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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 -
Gastroenterology Jan 2024The gut microbiota plays a significant role in the pathogenesis of both forms of inflammatory bowel disease (IBD), namely, Crohn's disease (CD) and ulcerative colitis... (Review)
Review
The gut microbiota plays a significant role in the pathogenesis of both forms of inflammatory bowel disease (IBD), namely, Crohn's disease (CD) and ulcerative colitis (UC). Although evidence suggests dysbiosis and loss of beneficial microbial species can exacerbate IBD, many new studies have identified microbes with pathogenic qualities, termed "pathobionts," within the intestines of patients with IBD. The concept of pathobionts initiating or driving the chronicity of IBD has largely focused on the putative aggravating role that adherent invasive Escherichia coli may play in CD. However, recent studies have identified additional bacterial and fungal pathobionts in patients with CD and UC. This review will highlight the characteristics of these pathobionts and their implications for IBD treatment. Beyond exploring the origins of pathobionts, we discuss those associated with specific clinical features and the potential mechanisms involved, such as creeping fat (Clostridium innocuum) and impaired wound healing (Debaryomyces hansenii) in patients with CD as well as the increased fecal proteolytic activity (Bacteroides vulgatus) seen as a biomarker for UC severity. Finally, we examine the potential impact of pathobionts on current IBD therapies, and several new approaches to target pathobionts currently in the early stages of development. Despite recognizing that pathobionts likely contribute to the pathogenesis of IBD, more work is needed to define their modes of action. Determining whether causal relationships exist between pathobionts and specific disease characteristics could pave the way for improved care for patients, particularly for those not responding to current IBD therapies.
Topics: Humans; Inflammatory Bowel Diseases; Colitis, Ulcerative; Crohn Disease; Intestines; Feces
PubMed: 37734419
DOI: 10.1053/j.gastro.2023.09.019 -
Frontiers in Microbiology 2023Patients with inflammatory bowel disease (IBD) have a higher prevalence of depression. Gut microbiota dysbiosis plays an important role in IBD and depression. However,...
BACKGROUND
Patients with inflammatory bowel disease (IBD) have a higher prevalence of depression. Gut microbiota dysbiosis plays an important role in IBD and depression. However, few studies have explored the characteristic microbiota of patients with IBD and depression (IBDD), or their role in IBDD.
METHODS
We performed deep metagenomic sequencing and 16S rDNA quantitative PCR to characterise the gut microbial communities of patients with IBDD and patients with IBD without depression (IBDND). We then assessed the effect of the microbiota on colitis and depression in mouse models of dextran sulfate sodium salt (DSS)-induced colitis and lipopolysaccharide (LPS)-induced depression. Furthermore, liquid chromatography-tandem mass spectrometry was used to analyse the microbiota-derived metabolites involved in gut-brain communication. Evans Blue tracer dye was used to assess blood-brain barrier (BBB) permeability.
RESULTS
Our results showed that the faecal abundance of () was lower in patients with IBDD than in those with IBDND. In the DSS-induced colitis mouse model, the group showed a significantly lower disease activity index score, lesser weight loss, and longer colon length than the DSS group. Moreover, relieved depression-like behaviour in the DSS-induced colitis mouse model and in the LPS-induced depression mouse model. Furthermore, the key metabolite of was p-hydroxyphenylacetic acid (4-HPAA), which was found to relieve intestinal inflammation and alleviate depression-like behaviours in mouse models. By increasing the expression of the tight junction protein claudin-5 in the vascular endothelium of the BBB, and 4-HPAA play critical roles in gut-brain communication.
CONCLUSION
and -derived 4-HPAA ameliorated intestinal inflammation and relieved depressive symptoms through the gut-brain axis. Thus, administration of or 4-HPAA supplementation is a promising therapeutic strategy for treating IBD, particularly IBDD.
