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Frontiers in Immunology 2022Previous researches have implicated a vital association between gut microbiota (GM) and diabetic retinopathy (DR) based on the association of the "gut-retina" axis. But...
BACKGROUND
Previous researches have implicated a vital association between gut microbiota (GM) and diabetic retinopathy (DR) based on the association of the "gut-retina" axis. But their causal relationship has not been elucidated.
METHODS
Instrumental variables of 211 GM taxa were obtained from genome wide association study (GWAS), and Mendelian randomization study was carried out to estimate their effects on DR risk from FinnGen GWAS (14,584 DR cases and 202,082 controls). Inverse variance weighted (IVW) is the main method to analyze causality, and MR results are verified by several sensitive analyses.
RESULTS
As for 211 GM taxa, IVW results confirmed that family- ( = 1.36×10) and family- ( = 3.13×10) were protective factors for DR. Genus- ( = 4.83×10), genus- ( = 3.44×10) and genus- ( = 4.82×10) were correlated with the risk of DR. At the phylum, class and order levels, we found no GM taxa that were causally related to DR (>0.05). Heterogeneity (>0.05) and pleiotropy (>0.05) analysis confirmed the robustness of MR results.
CONCLUSION
We confirmed that there was a potential causal relationship between some GM taxa and DR, which highlights the association of the "gut-retina" axis and offered new insights into the GM-mediated mechanism of DR. Further explorations of their association are required and will lead to find new biomarkers for targeted prevention strategies of DR.
Topics: Diabetes Mellitus; Diabetic Retinopathy; Gastrointestinal Microbiome; Genome-Wide Association Study; Humans; Mendelian Randomization Analysis; Polymorphism, Single Nucleotide
PubMed: 36159877
DOI: 10.3389/fimmu.2022.930318 -
Frontiers in Immunology 2023An association between Graves' disease (GD) and the gut microbiome has been identified, but the causal effect between them remains unclear.
BACKGROUND
An association between Graves' disease (GD) and the gut microbiome has been identified, but the causal effect between them remains unclear.
METHODS
Bidirectional two-sample Mendelian randomization (MR) analysis was used to detect the causal effect between GD and the gut microbiome. Gut microbiome data were derived from samples from a range of different ethnicities (18,340 samples) and data on GD were obtained from samples of Asian ethnicity (212,453 samples). Single nucleotide polymorphisms (SNPs) were selected as instrumental variables according to different criteria. They were used to evaluate the causal effect between exposures and outcomes through inverse-variance weighting (IVW), weighted median, weighted mode, MR-Egger, and simple mode methods. -statistics and sensitivity analyses were performed to evaluate bias and reliability.
RESULTS
In total, 1,560 instrumental variables were extracted from the gut microbiome data (< 1 × 10). The classes [odds ratio (OR) = 3.603] and , as well as the genera group, , and UCG 011 were identified as risk factors for GD. The family and the genus (OR = 0.489) were protective factors for GD. In addition, 13 instrumental variables were extracted from GD (< 1 × 10), causing one family and eight genera to be regulated. The genus group ( = 0.024, OR = 0.918) and ( = 0.049, OR = 1.584) had the greatest probability of being regulated. Significant bias, heterogeneity, and horizontal pleiotropy were not detected.
CONCLUSION
A causal effect relationship exists between GD and the gut microbiome, demonstrating regulatory activity and interactions, and thus providing evidence supporting the involvement of a thyroid-gut axis.
Topics: Humans; Gastrointestinal Microbiome; Mendelian Randomization Analysis; Reproducibility of Results; Graves Disease; Clostridiales; Lactobacillales
PubMed: 36865531
DOI: 10.3389/fimmu.2023.977587 -
Frontiers in Cellular and Infection... 2023The gut microbiota has been found to be associated with the risk of lung cancer. However, its causal relationship with various types of lung cancer remains unclear.
BACKGROUND
The gut microbiota has been found to be associated with the risk of lung cancer. However, its causal relationship with various types of lung cancer remains unclear.
