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Gut Dec 2022Cigarette smoking is a major risk factor for colorectal cancer (CRC). We aimed to investigate whether cigarette smoke promotes CRC by altering the gut microbiota and...
OBJECTIVE
Cigarette smoking is a major risk factor for colorectal cancer (CRC). We aimed to investigate whether cigarette smoke promotes CRC by altering the gut microbiota and related metabolites.
DESIGN
Azoxymethane-treated C57BL/6 mice were exposed to cigarette smoke or clean air 2 hours per day for 28 weeks. Shotgun metagenomic sequencing and liquid chromatography mass spectrometry were parallelly performed on mice stools to investigate alterations in microbiota and metabolites. Germ-free mice were transplanted with stools from smoke-exposed and smoke-free control mice.
RESULTS
Mice exposed to cigarette smoke had significantly increased tumour incidence and cellular proliferation compared with smoke-free control mice. Gut microbial dysbiosis was observed in smoke-exposed mice with significant differential abundance of bacterial species including the enrichment of and depletion of and spp. Metabolomic analysis showed increased bile acid metabolites, especially taurodeoxycholic acid (TDCA) in the colon of smoke-exposed mice. We found that had the most positive correlation with TDCA in smoke-exposed mice. Moreover, smoke-exposed mice manifested enhanced oncogenic MAPK/ERK (mitogen-activated protein kinase/extracellular signal‑regulated protein kinase 1/2) signalling (a downstream target of TDCA) and impaired gut barrier function. Furthermore, germ-free mice transplanted with stools from smoke-exposed mice (GF-AOMS) had increased colonocyte proliferation. Similarly, GF-AOMS showed increased abundances of gut and TDCA, activated MAPK/ERK pathway and impaired gut barrier in colonic epithelium.
CONCLUSION
The gut microbiota dysbiosis induced by cigarette smoke plays a protumourigenic role in CRC. The smoke-induced gut microbiota dysbiosis altered gut metabolites and impaired gut barrier function, which could activate oncogenic MAPK/ERK signalling in colonic epithelium.
Topics: Animals; Mice; Gastrointestinal Microbiome; Dysbiosis; Cigarette Smoking; Mice, Inbred C57BL; Carcinogenesis; Colorectal Neoplasms
PubMed: 35387878
DOI: 10.1136/gutjnl-2021-325021 -
JAMA Psychiatry Dec 2021Evidence of gut microbiota perturbations has accumulated for multiple psychiatric disorders, with microbiota signatures proposed as potential biomarkers. However, no... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Evidence of gut microbiota perturbations has accumulated for multiple psychiatric disorders, with microbiota signatures proposed as potential biomarkers. However, no attempts have been made to evaluate the specificity of these across the range of psychiatric conditions.
OBJECTIVE
To conduct an umbrella and updated meta-analysis of gut microbiota alterations in general adult psychiatric populations and perform a within- and between-diagnostic comparison.
DATA SOURCES
Cochrane Library, PubMed, PsycINFO, and Embase were searched up to February 2, 2021, for systematic reviews, meta-analyses, and original evidence.
STUDY SELECTION
A total of 59 case-control studies evaluating diversity or abundance of gut microbes in adult populations with major depressive disorder, bipolar disorder, psychosis and schizophrenia, anorexia nervosa, anxiety, obsessive compulsive disorder, posttraumatic stress disorder, or attention-deficit/hyperactivity disorder were included.
DATA EXTRACTION AND SYNTHESIS
Between-group comparisons of relative abundance of gut microbes and beta diversity indices were extracted and summarized qualitatively. Random-effects meta-analyses on standardized mean difference (SMD) were performed for alpha diversity indices.
MAIN OUTCOMES AND MEASURES
Alpha and beta diversity and relative abundance of gut microbes.
RESULTS
A total of 34 studies provided data and were included in alpha diversity meta-analyses (n = 1519 patients, n = 1429 control participants). Significant decrease in microbial richness in patients compared with control participants were found (observed species SMD = -0.26; 95% CI, -0.47 to -0.06; Chao1 SMD = -0.5; 95% CI, -0.79 to -0.21); however, this was consistently decreased only in bipolar disorder when individual diagnoses were examined. There was a small decrease in phylogenetic diversity (SMD = -0.24; 95% CI, -0.47 to -0.001) and no significant differences in Shannon and Simpson indices. Differences in beta diversity were consistently observed only for major depressive disorder and psychosis and schizophrenia. Regarding relative abundance, little evidence of disorder specificity was found. Instead, a transdiagnostic pattern of microbiota signatures was found. Depleted levels of Faecalibacterium and Coprococcus and enriched levels of Eggerthella were consistently shared between major depressive disorder, bipolar disorder, psychosis and schizophrenia, and anxiety, suggesting these disorders are characterized by a reduction of anti-inflammatory butyrate-producing bacteria, while pro-inflammatory genera are enriched. The confounding associations of region and medication were also evaluated.
