts. Although changes in the overall bacterial community were identified by our meta-analysis, depressive-correlated changes in alpha-diversity were absent. Enrichment of Bacteroidetes, Parabacteroides, Barnesiella, Bacteroides, and Bacteroides vulgatus, along with depletion in Firmicutes, Dialister, Oscillospiraceae UCG 003 and UCG 002, and Bacteroides plebeius, were observed in depressive-associated bacteria. By contrast, elevated L-glutamine degradation, and reduced L-glutamate and L-isoleucine biosynthesis were identified in depressive-associated microbiomes. After systemically reviewing the data of these collected cohorts, we have established a bacterial classifier to identify depressive symptoms with AUC 0.834 and 0.685 in the training and external validation dataset, respectively. Moreover, a low-risk bacterial cluster for depressive symptoms was identified, which was represented by a lower abundance of Escherichia-Shigella, and a higher abundance of Faecalibacterium, Oscillospiraceae UCG 002, Ruminococcus, and Christensenellaceae R.7 group.
Topics: Humans; RNA, Ribosomal, 16S; Feces; DNA, Bacterial; Bacteria; Bacteroidetes; Biomarkers; Cohort Studies
PubMed: 36495344
DOI: 10.1007/s00018-022-04650-2 -
Frontiers in Cellular and Infection... 2022Although the gut microbiota may be involved in obesity onset and progression, the exact association of the gut microbiota in metabolically healthy obesity (MHO) remains...
BACKGROUND
Although the gut microbiota may be involved in obesity onset and progression, the exact association of the gut microbiota in metabolically healthy obesity (MHO) remains largely unknown.
METHODS
An integrated paired-sample metagenomic analysis was conducted to investigate the gut microbial network and biomarkers of microbial species from the MHO and healthy non-obese subjects in the GMrepo database. Further explorations were performed in the MHO mice model using a multiomics analysis to detect changes in the composition and function of the intestinal microbiome and associated metabolites.
RESULTS
In the human study, 314 matched metagenomic data were qualified for the final analysis. We identified seven significantly changed species possibly involved in MHO pathogenesis (MHO-enriched: , ; MHO-depleted: , , ; ; ). In the murine study, we found 79 significantly-changed species which may have possible associations with the MHO phenotype. The depletion of was commonly recognized in the human and murine MHO phenotype. Consistent with the metagenomic data, liquid chromatography-mass spectrometry (LC/MS) revealed significantly changed gut metabolites, which may promote MHO pathogenesis by altering the amino acids and lipid metabolic pathways. In the microbe-metabolites interaction analysis, we identified certain fatty acids (Dodecanedioic acid, Arachidic Acid, Mevalonic acid, etc.) that were significantly correlated with the MHO-enriched or depleted species.
CONCLUSION
This study provides insights into identifying specific microbes and metabolites that may involve in the development of obesity without metabolic disorders. Future modalities for MHO intervention may be further validated by targeting these bacteria and metabolites.
Topics: Humans; Mice; Animals; Gastrointestinal Microbiome; Obesity, Metabolically Benign; Obesity; Metagenomics
PubMed: 36389176
DOI: 10.3389/fcimb.2022.1012028 -
Journal of Immunology Research 2021Although the strain-dependent effects of on alleviating intestinal inflammatory diseases have been demonstrated, the literature has rarely focused on the underlying...
Although the strain-dependent effects of on alleviating intestinal inflammatory diseases have been demonstrated, the literature has rarely focused on the underlying causes of this effect. In this study, we selected four strains (FTJS5K1, FTJS7K1, FSDTA11B14, and FSDLZ51K1) with different genomic characteristics and evaluated their protective roles against dextran sulfate sodium- (DSS-) induced colitis. Compared to the other three tested strains, 7K1 more strongly ameliorated the DSS-induced weight loss, shortening of the colon length, increased disease activity index scores, colonic tissue injury, and immunomodulatory disorder. In contrast, 51K1 significantly worsened the DSS-induced alterations in the tumor necrosis factor-alpha (TNF-) concentration and colonic histopathology. A comparative genomic analysis of 7K1 and 51K1 showed that the beneficial effects of 7K1 may be associated with some of its specific genes involved in the production of short-chain fatty acids or capsular polysaccharides and enhancement of its survivability in the gut. In conclusion, these findings indicate that the supplementation of 7K1 is a potentially efficacious intervention for alleviating colitis and provides scientific support for the screening of probiotics with anticolitis effect.
Topics: Animals; Bacteroides; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Fatty Acids; Humans; Inflammatory Bowel Diseases; Male; Mice; Mice, Inbred C57BL; Polysaccharides; Species Specificity; Tumor Necrosis Factor-alpha
PubMed: 34195297
DOI: 10.1155/2021/9117805 -
Gut Microbes 2023The gut microbiota is involved in the production of numerous metabolites that maintain host wellbeing. The assembly of the gut microbiome is highly dynamic, and...
The gut microbiota is involved in the production of numerous metabolites that maintain host wellbeing. The assembly of the gut microbiome is highly dynamic, and influenced by many postnatal factors, moreover, little is known about the development of the gut metabolome. We showed that geography has an important influence on the microbiome dynamics in the first year of life based on two independent cohorts from China and Sweden. Major compositional differences since birth were the high relative abundance of in the Swedish cohort and in the Chinese cohort. We analyzed the development of the fecal metabolome in the first year of life in the Chinese cohort. Lipid metabolism, especially acylcarnitines and bile acids, was the most abundant metabolic pathway in the newborn gut. Delivery mode and feeding induced particular differences in the gut metabolome since birth. In contrast to C-section newborns, medium- and long-chain acylcarnitines were abundant at newborn age only in vaginally delivered infants, associated by the presence of bacteria such as and . Our data provide a basis for understanding the maturation of the fecal metabolome and the metabolic role of gut microbiota in infancy.