METHODS
We conducted a Mendelian randomization (MR) study using the largest genome-wide association analysis of gut microbiota data to date from the MiBioGen consortium, with pooled statistics for various types of lung cancer from the Transdisciplinary Research in Cancer of the Lung, the International Lung Cancer Consortium, and FinnGen Consortium R7 release data. Inverse variance weighted, weighted model, MR-Egger regression, and weighted median were adapted to assess the causal relationship between gut microbiota and various types of lung cancer. Sensitivity analysis was used to test for the presence of pleiotropy and heterogeneity in instrumental variables. A reverse MR analysis was performed on these bacteria to determine their potential role in causing lung cancer. A reverse MR analysis was performed on these bacteria to determine their potential role in causing lung cancer. Multivariable Mendelian randomization (MVMR) was conducted to assess the direct causal impact of gut microbiota on the risk of various types of lung cancer.
RESULTS
Using IVW as the primary analytical method, we identified a total of 40 groups of gut microbiota with potential causal associations with various subtypes of lung cancer, of which 10 were associated with lung cancer, 10 with lung adenocarcinoma, 9 with squamous cell lung cancer, and 11 groups of bacteria associated with small cell lung cancer. After performing FDR correction, we further found that there was still a significant causal relationship between Peptococcaceae and lung adenocarcinoma. Sensitivity analyses demonstrated the robustness of these results, with no heterogeneity or pleiotropy found.
CONCLUSIONS
Our results confirm a causal relationship between specific gut microbiota and lung cancer, providing new insights into the role of gut microbiota in mediating the development of lung cancer.
Topics: Humans; Lung Neoplasms; Gastrointestinal Microbiome; Genome-Wide Association Study; Mendelian Randomization Analysis; Adenocarcinoma of Lung
PubMed: 37829610
DOI: 10.3389/fcimb.2023.1200299 -
Frontiers in Immunology 2021Cyclophosphamide (CTX), used in cancer chemotherapy, a high dose of which would cause immunosuppressive effect and intestinal mucosa damage. American ginseng ( L.)...
The Synergistic Effects of Polysaccharides and Ginsenosides From American Ginseng ( L.) Ameliorating Cyclophosphamide-Induced Intestinal Immune Disorders and Gut Barrier Dysfunctions Based on Microbiome-Metabolomics Analysis.
Cyclophosphamide (CTX), used in cancer chemotherapy, a high dose of which would cause immunosuppressive effect and intestinal mucosa damage. American ginseng ( L.) has a long history of functional food use for immunological disorder, colitis, cancer, and so on. This study aimed to illustrate the underlying mechanism of American ginseng's immunomodulatory effect in CTX-induced mice. In this study, all groups of American ginseng (American ginseng polysaccharide [AGP], American ginseng ginsenoside [AGG], co-treated with American ginseng polysaccharide and ginsenoside [AGP_AGG]) have relieve the immune disorder by reversing the lymphocyte subsets ratio in spleen and peripheral blood, as well as stimulating CD4T cells and IgA-secreting cells in small intestine. These three treatment groups, especially AGP_AGG co-treated group recovered the intestine morphology that up-regulated villus height (VH)/crypt depth (CD) ratio, areas of mucins expression, quantity of goblet cells, and expression of tight junction proteins (ZO-1, occludin). Importantly, the microbiome-metabolomics analysis was applied in this study to illustrate the possible immuno-modulating mechanism. The synergistic effect of polysaccharides and ginsenosides (AGP_AGG group) restored the gut microbiota composition and increased various beneficial mucosa-associated bacterial taxa Clostridiales, Bifidobacterium, and Lachnospiraceae, while decreased harmful bacteria Escherichia-Shigella and Peptococcaceae. Also, AGP_AGG group altered various fecal metabolites such as uric acid, xanthurenic acid, acylcarnitine, 9,10-DHOME, 13-HDoHE, LysoPE15:0, LysoPC 16:0, LysoPI 18:0, and so on, that associated with immunometabolism or protective effect of gut barrier. These results suggest AG, particularly co-treated of polysaccharide and ginsenoside may be used as immunostimulants targeting microbiome-metabolomics axis to prevent CTX-induced side effects in cancer patients.
Topics: Animals; Bacteria; Cyclophosphamide; Drug Therapy, Combination; Feces; Gastrointestinal Microbiome; Ginsenosides; Immune System Diseases; Immunomodulation; Immunosuppressive Agents; Intestinal Mucosa; Metabolomics; Mice; Panax; Polysaccharides
PubMed: 33968068
DOI: 10.3389/fimmu.2021.665901 -
Frontiers in Microbiology 2023A growing number of studies implies a strong association between gut microbiota and chronic obstructive pulmonary disease (COPD). However, the causal impact between gut...