PubMed: 38033588
DOI: 10.3389/fmicb.2023.1287271 -
EBioMedicine Jul 2023Obesity is a risk factor for colorectal cancer (CRC). The role of gut microbiota in mediating the cancer-promoting effect of obesity is unknown.
BACKGROUND
Obesity is a risk factor for colorectal cancer (CRC). The role of gut microbiota in mediating the cancer-promoting effect of obesity is unknown.
METHODS
Azoxymethane (AOM)-treated, Apc and germ-free mice were gavaged with feces from obese individuals and control subjects respectively. The colonic tumor load and number were recorded at the endpoint in two carcinogenic models. The gut microbiota composition and colonic transcriptome were assessed by metagenomic sequencing and RNA sequencing, respectively. The anticancer effects of bacteria depleted in fecal samples of obese individuals were validated.
FINDINGS
Conventional AOM-treated and Apc mice receiving feces from obese individuals showed significantly increased colon tumor formation compared with those receiving feces from control subjects. AOM-treated mice receiving feces from obese individuals showed impaired intestinal barrier function and significant upregulation of pro-inflammatory cytokines and activation of oncogenic Wnt signaling pathway. Consistently, transferring feces from obese individuals to germ-free mice led to increased colonic cell proliferation, intestinal barrier function impairment, and induction of oncogenic and proinflammatory gene expression. Moreover, germ-free mice transplanted with feces from obese human donors had increased abundance of potential pathobiont Alistipes finegoldii, and reduced abundance of commensals Bacteroides vulgatus and Akkermansia muciniphila compared with those receiving feces from human donors with normal body mass index (BMI). Validation experiments showed that B. vulgatus and A. muciniphila demonstrated anti-proliferative effects in CRC, while A. finegoldii promoted CRC tumor growth.
INTERPRETATION
Our results supported the role of obesity-associated microbiota in colorectal carcinogenesis and identified putative bacterial candidates that may mediate its mechanisms. Microbiota modulation in obese individuals may provide new approaches to prevent or treat obesity-related cancers including CRC.
FUNDING
This work was funded by National Key Research and Development Program of China (2020YFA0509200/2020YFA0509203), National Natural Science Foundation of China (81922082), RGC Theme-based Research Scheme Hong Kong (T21-705/20-N), RGC Research Impact Fund Hong Kong (R4632-21F), RGC-CRF Hong Kong (C4039-19GF and C7065-18GF), RGC-GRF Hong Kong (14110819, 14111621), and NTU Start-Up Grant (021337-00001).
Topics: Humans; Mice; Animals; Gastrointestinal Microbiome; Colonic Neoplasms; Carcinogenesis; Obesity; Azoxymethane; Colorectal Neoplasms; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 37343363
DOI: 10.1016/j.ebiom.2023.104670 -
Microbiome Aug 2023A growing body of evidence suggests that the gut microbiota is strongly linked to general human health. Microbiome-directed interventions, such as diet and exercise, are... (Meta-Analysis)
Meta-Analysis
BACKGROUND
A growing body of evidence suggests that the gut microbiota is strongly linked to general human health. Microbiome-directed interventions, such as diet and exercise, are acknowledged as a viable and achievable strategy for preventing disorders and improving human health. However, due to the significant inter-individual diversity of the gut microbiota between subjects, lifestyle recommendations are expected to have distinct and highly variable impacts to the microbiome structure.
RESULTS
Here, through a large-scale meta-analysis including 1448 shotgun metagenomics samples obtained longitudinally from 396 individuals during lifestyle studies, we revealed Bacteroides stercoris, Prevotella copri, and Bacteroides vulgatus as biomarkers of microbiota's resistance to structural changes, and aromatic and non-aromatic amino acid biosynthesis as important regulator of microbiome dynamics. We established criteria for distinguishing between significant compositional changes from normal microbiota fluctuation and classified individuals based on their level of response. We further developed a machine learning model for predicting "responders" and "non-responders" independently of the type of intervention with an area under the curve of up to 0.86 in external validation cohorts of different ethnicities.
