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Gastroenterology Sep 2020Alterations in the intestinal microbiota affect development of colorectal cancer and drug metabolism. We studied whether the intestinal microbiota affect the ability of...
BACKGROUND & AIMS
Alterations in the intestinal microbiota affect development of colorectal cancer and drug metabolism. We studied whether the intestinal microbiota affect the ability of aspirin to reduce colon tumor development in mice.
METHODS
We performed studies with APC mice and mice given azoxymethane and dextran sulfate sodium to induce colorectal carcinogenesis. Some mice were given antibiotics to deplete intestinal microbes, with or without aspirin, throughout the entire experiment. Germ-free mice were studied in validation experiments. Colon tissues were collected and analyzed by histopathology, quantitative reverse-transcription polymerase chain reaction, and immunoblots. Blood samples and gut luminal contents were analyzed by liquid chromatography/mass spectrometry and an arylesterase activity assay. Fecal samples were analyzed by 16S ribosomal RNA gene and shotgun metagenome sequencing.
RESULTS
Administration of aspirin to mice reduced colorectal tumor number and load in APC mice and mice given azoxymethane and dextran sulfate sodium that had been given antibiotics (depleted gut microbiota), but not in mice with intact microbiota. Germ-free mice given aspirin developed fewer colorectal tumors than conventionalized germ-free mice given aspirin. Plasma levels of aspirin were higher in mice given antibiotics than in mice with intact gut microbiota. Analyses of luminal contents revealed that aerobic gut microbes, including Lysinibacillus sphaericus, degrade aspirin. Germ-free mice fed L sphaericus had lower plasma levels of aspirin than germ-free mice that were not fed this bacterium. There was an inverse correlation between aspirin dose and colorectal tumor development in conventional mice, but this correlation was lost with increased abundance of L sphaericus. Fecal samples from mice fed aspirin were enriched in Bifidobacterium and Lactobacillus genera, which are considered beneficial, and had reductions in Alistipes finegoldii and Bacteroides fragili, which are considered pathogenic.
CONCLUSIONS
Aspirin reduces development of colorectal tumors in APC mice and mice given azoxymethane and dextran sulfate sodium, depending on the presence of intestinal microbes. L sphaericus in the gut degrades aspirin and reduced its chemopreventive effects in mice. Fecal samples from mice fed aspirin were enriched in beneficial bacteria, with reductions in pathogenic bacteria.
Topics: Adenomatous Polyposis Coli Protein; Animals; Anti-Bacterial Agents; Anticarcinogenic Agents; Aspirin; Azoxymethane; Bacillaceae; Bacteroides fragilis; Bacteroidetes; Biological Availability; Carcinogenesis; Colitis; Colon; Colorectal Neoplasms; DNA, Bacterial; Dextran Sulfate; Disease Models, Animal; Dose-Response Relationship, Drug; Feces; Gastrointestinal Microbiome; Germ-Free Life; Humans; Intestinal Mucosa; Male; Mice; Mice, Transgenic; RNA, Ribosomal, 16S
PubMed: 32387495
DOI: 10.1053/j.gastro.2020.05.004 -
MSystems Apr 2023Autoimmune hepatitis (AIH) is a liver disease characterized by chronic liver inflammation. The intestinal barrier and microbiome play critical roles in AIH progression....