BACKGROUND
A growing number of studies implies a strong association between gut microbiota and chronic obstructive pulmonary disease (COPD). However, the causal impact between gut microbiota and COPD remains unclear. As a result, we used a two-sample Mendelian randomization (MR) method to investigate the connection between gut microbiota and COPD in this study.
METHODS
The largest available genome-wide association study (GWAS) of gut microbiota was obtained from the MiBioGen consortium. Summary-level dataset for COPD were obtained from the FinnGen consortium. The main analysis method for determining the causal link between gut microbiota and COPD was inverse variance weighted (IVW). Subsequently, pleiotropy and heterogeneity tests were performed to determine the reliability of the results.
RESULTS
IVW method identified 9 bacterial taxa nominally associated with the risk of COPD. Class Actinobacteria ( = 0.020), genus ( = 0.024), genus ( = 0.002) and genus ( = 0.018) were protective against COPD. In addition, order Desulfovibrionales ( = 0.011), family Desulfovibrionaceae ( = 0.039), family Peptococcaceae ( = 0.020), family Victivallaceae ( = 0.012) and genus ( = 0.017) were associated with a higher risk of COPD. No pleiotropy or heterogeneity were found.
CONCLUSION
According to the findings of this MR analysis, a causal relationship exists between certain gut microbiota and COPD. New insights into the mechanisms of COPD mediated by gut microbiota are provided.
PubMed: 37405157
DOI: 10.3389/fmicb.2023.1196751 -
MBio Apr 2021Dichloroacetate (DCA) commonly occurs in the environment due to natural production and anthropogenic releases, but its fate under anoxic conditions is uncertain. Mixed...
Dichloroacetate (DCA) commonly occurs in the environment due to natural production and anthropogenic releases, but its fate under anoxic conditions is uncertain. Mixed culture RM comprising " Dichloromethanomonas elyunquensis" strain RM utilizes DCA as an energy source, and the transient formation of formate, H, and carbon monoxide (CO) was observed during growth. Only about half of the DCA was recovered as acetate, suggesting a fermentative catabolic route rather than a reductive dechlorination pathway. Sequencing of 16S rRNA gene amplicons and 16S rRNA gene-targeted quantitative real-time PCR (qPCR) implicated " Dichloromethanomonas elyunquensis" strain RM in DCA degradation. An ()-2-haloacid dehalogenase (HAD) encoded on the genome of strain RM was heterologously expressed, and the purified HAD demonstrated the cofactor-independent stoichiometric conversion of DCA to glyoxylate at a rate of 90 ± 4.6 nkat mg protein. Differential protein expression analysis identified enzymes catalyzing the conversion of DCA to acetyl coenzyme A (acetyl-CoA) via glyoxylate as well as enzymes of the Wood-Ljungdahl pathway. Glyoxylate carboligase, which catalyzes the condensation of two molecules of glyoxylate to form tartronate semialdehyde, was highly abundant in DCA-grown cells. The physiological, biochemical, and proteogenomic data demonstrate the involvement of an HAD and the Wood-Ljungdahl pathway in the anaerobic fermentation of DCA, which has implications for DCA turnover in natural and engineered environments, as well as the metabolism of the cancer drug DCA by gut microbiota. Dichloroacetate (DCA) is ubiquitous in the environment due to natural formation via biological and abiotic chlorination processes and the turnover of chlorinated organic materials (e.g., humic substances). Additional sources include DCA usage as a chemical feedstock and cancer drug and its unintentional formation during drinking water disinfection by chlorination. Despite the ubiquitous presence of DCA, its fate under anoxic conditions has remained obscure. We discovered an anaerobic bacterium capable of metabolizing DCA, identified the enzyme responsible for DCA dehalogenation, and elucidated a novel DCA fermentation pathway. The findings have implications for the turnover of DCA and the carbon and electron flow in electron acceptor-depleted environments and the human gastrointestinal tract.
Topics: Anaerobiosis; Bacteria, Anaerobic; Base Composition; Dichloroacetic Acid; Fermentation; Humans; Peptococcaceae; Phylogeny; RNA, Ribosomal, 16S; Sequence Analysis, DNA
PubMed: 33906923
DOI: 10.1128/mBio.00537-21 -
Journal of Electrocardiology 2023Past research based on observations has suggested that the gut microbiome (GM) could play a role in developing arrhythmias and conduction blocks. Nonetheless, the nature...