CONCLUSIONS
We propose here that microbiome-based stratification is possible for identifying individuals with highly plastic or highly resistant microbial structures. Identifying subjects that will not respond to generalized lifestyle therapeutic interventions targeting the restructuring of gut microbiota is important to ensure that primary end-points of clinical studies are reached. Video Abstract.
Topics: Humans; Microbiota; Gastrointestinal Microbiome; Biomarkers; Diet; Life Style
PubMed: 37553697
DOI: 10.1186/s40168-023-01604-z -
Cancer Medicine Sep 2023Aging is one of the factors leading to cancer. Gut microbiota is related to aging and colorectal cancer (CRC).
BACKGROUND
Aging is one of the factors leading to cancer. Gut microbiota is related to aging and colorectal cancer (CRC).
METHODS
A total of 11 metagenomic data sets related to CRC were collected from the R package curated Metagenomic Data. After batch effect correction, healthy individuals and CRC samples were divided into three age groups. Ggplot2 and Microbiota Process packages were used for visual description of species composition and PCA in healthy individuals and CRC samples. LEfSe analysis was performed for species relative abundance data in healthy/CRC groups according to age. Spearman correlation coefficient of age-differentiated bacteria in healthy individuals and CRC samples was calculated separately. Finally, the age prediction model and CRC risk prediction model were constructed based on the age-differentiated bacteria.
RESULTS
The structure and composition of the gut microbiota were significantly different among the three groups. For example, the abundance of Bacteroides vulgatus in the old group was lower than that in the other two groups, the abundance of Bacteroides fragilis increased with aging. In addition, seven species of bacteria whose abundance increases with aging were screened out. Furthermore, the abundance of pathogenic bacteria (Escherichia_coli, Butyricimonas_virosa, Ruminococcus_bicirculans, Bacteroides_fragilis and Streptococcus_vestibularis) increased with aging in CRCs. The abundance of probiotics (Eubacterium_eligens) decreased with aging in CRCs. The age prediction model for healthy individuals based on the 80 age-related differential bacteria and model of CRC patients based on the 58 age-related differential bacteria performed well, with AUC of 0.79 and 0.71, respectively. The AUC of CRC risk prediction model based on 45 disease differential bacteria was 0.83. After removing the intersection between the disease-differentiated bacteria and the age-differentiated bacteria from the healthy samples, the AUC of CRC risk prediction model based on remaining 31 bacteria was 0.8. CRC risk prediction models for each of the three age groups showed no significant difference in accuracy (young: AUC=0.82, middle: AUC=0.83, old: AUC=0.85).
CONCLUSION
Age as a factor affecting microbial composition should be considered in the application of gut microbiota to predict the risk of CRC.
Topics: Humans; Gastrointestinal Microbiome; Colorectal Neoplasms; Bacteria; Microbiota; Aging
PubMed: 37548332
DOI: 10.1002/cam4.6414 -
Pediatric Research Apr 2024We have identified a decreased abundance of microbial species known to have a potential anti-inflammatory, protective effect in subjects that developed Celiac Disease...
BACKGROUND AND AIMS
We have identified a decreased abundance of microbial species known to have a potential anti-inflammatory, protective effect in subjects that developed Celiac Disease (CeD) compared to those who did not. We aim to confirm the potential protective role of one of these species, namely Bacteroides vulgatus, and to mechanistically establish the effect of bacterial bioproducts on gluten-dependent changes on human gut epithelial functions.
METHODS
We identified, isolated, cultivated, and sequenced a unique novel strain (20220303-A2) of B. vulgatus found only in control subjects. Using a human gut organoid system developed from pre-celiac patients, we monitored epithelial phenotype and innate immune cytokines at baseline, after exposure to gliadin, or gliadin plus B. vulgatus cell free supernatant (CFS).
