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Biology Nov 2022The possession of two X chromosomes may come with the risk of various illnesses, females are more likely to be affected by osteoarthritis, heart disease, and anxiety.... (Review)
Review
The possession of two X chromosomes may come with the risk of various illnesses, females are more likely to be affected by osteoarthritis, heart disease, and anxiety. Given the reported correlations between gut microbiome dysbiosis and various illnesses, the female gut microbiome is worthy of exploration. Herein, we discuss the composition of the female gut microbiota and its dysbiosis in pathologies affecting the female population. Using PubMed, we performed a literature search, using key terms, namely: "gut microbiome", "estrogen", "menopause", "polycystic ovarian syndrome", "pregnancy", and "menstruation". In polycystic ovarian syndrome (PCOS), the abundance of and the ratio of was found to be increased while that of ML615J-28 124-7 and S24-7 was reduced. In breast cancer, the abundance of was enhanced, while in cervical cancer, and were enhanced but and members of were decreased. In ovarian cancer, abundance was increased. Interestingly, the administration of , and ameliorated PCOS symptoms while that of a mix of W51, W23, W63, W52, W24, W37, W19, W56, and W58 alleviated vascular malfunction and arterial stiffness in obese postmenopausal women, and finally, while further research is needed, maybe protective against postmenopausal bone mass loss. As several studies report the therapeutic potential of probiotics and since the gut microbiota of certain female pathological states has been relatively characterized, we speculate that the administration of certain bacterial species as probiotics is warranted, as novel independent or adjunct therapies for various female pathologies.
PubMed: 36421397
DOI: 10.3390/biology11111683 -
Nature Medicine Aug 2019Polycystic ovary syndrome (PCOS) is characterized by androgen excess, ovulatory dysfunction and polycystic ovaries, and is often accompanied by insulin resistance. The...
Polycystic ovary syndrome (PCOS) is characterized by androgen excess, ovulatory dysfunction and polycystic ovaries, and is often accompanied by insulin resistance. The mechanism of ovulatory dysfunction and insulin resistance in PCOS remains elusive, thus limiting the development of therapeutics. Improved metabolic health is associated with a relatively high microbiota gene content and increased microbial diversity. This study aimed to investigate the impact of the gut microbiota and its metabolites on the regulation of PCOS-associated ovarian dysfunction and insulin resistance. Here, we report that Bacteroides vulgatus was markedly elevated in the gut microbiota of individuals with PCOS, accompanied by reduced glycodeoxycholic acid and tauroursodeoxycholic acid levels. Transplantation of fecal microbiota from women with PCOS or B. vulgatus-colonized recipient mice resulted in increased disruption of ovarian functions, insulin resistance, altered bile acid metabolism, reduced interleukin-22 secretion and infertility. Mechanistically, glycodeoxycholic acid induced intestinal group 3 innate lymphoid cell IL-22 secretion through GATA binding protein 3, and IL-22 in turn improved the PCOS phenotype. This finding is consistent with the reduced levels of IL-22 in individuals with PCOS. This study suggests that modifying the gut microbiota, altering bile acid metabolism and/or increasing IL-22 levels may be of value for the treatment of PCOS.
Topics: Animals; Bile Acids and Salts; Female; GATA3 Transcription Factor; Gastrointestinal Microbiome; Humans; Inflammation; Insulin Resistance; Interleukins; Mice; Mice, Inbred C57BL; Ovary; Polycystic Ovary Syndrome; Interleukin-22
PubMed: 31332392
DOI: 10.1038/s41591-019-0509-0 -
Cancer Cell Jan 2023Preoperative neoadjuvant chemoradiotherapy (nCRT) is a standard treatment for locally advanced rectal cancer (LARC) patients, yet little is known about the mediators...
Preoperative neoadjuvant chemoradiotherapy (nCRT) is a standard treatment for locally advanced rectal cancer (LARC) patients, yet little is known about the mediators underlying the heterogeneous patient response. In this longitudinal study, we performed 16S rRNA sequencing on 353 fecal specimens and find reduced microbial diversity after nCRT. Multi-omics data integration reveals that Bacteroides vulgatus-mediated nucleotide biosynthesis associates with nCRT resistance in LARC patients, and nonresponsive tumors are characterized by the upregulation of genes related to DNA repair and nucleoside transport. Nucleosides supplementation or B. vulgatus gavage protects cancer cells from the 5-fluorouracil or irradiation treatment. An analysis of 2,205 serum samples from 735 patients suggests that uric acid is a potential prognosis marker for LARC patients receiving nCRT. Our data unravel the role of intestinal microbiota-mediated nucleotide biosynthesis in the response of rectal tumors to nCRT, and highlight the importance of deciphering the cross-talk between cancer cells and gut microorganisms during cancer therapies.