Autoimmune hepatitis (AIH) is a liver disease characterized by chronic liver inflammation. The intestinal barrier and microbiome play critical roles in AIH progression. AIH treatment remains challenging because first-line drugs have limited efficacy and many side effects. Thus, there is growing interest in developing synbiotic therapies. This study investigated the effects of a novel synbiotic in an AIH mouse model. We found that this synbiotic (Syn) ameliorated liver injury and improved liver function by reducing hepatic inflammation and pyroptosis. The Syn reversed gut dysbiosis, as indicated by an increase in beneficial bacteria (e.g., and ) and a decrease in potentially harmful bacteria (e.g., Escherichia) and lipopolysaccharide (LPS)-bearing Gram-negative bacterial levels. The Syn maintained intestinal barrier integrity, reduced LPS, and inhibited the TLR4/NF-κB and NLRP3/Caspase-1 signaling pathway. In addition, microbiome phenotype prediction by BugBase and bacterial functional potential prediction using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) showed that Syn improved gut microbiota function involving inflammatory injury, metabolism, immune response, and pathopoiesia. Furthermore, the new Syn was as effective as prednisone against AIH. Therefore, this novel Syn could be a candidate drug for alleviating AIH through its anti-inflammatory and antipyroptosis properties that relieve endothelial dysfunction and gut dysbiosis. Synbiotics can ameliorate liver injury and improve liver function by reducing hepatic inflammation and pyroptosis. Our data indicate that our new Syn not only reverses gut dysbiosis by increasing beneficial bacteria and decreasing lipopolysaccharide (LPS)-bearing Gram-negative bacteria but also maintains intestinal barrier integrity. Thus, its mechanism might be associated with modulating gut microbiota composition and intestinal barrier function by inhibiting the TLR4/NF-κB/NLRP3/pyroptosis signaling pathway in the liver. This Syn is as effective as prednisone in treating AIH without side effects. Based on these findings, this novel Syn represents a potential therapeutic agent for AIH in clinical practice.
Topics: Animals; Mice; Hepatitis, Autoimmune; NF-kappa B; Lipopolysaccharides; NLR Family, Pyrin Domain-Containing 3 Protein; Synbiotics; Toll-Like Receptor 4; Gastrointestinal Microbiome; Dysbiosis; Prednisone; Phylogeny; Signal Transduction; Inflammation
PubMed: 36794950
DOI: 10.1128/msystems.01127-22 -
Science Translational Medicine Nov 2023Multidrug-resistant organism (MDRO) colonization is a fundamental challenge in antimicrobial resistance. Limited studies have shown that fecal microbiota transplantation... (Randomized Controlled Trial)
Randomized Controlled Trial
Multidrug-resistant organism (MDRO) colonization is a fundamental challenge in antimicrobial resistance. Limited studies have shown that fecal microbiota transplantation (FMT) can reduce MDRO colonization, but its mechanisms are poorly understood. We conducted a randomized, controlled trial of FMT for MDRO decolonization in renal transplant recipients called PREMIX (NCT02922816). Eleven participants were enrolled and randomized 1:1 to FMT or an observation period followed by delayed FMT if stool cultures were MDRO positive at day 36. Participants who were MDRO positive after one FMT were treated with a second FMT. At last visit, eight of nine patients who completed all treatments were MDRO culture negative. FMT-treated participants had longer time to recurrent MDRO infection versus PREMIX-eligible controls who were not treated with FMT. Key taxa (, , , , species, , , and ) from the single feces donor used in the study that engrafted in recipients and metabolites such as short-chain fatty acids and bile acids in FMT-responding participants uncovered leads for rational microbiome therapeutic and diagnostic development. Metagenomic analyses revealed a previously unobserved mechanism of MDRO eradication by conspecific strain competition in an FMT-treated subset. Susceptible strains that replaced baseline extended-spectrum β-lactamase-producing strains were not detectable in donor microbiota manufactured as FMT doses but in one case were detectable in the recipient before FMT. These data suggest that FMT may provide a path to exploit strain competition to reduce MDRO colonization.
Topics: Humans; Fecal Microbiota Transplantation; Anti-Bacterial Agents; Gastrointestinal Microbiome; Drug Resistance, Bacterial; Feces; Treatment Outcome
PubMed: 37910603
DOI: 10.1126/scitranslmed.abo2750 -
Frontiers in Public Health 2023Type 2 diabetes mellitus (T2DM) is a commonly observed metabolic anomaly globally, and as of the present time, there's no recognized solution. There is an increasing... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Type 2 diabetes mellitus (T2DM) is a commonly observed metabolic anomaly globally, and as of the present time, there's no recognized solution. There is an increasing body of evidence from numerous observational studies indicating a significant correlation between gut flora and metabolic disease progression, particularly in relation to T2DM. Despite this, the direct impact of gut microbiota on T2DM isn't fully understood yet.