RESULTS
Following gliadin exposure, we observed increases in epithelial cell death, epithelial monolayer permeability, and secretion of pro-inflammatory cytokines. These effects were mitigated upon exposure to B. vulgatus 20220303-A2 CFS, which had matched phenotype gene product mutations. These protective effects were mediated by epigenetic reprogramming of the organoids treated with B. vulgatus CFS.
CONCLUSIONS
We identified a unique strain of B. vulgatus that may exert a beneficial role by protecting CeD epithelium against a gluten-induced break of epithelial tolerance through miRNA reprogramming.
IMPACT
Gut dysbiosis precedes the onset of celiac disease in genetically at-risk infants. This dysbiosis is characterized by the loss of protective bacterial strains in those children who will go on to develop celiac disease. The paper reports the mechanism by which one of these protective strains, B. vulgatus, ameliorates the gluten-induced break of gut epithelial homeostasis by epigenetically re-programming the target intestinal epithelium involving pathways controlling permeability, immune response, and cell turnover.
PubMed: 38177249
DOI: 10.1038/s41390-023-02960-0 -
BMC Microbiology Dec 2023The promising yet barely investigated anaerobic species Phocaeicola vulgatus (formerly Bacteroides vulgatus) plays a vital role for human gut health and effectively...
BACKGROUND
The promising yet barely investigated anaerobic species Phocaeicola vulgatus (formerly Bacteroides vulgatus) plays a vital role for human gut health and effectively produces organic acids. Among them is succinate, a building block for high-value-added chemicals. Cultivating anaerobic bacteria is challenging, and a detailed understanding of P. vulgatus growth and metabolism is required to improve succinate production. One significant aspect is the influence of different gas concentrations. CO is required for the growth of P. vulgatus. However, it is a greenhouse gas that should not be wasted. Another highly interesting aspect is the sensitivity of P. vulgatus towards O. In this work, the effects of varying concentrations of both gases were studied in the in-house developed Respiratory Activity MOnitoring System (RAMOS), which provides online monitoring of CO, O and pressure under gassed conditions. The RAMOS was combined with a gas mixing system to test CO and O concentrations in a range of 0.25-15.0 vol% and 0.0-2.5 vol%, respectively.
RESULTS
Changing the CO concentration in the gas supply revealed a CO optimum of 3.0 vol% for total organic acid production and 15.0 vol% for succinate production. It was demonstrated that the organic acid composition changed depending on the CO concentration. Furthermore, unrestricted growth of P. vulgatus up to an O concentration of 0.7 vol% in the gas supply was proven. The viability decreased rapidly at concentrations larger than or equal to 1.3 vol% O.
CONCLUSIONS
The study showed that P. vulgatus requires little CO, has a distinct O tolerance and is therefore well suited for industrial applications.
Topics: Humans; Carbon Dioxide; Bacteroides; Succinates; Succinic Acid; Oxygen
PubMed: 38062358
DOI: 10.1186/s12866-023-03127-x -
Gut Microbes Dec 2023Morphine addiction is closely associated with dysbiosis of the gut microbiota. miRNAs play a crucial role in regulating intestinal bacterial growth and are involved in...