Topics: Humans; Gastrointestinal Microbiome; Neoadjuvant Therapy; Longitudinal Studies; RNA, Ribosomal, 16S; Rectal Neoplasms; Nucleotides; Chemoradiotherapy
PubMed: 36563680
DOI: 10.1016/j.ccell.2022.11.013 -
International Journal of Molecular... Feb 2021Polycystic ovary syndrome (PCOS) is a complex and heterogeneous endocrine disease. The hypothesis that alterations in the microbiome are involved in the genesis of PCOS... (Review)
Review
Polycystic ovary syndrome (PCOS) is a complex and heterogeneous endocrine disease. The hypothesis that alterations in the microbiome are involved in the genesis of PCOS has been postulated. Aim of this review is to summarize the available literature data about the relationship between microbiome and PCOS. A search on PubMed and Medline databases was performed from inception to November 20Most of evidence has focused on the connection of intestinal bacteria with sex hormones and insulin-resistance: while in the first case, a relationship with hyperandrogenism has been described, although it is still unclear, in the second one, chronic low-grade inflammation by activating the immune system, with increased production of proinflammatory cytokines which interfere with insulin receptor function, causing IR (Insulin Resistance)/hyperinsulinemia has been described, as well as the role of gastrointestinal hormones like Ghrelin and peptide YY (PYY), bile acids, interleukin-22 and Bacteroides vulgatus have been highlighted. The lower genital tract microbiome would be affected by changes in PCOS patients too. The therapeutic opportunities include probiotic, prebiotics and synbiotics, as well as fecal microbiota transplantation and the use of IL-22, to date only in animal models, as a possible future drug. Current evidence has shown the involvement of the gut microbiome in PCOS, seen how humanized mice receiving a fecal transplant from women with PCOS develop ovarian dysfunction, immune changes and insulin resistance and how it is capable of disrupting the secondary bile acid biosynthesis. A future therapeutic approach for PCOS may involve the human administration of IL-22 and bile acid glycodeoxycholic acid.
Topics: Animals; Diet; Female; Gastrointestinal Microbiome; Genitalia, Female; Hormones; Humans; Insulin Resistance; Polycystic Ovary Syndrome
PubMed: 33669557
DOI: 10.3390/ijms22042048 -
Gut Apr 2022Programmed death 1 and its ligand 1 (PD-1/PD-L1) immunotherapy is promising for late-stage lung cancer treatment, however, the response rate needs to be improved. Gut...
Ginseng polysaccharides alter the gut microbiota and kynurenine/tryptophan ratio, potentiating the antitumour effect of antiprogrammed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) immunotherapy.
OBJECTIVE
Programmed death 1 and its ligand 1 (PD-1/PD-L1) immunotherapy is promising for late-stage lung cancer treatment, however, the response rate needs to be improved. Gut microbiota plays a crucial role in immunotherapy sensitisation and has been shown to possess immunomodulatory potential. In this study, we aimed to investigate whether the combination treatment of ginseng polysaccharides (GPs) and αPD-1 monoclonal antibody (mAb) could sensitise the response by modulating gut microbiota.
DESIGN
Syngeneic mouse models were administered GPs and αPD-1 mAb, the sensitising antitumour effects of the combination therapy on gut microbiota were assessed by faecal microbiota transplantation (FMT) and 16S PacBio single-molecule real-time (SMRT) sequencing. To assess the immune-related metabolites, metabolomics analysis of the plasma samples was performed.
RESULTS
We found GPs increased the antitumour response to αPD-1 mAb by increasing the microbial metabolites valeric acid and decreasing L-kynurenine, as well as the ratio of Kyn/Trp, which contributed to the suppression of regulatory T cells and induction of T cells after combination treatment. Besides, the microbial analysis indicated that the abundance of and was higher in responders to anti-PD-1 blockade than non-responders in the clinic. Furthermore, the combination therapy sensitised the response to PD-1 inhibitor in the mice receiving microbes by FMT from six non-responders by reshaping the gut microbiota from non-responders towards that of responders.
CONCLUSION
Our results demonstrate that GPs combined with αPD-1 mAb may be a new strategy to sensitise non-small cell lung cancer patients to anti-PD-1 immunotherapy. The gut microbiota can be used as a novel biomarker to predict the response to anti-PD-1 immunotherapy.