CONCLUSIONS AND RELEVANCE
This systematic review and meta-analysis found that gut microbiota perturbations were associated with a transdiagnostic pattern with a depletion of certain anti-inflammatory butyrate-producing bacteria and an enrichment of pro-inflammatory bacteria in patients with depression, bipolar disorder, schizophrenia, and anxiety.
Topics: Dysbiosis; Gastrointestinal Microbiome; Humans; Mental Disorders
PubMed: 34524405
DOI: 10.1001/jamapsychiatry.2021.2573 -
Psychological Medicine May 2022Major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia-spectrum disorders (SSD) are heterogeneous psychiatric disorders, which place significant burden... (Review)
Review
Major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia-spectrum disorders (SSD) are heterogeneous psychiatric disorders, which place significant burden on patient's well-being and global health. Disruptions in the gut-microbiome may play a role in these psychiatric disorders. This review presents current data on composition of the human gastrointestinal microbiota, and its interaction mechanisms in the gut-brain axis in MDD, BD and SSD. Diversity metrics and microbial relative abundance differed across studies. More studies reported inconsistent findings (n = 7) or no differences (n = 8) than studies who reported lower α-diversity in these psychiatric disorders (n = 5). The most consistent findings across studies were higher relative abundances of the genera Streptococcus, Lactobacillus, and Eggerthella and lower relative abundance of the butyrate producing Faecalibacterium in patients with psychiatric disorders. All three increased genera were associated with higher symptom severity. Confounders, such as medication use and life style have not been accounted for. So far, the results of probiotics trials have been inconsistent. Most traditional and widely used probiotics (consisting of Bifidobacterium spp. and Lactobacillus spp.) are safe, however, they do not correct potential microbiota disbalances in these disorders. Findings on prebiotics and faecal microbiota transplantation (FMT) are too limited to draw definitive conclusions. Disease-specific pro/prebiotic treatment or even FMT could be auspicious interventions for prevention and therapy for psychiatric disorders and should be investigated in future trials.
Topics: Bipolar Disorder; Depressive Disorder, Major; Gastrointestinal Microbiome; Humans; Mental Disorders; Probiotics
PubMed: 35506416
DOI: 10.1017/S0033291722000897 -
Toxins Feb 2022Chronic kidney disease (CKD) is predominant in 10% of the world's adult population, and is increasingly considered a silent epidemic. Gut microbiota plays an essential... (Review)
Review
Chronic kidney disease (CKD) is predominant in 10% of the world's adult population, and is increasingly considered a silent epidemic. Gut microbiota plays an essential role in maintaining host energy homeostasis and gut epithelial integrity. Alterations in gut microbiota composition, functions and, specifically, production of metabolites causing uremic toxicity are often associated with CKD onset and progression. Here, we present the latest omics (transcriptomics, proteomics and metabolomics) studies that explore the connection between CKD and gut microbiome. A review of the available literature using PubMed was performed using the keywords "microb*", "kidney", "proteom", "metabolom" and "transcript" for the last 10 years, yielding a total of 155 publications. Following selection of the relevant studies (focusing on microbiome in CKD), a predominance of metabolomics ( = 12) over transcriptomics ( = 1) and proteomics ( = 6) analyses was observed. A consensus arises supporting the idea that the uremic toxins produced in the gut cause oxidative stress, inflammation and fibrosis in the kidney leading to CKD. Collectively, findings include an observed enrichment of and spp., and a depletion in and spp. occurring in CKD models. Bacterial species involved in butyrate production, indole synthesis and mucin degradation were also related to CKD. Consequently, strong links between CKD and gut microbial dysbiosis suggest potential therapeutic strategies to prevent CKD progression and portray the gut as a promising therapeutic target.