INTRODUCTION
Past research based on observations has suggested that the gut microbiome (GM) could play a role in developing arrhythmias and conduction blocks. Nonetheless, the nature of this association remains uncertain due to the potential for reverse causation and confounding factors in observational research. The aim of this investigation is to elucidate the causal relationship between GM and the development of arrhythmias as well as conduction blocks.
METHODS
This study collected summary statistics regarding GM, arrhythmias, and conduction blocks. Two-sample Mendelian randomization (MR) analysis was carried out employing various methods, with inverse variance weighted being the primary approach, followed by weighted median, simple mode, MR-Egger, and MR-PRESSO. Moreover, the MR findings were corroborated through multiple sensitivity analyses.
RESULTS
Among them, for atrial fibrillation and flutter (AF), phylum_Actinobacteria and genus_RuminococcaceaeUCG004 demonstrated a negative correlation, while order_Pasteurellales, family_Pasteurellaceae, and genus_Turicibacter were associated with an increased risk. In the case of paroxysmal tachycardia (PT), genus_Holdemania and genus_Roseburia were found to reduce risk. For atrioventricular block (AVB), order_Bifidobacteriales, family_Bifidobacteriaceae, and genus_Alistipes exhibited a negative correlation, whereas genus_CandidatusSoleaferrea showed a positive correlation. Concerning the left bundle-branch block (LBBB), family_Peptococcaceae appeared to decrease the risk, while genus_Flavonifractor was linked to an increased risk. Lastly, no causative GM was identified in the right bundle-branch block (RBBB) context.
CONCLUSION
We have uncovered potential causal links between some GM, arrhythmias, and conduction blocks. This insight may aid in designing microbiome-based interventions for these conditions and their risk factors in future trials. Additionally, it could facilitate the discovery of novel biomarkers for targeted prevention strategies.
Topics: Humans; Gastrointestinal Microbiome; Mendelian Randomization Analysis; Electrocardiography; Bundle-Branch Block; Atrial Fibrillation
PubMed: 37422943
DOI: 10.1016/j.jelectrocard.2023.06.006 -
Diagnostics (Basel, Switzerland) Apr 2022Through a multitude of studies, the gut microbiota has been recognized as a significant influencer of both homeostasis and pathophysiology. Certain microbial taxa can...
Through a multitude of studies, the gut microbiota has been recognized as a significant influencer of both homeostasis and pathophysiology. Certain microbial taxa can even affect treatments such as cancer immunotherapies, including the immune checkpoint blockade. These taxa can impact such processes both individually as well as collectively through mechanisms from quorum sensing to metabolite production. Due to this overarching presence of the gut microbiota in many physiological processes distal to the GI tract, we hypothesized that mice bearing tumors at extraintestinal sites would display a distinct intestinal microbial signature from non-tumor-bearing mice, and that such a signature would involve taxa that collectively shift with tumor presence. Microbial OTUs were determined from 16S rRNA genes isolated from the fecal samples of C57BL/6 mice challenged with either B16-F10 melanoma cells or PBS control and analyzed using QIIME. Relative proportions of bacteria were determined for each mouse and, using machine-learning approaches, significantly altered taxa and co-occurrence patterns between tumor- and non-tumor-bearing mice were found. Mice with a tumor had elevated proportions of , .g_rc4.4, and as well as significant information gains and ReliefF weights for , , , and . , , and were also implicated through shifting co-occurrences and PCA values. Using these seven taxa as a melanoma signature, a neural network reached an 80% tumor detection accuracy in a 10-fold stratified random sampling validation. These results indicated gut microbial proportions as a biosensor for tumor detection, and that shifting co-occurrences could be used to reveal relevant taxa.
PubMed: 35454006
DOI: 10.3390/diagnostics12040958 -
Frontiers in Immunology 2021Levels of type 2 cytokines are elevated in the blood and intestinal tissues of ulcerative colitis (UC) patients in the active phase; this phenomenon indicates the...