Topics: Animals; Antibodies, Monoclonal; Apoptosis; B7-H1 Antigen; Carcinoma, Non-Small-Cell Lung; Cell Death; Gastrointestinal Microbiome; Humans; Immunologic Factors; Immunotherapy; Kynurenine; Ligands; Lung Neoplasms; Mice; Panax; Polysaccharides; Tryptophan
PubMed: 34006584
DOI: 10.1136/gutjnl-2020-321031 -
Nature Microbiology Feb 2022Ulcerative colitis (UC) is driven by disruptions in host-microbiota homoeostasis, but current treatments exclusively target host inflammatory pathways. To understand how...
Ulcerative colitis (UC) is driven by disruptions in host-microbiota homoeostasis, but current treatments exclusively target host inflammatory pathways. To understand how host-microbiota interactions become disrupted in UC, we collected and analysed six faecal- or serum-based omic datasets (metaproteomic, metabolomic, metagenomic, metapeptidomic and amplicon sequencing profiles of faecal samples and proteomic profiles of serum samples) from 40 UC patients at a single inflammatory bowel disease centre, as well as various clinical, endoscopic and histologic measures of disease activity. A validation cohort of 210 samples (73 UC, 117 Crohn's disease, 20 healthy controls) was collected and analysed separately and independently. Data integration across both cohorts showed that a subset of the clinically active UC patients had an overabundance of proteases that originated from the bacterium Bacteroides vulgatus. To test whether B. vulgatus proteases contribute to UC disease activity, we first profiled B. vulgatus proteases found in patients and bacterial cultures. Use of a broad-spectrum protease inhibitor improved B. vulgatus-induced barrier dysfunction in vitro, and prevented colitis in B. vulgatus monocolonized, IL10-deficient mice. Furthermore, transplantation of faeces from UC patients with a high abundance of B. vulgatus proteases into germfree mice induced colitis dependent on protease activity. These results, stemming from a multi-omics approach, improve understanding of functional microbiota alterations that drive UC and provide a resource for identifying other pathways that could be inhibited as a strategy to treat this disease.
Topics: Adult; Animals; Bacterial Proteins; Bacteroides; Cohort Studies; Colitis, Ulcerative; Feces; Female; Gastrointestinal Microbiome; Humans; Longitudinal Studies; Male; Metagenome; Metagenomics; Mice; Middle Aged; Peptide Hydrolases; Proteomics; Severity of Illness Index
PubMed: 35087228
DOI: 10.1038/s41564-021-01050-3 -
Nature Communications Oct 2023Although the gut microbiota has been reported to influence osteoporosis risk, the individual species involved, and underlying mechanisms, remain largely unknown. We...
Although the gut microbiota has been reported to influence osteoporosis risk, the individual species involved, and underlying mechanisms, remain largely unknown. We performed integrative analyses in a Chinese cohort of peri-/post-menopausal women with metagenomics/targeted metabolomics/whole-genome sequencing to identify novel microbiome-related biomarkers for bone health. Bacteroides vulgatus was found to be negatively associated with bone mineral density (BMD), which was validated in US white people. Serum valeric acid (VA), a microbiota derived metabolite, was positively associated with BMD and causally downregulated by B. vulgatus. Ovariectomized mice fed B. vulgatus demonstrated increased bone resorption and poorer bone micro-structure, while those fed VA demonstrated reduced bone resorption and better bone micro-structure. VA suppressed RELA protein production (pro-inflammatory), and enhanced IL10 mRNA expression (anti-inflammatory), leading to suppressed maturation of osteoclast-like cells and enhanced maturation of osteoblasts in vitro. The findings suggest that B. vulgatus and VA may represent promising targets for osteoporosis prevention/treatment.
Topics: Humans; Female; Mice; Animals; Gastrointestinal Microbiome; Bone Resorption; Osteoporosis
PubMed: 37891329
DOI: 10.1038/s41467-023-42005-y -
International Journal of Molecular... Apr 2020An increasing number of studies have shown that the brain-gut-microbiota axis may significantly contribute to Alzheimer's disease (AD) pathogenesis. Moreover, impaired... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
An increasing number of studies have shown that the brain-gut-microbiota axis may significantly contribute to Alzheimer's disease (AD) pathogenesis. Moreover, impaired memory and learning involve the dysfunction neurotransmission of glutamate, the agonist of the -methyl-d-aspartate receptor and a major excitatory neurotransmitter in the brain. This systematic review aimed to summarize the current cutting-edge research on the gut microbiota and glutamate alterations associated with dementia.
METHODS
PubMed, the Cochrane Collaboration Central Register of Controlled Clinical Trials, and Cochrane Systematic Reviews were reviewed for all studies on glutamate and gut microbiota in dementia published up until Feb 2020.