Topics: Adult; Dysbiosis; Female; Gastrointestinal Microbiome; Humans; Kidney; Male; Microbiota; Renal Insufficiency, Chronic; Uremic Toxins
PubMed: 35324673
DOI: 10.3390/toxins14030176 -
Advanced Science (Weinheim,... Dec 2022The emergence of the coronavirus disease 2019 pandemic has dramatically increased the global prevalence of depression. Unfortunately, antidepressant drugs benefit only a... (Review)
Review
The emergence of the coronavirus disease 2019 pandemic has dramatically increased the global prevalence of depression. Unfortunately, antidepressant drugs benefit only a small minority of patients. Thus, there is an urgent need to develop new interventions. Accumulating evidence supports a causal relationship between gut microbiota dysbiosis and depression. To advance microbiota-based diagnostics and therapeutics of depression, a comprehensive overview of microbial alterations in depression is presented to identify effector microbial biomarkers. This procedure generated 215 bacterial taxa from humans and 312 from animal models. Compared to controls, depression shows significant differences in β-diversity, but no changes in microbial richness and diversity. Additionally, species-specific microbial changes are identified like increased Eggerthella in humans and decreased Acetatifactor in rodent models. Moreover, a disrupted microbiome balance and functional changes, characterized by an enrichment of pro-inflammatory bacteria (e.g., Desulfovibrio and Escherichia/Shigella) and depletion of anti-inflammatory butyrate-producing bacteria (e.g., Bifidobacterium and Faecalibacterium) are consistently shared across species. Confounding effects of geographical region, depression type, and intestinal segments are also investigated. Ultimately, a total of 178 species and subspecies probiotics are identified to alleviate the depressive phenotypes. Current findings provide a foundation for developing microbiota-based diagnostics and therapeutics and advancing microbiota-oriented precision medicine for depression.
Topics: Animals; Humans; Gastrointestinal Microbiome; Depression; COVID-19; Intestines; Microbiota; Bacteria
PubMed: 36285702
DOI: 10.1002/advs.202203707 -
Frontiers in Immunology 2021The observational association between gut microbiome and systemic lupus erythematosus (SLE) has been well documented. However, whether the association is causal remains...
The observational association between gut microbiome and systemic lupus erythematosus (SLE) has been well documented. However, whether the association is causal remains unclear. The present study used publicly available genome-wide association study (GWAS) summary data to perform two-sample Mendelian randomization (MR), aiming to examine the causal links between gut microbiome and SLE. Two sets of MR analyses were conducted. A group of single nucleotide polymorphisms (SNPs) that less than the genome-wide statistical significance threshold (5 × 10) served as instrumental variables. To obtain a comprehensive conclusion, the other group where SNPs were smaller than the locus-wide significance level (1 × 10) were selected as instrumental variables. Based on the locus-wide significance level, the results indicated that there were causal effects of gut microbiome components on SLE risk. The inverse variance weighted (IVW) method suggested that and were positively correlated with the risk of SLE and , and were negatively correlated with SLE risk. The results of weighted median method supported that , , and were risk factors for SLE and and served as protective factors for SLE. The estimates of MR Egger suggested that genetically predicted was negatively associated with SLE. Based on the genome-wide statistical significance threshold, the results showed that might reduce the SLE risk. However, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) detected significant horizontal pleiotropy between the instrumental variables of and outcome. This study support that there are beneficial or detrimental causal effects of gut microbiome components on SLE risk.
Topics: Bacteria; Dysbiosis; Gastrointestinal Microbiome; Gene-Environment Interaction; Genome-Wide Association Study; Humans; Intestines; Lupus Erythematosus, Systemic; Mendelian Randomization Analysis; Polymorphism, Single Nucleotide; Protective Factors; Risk Assessment; Risk Factors
PubMed: 34557183
DOI: 10.3389/fimmu.2021.667097 -
Nature Communications Dec 2022Depression is one of the most poorly understood diseases due to its elusive pathogenesis. There is an urgency to identify molecular and biological mechanisms underlying...
Depression is one of the most poorly understood diseases due to its elusive pathogenesis. There is an urgency to identify molecular and biological mechanisms underlying depression and the gut microbiome is a novel area of interest. Here we investigate the relation of fecal microbiome diversity and composition with depressive symptoms in 1,054 participants from the Rotterdam Study cohort and validate these findings in the Amsterdam HELIUS cohort in 1,539 subjects. We identify association of thirteen microbial taxa, including genera Eggerthella, Subdoligranulum, Coprococcus, Sellimonas, Lachnoclostridium, Hungatella, Ruminococcaceae (UCG002, UCG003 and UCG005), LachnospiraceaeUCG001, Eubacterium ventriosum and Ruminococcusgauvreauiigroup, and family Ruminococcaceae with depressive symptoms. These bacteria are known to be involved in the synthesis of glutamate, butyrate, serotonin and gamma amino butyric acid (GABA), which are key neurotransmitters for depression. Our study suggests that the gut microbiome composition may play a key role in depression.
PubMed: 36473852
DOI: 10.1038/s41467-022-34502-3 -
Science (New York, N.Y.) Jun 2019The human gut microbiota metabolizes the Parkinson's disease medication Levodopa (l-dopa), potentially reducing drug availability and causing side effects. However, the...