METHODS
The summary statistical figures for intestinal microbiota were sourced from the MiBioGen consortium, while the summary statistical data for T2DM were gathered from the Genome-Wide Association Studies (GWAS) database. These datasets were used to execute a two-sample Mendelian randomization (MR) investigation. The Inverse Variance Weighted (IVW), Maximum Likelihood, MR-Egger, Weighted Median, and Weighted Models strategies were employed to assess the impact of gut microbiota on T2DM. Findings were primarily obtained using the IVW technique. Techniques like MR-Egger were employed to identify the occurrence of horizontal pleiotropy among instrumental variables. Meanwhile, Cochran's Q statistical measures were utilized to assess the variability or heterogeneity within these instrumental variables.
RESULTS
The outcomes from the IVW analysis demonstrated that the genus (OR = 0.998, 95% confidence interval: 0.996-1.000, and = 0.038), genus (OR = 0.998, 95% confidence interval: 0.997-0.999, = 0.033), genus (OR = 0.995, 95% confidence interval: 0.993-0.998, = 3.78 × 10), and genus (OR = 0.995, 95% confidence interval: 0.993-0.998, = 8.08 × 10) all acted as defense elements against type 2 diabetes. Family (OR = 1.003, 95% confidence interval: 1.001-1.005, = 0.012), family (OR = 1.0025, 95% confidence interval: 1.000-1.005, = 0.043), genus (OR = 1.003,95% confidence interval: 1.001-1.005, = 4.38 × 10), genus (OR = 1.001,95% confidence interval: 1.000-1.002 = 0.012) were risk factors for type 2 diabetes. False Discovery Rate correction was performed with finding that genus., genus, family and T2DM no longer displayed a significant causal association. In addition, no significant heterogeneity or horizontal pleiotropy was found for instrumental variable.
CONCLUSION
This MR study relies on genetic variation tools to confirm the causal effect of genus , genus , family , genus and genus on T2DM in the gut microbiome, providing new directions and strategies for the treatment and early screening of T2DM, which carries significant clinical relevance. To develop new biomarkers and better understand targeted prevention strategies for T2DM, further comprehensive investigations are required into the protective and detrimental mechanisms exerted by these five genera against T2DM.
Topics: Humans; Clinical Relevance; Diabetes Mellitus, Type 2; Gastrointestinal Microbiome; Genome-Wide Association Study; Risk Factors; Mendelian Randomization Analysis
PubMed: 37808975
DOI: 10.3389/fpubh.2023.1255059 -
Scientific Reports Jun 2023Metabolic associated fatty liver disease (MAFLD) is rising in incidence and is an increasingly common cause of cirrhosis and hepatocellular carcinoma (HCC). Alterations...
Metabolic associated fatty liver disease (MAFLD) is rising in incidence and is an increasingly common cause of cirrhosis and hepatocellular carcinoma (HCC). Alterations in the gut microbiota have been shown to correlate with the development and progression of MAFLD. However, little is known regarding differences in the gut microbiomes of MAFLD patients and healthy cohorts, and subgroups at the abnormal activity of hepatic enzymes in China. In this study, we enrolled 81 MAFLD patients and 25 healthy volunteers. The fecal microbiota was assessed using 16S rRNA gene sequencing and metagenomic sequencing. The results suggested that Ruminococcus obeum and Alistipes were most enriched in healthy individuals when compared with MAFLD patients. Microbe-set Enrichment Analysis (MSEA) results showed Dorea, Lactobacillus and Megasphaera are enriched in MAFLD group. We also found that Alistipes has negatively related to serum glucose (GLU), gamma-glutamyl transferase (GGT), and alanine aminotransferase (ALT). Moreover, the abundance of Dorea was found to be significantly overrepresented in the MAFLD patients and the degree of enrichment increased with the increasing abnormal liver enzyme. An increase in Dorea, combined with decreases in Alistipes appears to be characteristic of MAFLD patients. Further study of microbiota may provide a novel insight into the pathogenesis of MAFLD as well as a novel treatment strategy.