RESULTS
Several pilot studies have reported alterations of gut microbiota and metabolites in AD patients and other forms of dementia. Gut microbiota including and affect glutamate metabolism and decrease the glutamate metabolite 2-keto-glutaramic acid. Meanwhile, gut bacteria with glutamate racemase including , and can convert l-glutamate to d-glutamate. N-methyl-d-aspartate glutamate receptor (NMDAR)-enhancing agents have been found to potentially improve cognition in AD or Parkinson's disease patients. These findings suggest that d-glutamate (d-form glutamate) metabolized by the gut bacteria may influence the glutamate NMDAR and cognitive function in dementia patients.
CONCLUSIONS
Gut microbiota and glutamate are potential novel interventions to be developed for dementia. Exploring comprehensive cognitive functions in animal and human trials with glutamate-related NMDAR enhancers are warranted to examine d-glutamate signaling efficacy in gut microbiota in patients with AD and other neurodegenerative dementias.
Topics: Alzheimer Disease; Animals; Blood-Brain Barrier; Brain; Diet; Disease Susceptibility; Gastrointestinal Microbiome; Glutamic Acid; Humans; Metabolic Networks and Pathways; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Synaptic Transmission
PubMed: 32290475
DOI: 10.3390/ijms21082676 -
Gastroenterology Jan 2023Weight loss and exercise intervention have been reported to increase the interaction between Bacteroides spp and Akkermansiamuciniphila (Am), although the underlying...
BACKGROUND & AIMS
Weight loss and exercise intervention have been reported to increase the interaction between Bacteroides spp and Akkermansiamuciniphila (Am), although the underlying mechanisms and consequences of the interaction remain unknown.
METHODS
Using a healthy Korean twin cohort (n = 582), we analyzed taxonomic associations with host body mass index. B vulgatus strains were isolated from mice and human subjects to investigate the strain-specific effect of B vulgatus SNUG 40005 (Bvul) on obesity. The mechanisms underlying Am enrichment by Bvul administration were investigated by multiple experiments: (1) in vitro cross-feeding experiments, (2) construction of Bvul mutants with the N-acetylglucosaminidase gene knocked out, and (3) in vivo validation cohorts with different metabolites. Finally, metabolite profiling in mouse and human fecal samples was performed.
RESULTS
An interaction between Bvul and Am was observed in lean subjects but was disrupted in obese subjects. The administration of Bvul to mice fed a high-fat diet decreased body weight, insulin resistance, and gut permeability. In particular, Bvul restored the abundance of Am, which decreased significantly after a long-term high-fat diet. A cross-feeding analysis of Am with cecal contents or Bvul revealed that Am enrichment was attributed to metabolites produced during mucus degradation by Bvul. The metabolome profile of mouse fecal samples identified N-acetylglucosamine as contributing to Am enrichment, which was confirmed by in vitro and in vivo experiments. Metabolite network analysis of the twin cohort found that lysine serves as a bridge between N-acetylglucosamine, Bvul, and Am.
CONCLUSIONS
Strain-specific microbe-microbe interactions modulate the mucosal environment via metabolites produced during mucin degradation in the gut.
Topics: Humans; Mice; Animals; Akkermansia; Acetylglucosamine; Bacteroides; Obesity; Diet, High-Fat
PubMed: 36240952
DOI: 10.1053/j.gastro.2022.09.040 -
Cell Metabolism Oct 2021Accumulating evidence suggests that the gut microbiota regulates obesity through metabolite-host interactions. However, the mechanisms underlying such interactions have...
Accumulating evidence suggests that the gut microbiota regulates obesity through metabolite-host interactions. However, the mechanisms underlying such interactions have been unclear. Here, we found that intestinal hypoxia-inducible factor 2α (HIF-2α) positively regulates gut lactate by controlling the expression of intestinal Ldha. Intestine-specific HIF-2α ablation in mice resulted in lower lactate levels, and less Bacteroides vulgatus and greater Ruminococcus torques abundance, respectively. Together, these changes resulted in elevated taurine-conjugated cholic acid (TCA) and deoxycholic acid (DCA) levels and activation of the adipose G-protein-coupled bile acid receptor, GPBAR1 (TGR5). This activation upregulated expression of uncoupling protein (UCP) 1 and mitochondrial creatine kinase (CKMT) 2, resulting in elevation of white adipose tissue thermogenesis. Administration of TCA and DCA mirrored these phenotypes, and colonization with B. vulgatus and R. torques inhibited and induced thermogenesis, respectively. This work deepens our understanding of how host genes regulate the microbiome and provides novel strategies for alleviating obesity.
Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Gastrointestinal Microbiome; Hypoxia; Lactic Acid; Mice; Mice, Inbred C57BL; Receptors, G-Protein-Coupled; Thermogenesis; Uncoupling Protein 1
PubMed: 34329568
DOI: 10.1016/j.cmet.2021.07.007