The human gut microbiota metabolizes the Parkinson's disease medication Levodopa (l-dopa), potentially reducing drug availability and causing side effects. However, the organisms, genes, and enzymes responsible for this activity in patients and their susceptibility to inhibition by host-targeted drugs are unknown. Here, we describe an interspecies pathway for gut bacterial l-dopa metabolism. Conversion of l-dopa to dopamine by a pyridoxal phosphate-dependent tyrosine decarboxylase from is followed by transformation of dopamine to -tyramine by a molybdenum-dependent dehydroxylase from These enzymes predict drug metabolism in complex human gut microbiotas. Although a drug that targets host aromatic amino acid decarboxylase does not prevent gut microbial l-dopa decarboxylation, we identified a compound that inhibits this activity in Parkinson's patient microbiotas and increases l-dopa bioavailability in mice.
Topics: Actinobacteria; Animals; Antiparkinson Agents; Bacterial Proteins; Decarboxylation; Dopamine; Enterococcus faecalis; Gastrointestinal Microbiome; Genome, Bacterial; HeLa Cells; Humans; Levodopa; Male; Metabolic Networks and Pathways; Mice, Inbred BALB C; Tyrosine; Tyrosine Decarboxylase
PubMed: 31196984
DOI: 10.1126/science.aau6323 -
Cell Host & Microbe Jan 2022Bacterial activation of T helper 17 (Th17) cells exacerbates mouse models of autoimmunity, but how human-associated bacteria impact Th17-driven disease remains elusive....
Bacterial activation of T helper 17 (Th17) cells exacerbates mouse models of autoimmunity, but how human-associated bacteria impact Th17-driven disease remains elusive. We show that human gut Actinobacterium Eggerthella lenta induces intestinal Th17 activation by lifting inhibition of the Th17 transcription factor Rorγt through cell- and antigen-independent mechanisms. E. lenta is enriched in inflammatory bowel disease (IBD) patients and worsens colitis in a Rorc-dependent manner in mice. Th17 activation varies across E. lenta strains, which is attributable to the cardiac glycoside reductase 2 (Cgr2) enzyme. Cgr2 is sufficient to induce interleukin (IL)-17a, a major Th17 cytokine. cgr2+ E. lenta deplete putative steroidal glycosides in pure culture; related compounds are negatively associated with human IBD severity. Finally, leveraging the sensitivity of Cgr2 to dietary arginine, we prevented E. lenta-induced intestinal inflammation in mice. Together, these results support a role for human gut bacterial metabolism in driving Th17-dependent autoimmunity.
Topics: Actinobacteria; Animals; Bacteria; Colitis; Cytokines; Dietary Supplements; Disease Models, Animal; Female; Gastrointestinal Microbiome; Humans; Inflammatory Bowel Diseases; Interleukin-17; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Nuclear Receptor Subfamily 1, Group F, Member 3; Th17 Cells
PubMed: 34822777
DOI: 10.1016/j.chom.2021.11.001 -
Gut Dec 2020Patients with renal failure suffer from symptoms caused by uraemic toxins, possibly of gut microbial origin, as deduced from studies in animals. The aim of the study is... (Observational Study)
Observational Study
OBJECTIVE
Patients with renal failure suffer from symptoms caused by uraemic toxins, possibly of gut microbial origin, as deduced from studies in animals. The aim of the study is to characterise relationships between the intestinal microbiome composition, uraemic toxins and renal failure symptoms in human end-stage renal disease (ESRD).
DESIGN
Characterisation of gut microbiome, serum and faecal metabolome and human phenotypes in a cohort of 223 patients with ESRD and 69 healthy controls. Multidimensional data integration to reveal links between these datasets and the use of chronic kidney disease (CKD) rodent models to test the effects of intestinal microbiome on toxin accumulation and disease severity.
RESULTS
A group of microbial species enriched in ESRD correlates tightly to patient clinical variables and encode functions involved in toxin and secondary bile acids synthesis; the relative abundance of the microbial functions correlates with the serum or faecal concentrations of these metabolites. Microbiota from patients transplanted to renal injured germ-free mice or antibiotic-treated rats induce higher production of serum uraemic toxins and aggravated renal fibrosis and oxidative stress more than microbiota from controls. Two of the species, and , increase uraemic toxins production and promote renal disease development in a CKD rat model. A probiotic decreases abundance of these species, reduces levels of toxins and the severity of the disease in rats.
CONCLUSION
Aberrant gut microbiota in patients with ESRD sculpts a detrimental metabolome aggravating clinical outcomes, suggesting that the gut microbiota will be a promising target for diminishing uraemic toxicity in those patients.
TRIAL REGISTRATION NUMBER
This study was registered at ClinicalTrials.gov (NCT03010696).
Topics: Animals; Bile Acids and Salts; Case-Control Studies; Disease Models, Animal; Feces; Female; Gastrointestinal Microbiome; Humans; Kidney Failure, Chronic; Male; Metabolome; Mice; Oxidative Stress; Rats; Toxins, Biological; Uremia
PubMed: 32241904
DOI: 10.1136/gutjnl-2019-319766