Levels of type 2 cytokines are elevated in the blood and intestinal tissues of ulcerative colitis (UC) patients in the active phase; this phenomenon indicates the participation of type 2 immune response in UC progression. The beneficial effects of melatonin in dextran sodium sulfate (DSS) and 2,4,6-trinitrobenzene sulfonic acid (TNBS) colitis models have been illustrated, but its role in the oxazolone (Oxa)-induced colitis model (driven by type 2 immune response) remains relatively unknown. We investigated the relationship between melatonin concentration and the severity of UC, revealing a significantly negative correlation. Subsequently, we investigated the effects of melatonin in Oxa-induced colitis mice and the potential underlying mechanisms. Administration of melatonin significantly counteracted body weight loss, colon shortening, and neutrophil infiltration in Oxa-induced colitis mice. Melatonin treatment mitigated Oxa-induced colitis by suppressing type 2 immune response. In addition, melatonin attenuated intestinal permeability by enhancing the expression of ZO-1 and occludin in colitis mice. Interestingly, the protective effect of melatonin was abolished when the mice were co-housed, indicating that the regulation of gut microbiota by melatonin was critical in alleviating Oxa-induced colitis. Subsequently, 16S rRNA sequencing was performed to explore the microbiota composition. Decreased richness and diversity of intestinal microbiota at the operational taxonomic unit (OTU) level resulted from melatonin treatment. Melatonin also elevated the abundance of , a well-known probiotic, and reduced proportions of several harmful bacterial genera, such as , Peptococcaceae, and Lachnospiraceae. Fecal microbiota transplantation (FMT) was used to explore the role of microbiota in the function of melatonin in Oxa-induced colitis. Microbiota transplantation from melatonin-treated mice alleviated Oxa-induced colitis, suggesting that the microbiome participates in the relief of Oxa-induced colitis by melatonin. Our findings demonstrate that melatonin ameliorates Oxa-induced colitis in a microbiota-dependent manner, suggesting the therapeutic potential of melatonin in treating type 2 immunity-associated UC.
Topics: Animals; Colitis, Ulcerative; Colon; Fecal Microbiota Transplantation; Gastrointestinal Microbiome; Humans; Melatonin; Mice; Oxazolone
PubMed: 35116024
DOI: 10.3389/fimmu.2021.783806 -
Nutrients Jun 2021Glucosamine (GLU) is a natural compound found in cartilage, and supplementation with glucosamine has been shown to improve joint heath and has been linked to reduced... (Randomized Controlled Trial)
Randomized Controlled Trial
Glucosamine (GLU) is a natural compound found in cartilage, and supplementation with glucosamine has been shown to improve joint heath and has been linked to reduced mortality rates. GLU is poorly absorbed and may exhibit functional properties in the gut. The purpose of this study was to examine the impact of glucosamine on gastrointestinal function as well as changes in fecal microbiota and metabolome. Healthy males ( = 6) and females ( = 5) (33.4 ± 7.7 years, 174.1 ± 12.0 cm, 76.5 ± 12.9 kg, 25.2 ± 3.1 kg/m, = 11) completed two supplementation protocols that each spanned three weeks separated by a washout period that lasted two weeks. In a randomized, double-blind, placebo-controlled, crossover fashion, participants ingested a daily dose of GLU hydrochloride (3000 mg GlucosaGreen, TSI Group Ltd., Missoula, MT, USA) or maltodextrin placebo. Study participants completed bowel habit and gastrointestinal symptoms questionnaires in addition to providing a stool sample that was analyzed for fecal microbiota and metabolome at baseline and after the completion of each supplementation period. GLU significantly reduced stomach bloating and showed a trend towards reducing constipation and hard stools. Phylogenetic diversity (Faith's PD) and proportions of , , and were significantly reduced following GLU consumption. GLU supplementation significantly reduced individual, total branched-chain, and total amino acid excretion, with no glucosamine being detected in any of the fecal samples. GLU had no effect on fecal short-chain fatty acids levels. GLU supplementation provided functional gut health benefits and induced fecal microbiota and metabolome changes.
Topics: Adult; Cross-Over Studies; Defecation; Dietary Supplements; Double-Blind Method; Feces; Female; Gastrointestinal Microbiome; Gastrointestinal Tract; Glucosamine; Healthy Volunteers; Humans; Male; Phylogeny; Pilot Projects; Polysaccharides
PubMed: 34202877
DOI: 10.3390/nu13072180