Morphine addiction is closely associated with dysbiosis of the gut microbiota. miRNAs play a crucial role in regulating intestinal bacterial growth and are involved in the development of disease. Ginsenoside Rg1 exhibits an anti-addiction effect and significantly improves intestinal microbiota disorders. In pseudo-germfree mice, supplementation with () synergistically enhanced Rg1 to alleviate morphine addiction. However, it is currently unknown the relationship between fecal miRNAs in morphine-exposed mice and their potential modulation of gut microbiome, as well as their role in mediating the resistance of ginsenoside Rg1 to drug addiction. Here, we studied the fecal miRNA abundance in mice treated with morphine to explore the different miRNAs expressed, their association with and their role in the amelioration of morphine reward by ginsenoside Rg1. Our results indicated ginsenoside Rg1 attenuated the significant increase in miR-129-5p expression observed in the feces of morphine-treated mice. The miR-129-5p, specifically, inhibited the growth of by modulating the transcript of the site-tag BVU_RS11835 and increased the levels of 5-hydroxytryptophan and indole-3-carboxaldehyde in vitro. Subsequently, we noticed that oral administration of synthetic miR-129-5p increased 5-HT levels in the hippocampus and inhibited the reversal effect of ginsenoside Rg1 both on the relative abundance of in the feces and CPP effect induced by morphine exposure. In short, Ginsenoside Rg1 might play an indirect role in remodeling the against morphine reward by suppressing miR-129-5p expression. These results highlight the role of miR-129-5p and in morphine reward and the anti-morphine addiction of ginsenoside Rg1.
Topics: Animals; Mice; Gastrointestinal Microbiome; Hippocampus; MicroRNAs; Morphine; Reward; Serotonin
PubMed: 37698853
DOI: 10.1080/19490976.2023.2254946 -
Molecular Medicine Reports Oct 2023Pathological epithelial‑mesenchymal transition (EMT) has been shown to fulfill a key role in the development and progression of a variety of lung diseases. It has been...
Pathological epithelial‑mesenchymal transition (EMT) has been shown to fulfill a key role in the development and progression of a variety of lung diseases. It has been demonstrated that the inflammatory microenvironment is a decisive factor in inducing pathological EMT. Hexacylated lipopolysaccharide (LPS) [or proacylated lipopolysaccharide (P‑LPS), which functions as proinflammatory lipopolysaccharide] is one of the most effective Toll‑like receptor 4 (TLR4) agonists. Furthermore, the pentacylated and tetracylated form of lipopolysaccharide (or A‑LPS, which functions as anti‑inflammatory lipopolysaccharide) has been shown to elicit competitive antagonistic effects against the pro‑inflammatory activity of P‑LPS. At present, it remains unclear whether LPS extracted from (BV‑LPS) can prevent LPS extracted from (EC‑LPS) from inducing pathological EMT. In the present study, A549 cells and C57BL/6 mice lung tissue were both induced by EC‑LPS (P‑LPS) and BV‑LPS (A‑LPS), either alone or in combination. The anticipated anti‑inflammatory effects of BV‑LPS were analyzed by examining the lung coefficient, lung pathology, A549 cell morphology and expression levels both of the inflammatory cytokines, IL‑1β, IL‑6 and TNF‑α and of the EMT signature proteins, epithelial cadherin (E‑cadherin), α‑smooth muscle actin (α‑SMA) and vimentin. In addition, the expression levels of TLR4, bone morphogenic protein and activin membrane‑bound inhibitor (BAMBI) and Snail were detected and the possible mechanism underlying how BV‑LPS may prevent EC‑LPS‑induced EMT was analyzed. The results obtained showed that the morphology of the A549 cells was significantly polarized, the lung index was significantly increased, the alveolar structure was collapsed and the expression levels of IL‑1β, IL‑6, TNF‑α, α‑SMA, vimentin, TLR4 and Snail in both lung tissue and A549 cells were significantly increased, whereas those of E‑cadherin and BAMBI were significantly decreased. Treatment with BV‑LPS in combination with EC‑LPS was found to reverse these changes. In conclusion, the present study demonstrated that BV‑LPS is able to effectively prevent EC‑LPS‑induced EMT in A549 cells and in mouse lung tissue and furthermore, the underlying mechanism may be associated with inhibition of the TLR4/BAMBI/Snail signaling pathway.
Topics: Lipopolysaccharides; Escherichia coli; Epithelial-Mesenchymal Transition; Bacteroides; Acylation; Inflammation; A549 Cells; Lung; Signal Transduction; Humans; Animals; Mice; Mice, Inbred C57BL
PubMed: 37681466
DOI: 10.3892/mmr.2023.13082