Topics: Gastrointestinal Microbiome; Humans; Infant, Newborn; Infant; China; Bile Acids and Salts; Amino Acids; Sweden; Bacteroides; Streptococcus; Feces; Lipid Metabolism; Feeding Behavior; Metabolic Networks and Pathways; Delivery, Obstetric; Female; Pregnancy; Cesarean Section; Longitudinal Studies; Male
PubMed: 37424334
DOI: 10.1080/19490976.2023.2231596 -
Frontiers in Cellular and Infection... 2023Birth mode has been implicated as a major factor influencing neonatal gut microbiome development, and it has been assumed that lack of exposure to the maternal vaginal...
Birth mode has been implicated as a major factor influencing neonatal gut microbiome development, and it has been assumed that lack of exposure to the maternal vaginal microbiome is responsible for gut dysbiosis among caesarean-delivered infants. Consequently, practices to correct dysbiotic gut microbiomes, such as vaginal seeding, have arisen while the effect of the maternal vaginal microbiome on that of the infant gut remains unknown. We conducted a longitudinal, prospective cohort study of 621 Canadian pregnant women and their newborn infants and collected pre-delivery maternal vaginal swabs and infant stool samples at 10-days and 3-months of life. Using 60-based amplicon sequencing, we defined vaginal and stool microbiome profiles and evaluated the effect of maternal vaginal microbiome composition and various clinical variables on the development of the infant stool microbiome. Infant stool microbiomes showed significant differences in composition by delivery mode at 10-days postpartum; however, this effect could not be explained by maternal vaginal microbiome composition and was vastly reduced by 3 months. Vaginal microbiome clusters were distributed across infant stool clusters in proportion to their frequency in the overall maternal population, indicating independence of the two communities. Intrapartum antibiotic administration was identified as a confounder of infant stool microbiome differences and was associated with lower abundances of , , and . Our findings demonstrate that maternal vaginal microbiome composition at delivery does not affect infant stool microbiome composition and development, suggesting that practices to amend infant stool microbiome composition focus factors other than maternal vaginal microbes.
Topics: Infant, Newborn; Humans; Infant; Pregnancy; Female; Gastrointestinal Microbiome; Prospective Studies; Canada; Microbiota; Feces
PubMed: 37065202
DOI: 10.3389/fcimb.2023.1144254 -
Nature Communications Jul 2022Phocaeicola vulgatus is one of the most abundant and ubiquitous bacterial species of the human gut microbiota, yet a comprehensive analysis of antibacterial toxin...
Phocaeicola vulgatus is one of the most abundant and ubiquitous bacterial species of the human gut microbiota, yet a comprehensive analysis of antibacterial toxin production by members of this species has not been reported. Here, we identify and characterize a previously undescribed antibacterial protein. This toxin, designated BcpT, is encoded on a small mobile plasmid that is largely confined to strains of the closely related species Phocaeicola vulgatus and Phocaeicola dorei. BcpT is unusual in that it requires cleavage at two distinct sites for activation, and we identify bacterial proteases that perform this activation. We further identify BcpT's receptor as the Lipid A-core glycan, allowing BcpT to target species of other Bacteroidales families. Exposure of cells to BcpT induces a response involving an unusual sigma/anti-sigma factor pair that is likely triggered by cell envelope stress, resulting in the expression of genes that partially protect cells from multiple antimicrobial toxins.
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Bacteria; Bacterial Proteins; Bacteroides; Bacteroidetes; Humans; Plasmids
PubMed: 35871068
DOI: 10.1038/s41467-022-31925-w -
Gut and Liver Jul 2022This study aimed to explore the effect of gut microbiota-regulated Kupffer cells (KCs) on colorectal cancer (CRC) liver metastasis.
BACKGROUND/AIMS
This study aimed to explore the effect of gut microbiota-regulated Kupffer cells (KCs) on colorectal cancer (CRC) liver metastasis.
METHODS
A series of and researches were showed to demonstrate the gut microbiota and its possible mechanism in CRC liver metastasis.
RESULTS
Fewer liver metastases were identified in the ampicillin-streptomycin-colistin and colistin groups. Increased proportions of , , , and were observed in the colistin group. The significant expansion of KCs was identified in the ampicillin-streptomycin-colistin and colistin groups. levels were positively correlated with KC levels. More liver metastases were observed in the vancomycin group. An increased abundance of and Proteus mirabilis and an obvious reduction of KCs were noted in the vancomycin group. levels were negatively related to KC levels. The number of liver metastatic nodules was increased in the group and decreased in the group. The number of KCs decreased in the group and increased in the group. In vitro, as or doses increased, there was an opposite effect on KC proliferation in dose- and time-dependent manners. induced CT26 cell migration by controlling KC proliferation, whereas prevented this migration.
CONCLUSIONS
An increased abundance of and decreased amount of play key roles in CRC liver metastasis, which might be related to KC reductions in the liver.
Topics: Ampicillin; Colistin; Colorectal Neoplasms; Gastrointestinal Microbiome; Humans; Liver; Liver Neoplasms; Streptomycin; Tumor Microenvironment; Vancomycin
PubMed: 35318288
DOI: 10.5009/gnl210177