Topics: Humans; Gastrointestinal Microbiome; Carcinoma, Hepatocellular; RNA, Ribosomal, 16S; Liver Neoplasms; Microbiota; Non-alcoholic Fatty Liver Disease; Bacteroidetes; Clostridiaceae
PubMed: 37340081
DOI: 10.1038/s41598-023-37163-4 -
Biomedicines Jul 2022Opioid-induced dysbiosis (OID) is a specific condition describing the consequences of opioid use on the bacterial composition of the gut. Opioids have been shown to... (Review)
Review
Opioid-induced dysbiosis (OID) is a specific condition describing the consequences of opioid use on the bacterial composition of the gut. Opioids have been shown to affect the epithelial barrier in the gut and modulate inflammatory pathways, possibly mediating opioid tolerance or opioid-induced hyperalgesia; in combination, these allow the invasion and proliferation of non-native bacterial colonies. There is also evidence that the gut-brain axis is linked to the emotional and cognitive aspects of the brain with intestinal function, which can be a factor that affects mental health. For example, , and are linked to Irritable Bowel Disease; and have associations with Parkinson's disease, and has increased prevalence in depression. However, changes to the gut microbiome can be therapeutically influenced with treatments such as faecal microbiota transplantation, targeted antibiotic therapy and probiotics. There is also evidence of emerging therapies to combat OID. This review has collated evidence that shows that there are correlations between OID and depression, Parkinson's Disease, infection, and more. Specifically, in pain management, targeting OID deserves specific investigations.
PubMed: 36009361
DOI: 10.3390/biomedicines10081815 -
Nutrients Jul 2022Frailty during aging is an increasing problem associated with locomotor and cognitive decline, implicated in poor quality of life and adverse health consequences....
Frailty during aging is an increasing problem associated with locomotor and cognitive decline, implicated in poor quality of life and adverse health consequences. Considering the microbiome-gut-brain axis, we investigated, in a longitudinal study, whether and how physiological aging affects gut microbiome composition in wild-type male mice, and if and how cognitive frailty is related to gut microbiome composition. To assess these points, we monitored mice during aging at five selected experimental time points, from adulthood to senescence. At all selected experimental times, we monitored cognitive performance using novel object recognition and emergence tests and measured the corresponding Cognitive Frailty Index. Parallelly, murine fecal samples were collected and analyzed to determine the respective alpha and beta diversities, as well as the relative abundance of different bacterial taxa. We demonstrated that physiological aging significantly affected the overall gut microbiome composition, as well as the relative abundance of specific bacterial taxa, including , , , , and . We also revealed that 218 amplicon sequence variants were significantly associated to the Cognitive Frailty Index. We speculated that some of them may guide the microbiome toward maladaptive and dysbiotic conditions, while others may compensate with changes toward adaptive and eubiotic conditions.
Topics: Animals; Bacteria; Brain-Gut Axis; Dysbiosis; Frailty; Longitudinal Studies; Male; Mice; Microbiota; Quality of Life
PubMed: 35889894
DOI: 10.3390/nu14142937 -
Scientific Reports Dec 2022The association between gut microbiome and chronic metabolic disease including polycystic ovary syndrome (PCOS), is well documented, however, the relationship between...
The association between gut microbiome and chronic metabolic disease including polycystic ovary syndrome (PCOS), is well documented, however, the relationship between the gut microbiota and serum metabolites remains unknown. In this study, untargeted metabolomics together with a 16S rRNA gene sequencing tool was used to detect small molecule serum metabolites and the gut microbiome. We identified 15 differential metabolites between PCOS patients and the healthy control. Lysophosphatidylcholine (LPC) (18:2, 20:3, 18:1, P-16:0, 17:0, 15:0, 18:3, 20:4), phosphatidylcholine(PC), ganglioside GA2 (d18:1/16:0) and 1-linoleoylglycerophosphocholine were increased in the PCOS group, and the concentrations of phosphoniodidous acid, bilirubin, nicotinate beta-D-ribonucleotide and citric acid were decreased in the PCOS group, suggesting a lipid metabolism and energy metabolism disorder in the PCOS patients. The diversity of gut microbiota in PCOS group was lower than that in healthy controls. Escherichia/Shigella, Alistipes and an unnamed strain 0319_6G20 belonging to Proteobacteria were important distinguishing genera (LDA > 3.5) in PCOS. Prevotella_9 was positively correlated with phosphoniodidous acid, nicotinate beta-D-ribonucleotide and citric acid concentrations, and negatively correlated with the concentration of LPC (20:3) and 1-linoleoylglycerophosphocholine; Roseburia was negatively correlated with LPC concentration (20:4), while the characteristic genus 0319_6G20 of PCOS was positively correlated with LPC concentration (20:3) (COR > 0.45). SF-36 in the PCOS group was significantly lower than that in the healthy control (HC) group, which was associated with the presence of Escherichia-Shigella and Alistipes. Our finding demonstrated the correlation between the gut microbiota and serum metabolites in PCOS, and therefore characteristic gut microbiota and metabolites may play an important role in the insulin resistance and the mood changes of PCOS patients.
Topics: Female; Humans; Polycystic Ovary Syndrome; Gastrointestinal Microbiome; Cross-Sectional Studies; Niacin; RNA, Ribosomal, 16S; Metabolomics; Bacteroidetes
PubMed: 36564416
DOI: 10.1038/s41598-022-25041-4 -
Journal of Cancer 2024Regulating the immune system is a crucial measure of gut microbiota (GM) that influences the development of diseases. The causal role of GM on Non-small cell lung...
Regulating the immune system is a crucial measure of gut microbiota (GM) that influences the development of diseases. The causal role of GM on Non-small cell lung cancer (NSCLC) and whether it can be mediated by immune cells is still unknown. We performed a two-step, two-sample Mendelian randomization study with an Inverse variance weighted (IVW) approach to investigate the causal role of GM on NSCLC and the mediation effect of immune cells between the association of GM and NSCLC. MR analyses determined the protective effects of 6 genera on NSCLC (Bacteroides, Roseburia, Alistipes, Methanobrevibacter, Ruminococcus gauvreauii group, and Peptococcus). In addition, 38 immune cell traits were suggestively associated with NSCLC. Of note, the mediation MR illustrated the causal role of Genus-Peptococcus on NSCLC (Total effect IVW: OR = 0.790, 95% CI [0.657, 0.950], P = 0.012) was to a large proportion mediated by CD45 on HLA DR CD4 in TBNK panel (-034 (95% CI [-0.070, -0.005]; P = 0.037), accounting for 14.4% of Total effect). The study suggested a causal relationship between GM and NSCLC, which may be mediated by immune cells.
PubMed: 38434967
DOI: 10.7150/jca.92699 -
Microbial Biotechnology Oct 2023It has been reported that Akkermansia muciniphila improves host metabolism and reduces inflammation; however, its potential effects on bile acid metabolism and metabolic...
It has been reported that Akkermansia muciniphila improves host metabolism and reduces inflammation; however, its potential effects on bile acid metabolism and metabolic patterns in metabolic-associated fatty liver disease (MAFLD) are unknown. In this study, we have analysed C57BL/6 mice under three feeding conditions: (i) a low-fat diet group (LP), (ii) a high-fat diet group (HP) and (iii) a high-fat diet group supplemented with A. muciniphila (HA). The results found that A. muciniphila administration relieved weight gain, hepatic steatosis and liver injury induced by the high-fat diet. A. muciniphila altered the gut microbiota with a decrease in Alistipes, Lactobacilli, Tyzzerella, Butyricimonas and Blautia, and an enrichment of Ruminiclostridium, Osclibacter, Allobaculum, Anaeroplasma and Rikenella. The gut microbiota changes correlated significantly with bile acids. Meanwhile, A. muciniphila also improved glucose tolerance, gut barriers and adipokines dysbiosis. Akkermansia muciniphila regulated the intestinal FXR-FGF15 axis and reshaped the construction of bile acids, with reduced secondary bile acids in the caecum and liver, including DCA and LCA. These findings provide new insights into the relationships between probiotics, microflora and metabolic disorders, highlighting the potential role of A. muciniphila in the management of MAFLD.
Topics: Animals; Mice; Diet, High-Fat; Gastrointestinal Microbiome; Bile Acids and Salts; Mice, Inbred C57BL; Verrucomicrobia; Metabolic Diseases; Liver Diseases
PubMed: 37377410
DOI: 10.1111/1751-7915.14293