-
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 -
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 -
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 -
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 -
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 -
Polish Journal of Microbiology Jun 2022The identification and antibiotic susceptibility of two clinical isolates of from bloodstream infections were determined. This microorganism is rarely pathogenic, and...
The identification and antibiotic susceptibility of two clinical isolates of from bloodstream infections were determined. This microorganism is rarely pathogenic, and the findings are presented here to promote the detection and awareness of this infection. The bacteria were obtained from one patient with pressure sores and another with a malignant gastric tumor. Smears were prepared, stained, and examined by microscopy. Single colonies were analyzed by Gram staining, MALDI-TOF MS, and the 16S rRNA gene sequencing. Antibiotic sensitivity was assessed by the agar dilution method. The bacilli were found to be Gram-positive, and the MS results showed 99.8% homology with . It was confirmed by gene sequencing. Antibiotic susceptibility tests demonstrated that was sensitive to piperacillin-tazobactam, ampicillin-sulbactam, imipenem, meropenem, metronidazole, clindamycin, and vancomycin. This study could increase awareness of this rare infection.
Topics: Actinobacteria; Anti-Bacterial Agents; Bacteremia; Humans; Microbial Sensitivity Tests; RNA, Ribosomal, 16S
PubMed: 35716165
DOI: 10.33073/pjm-2022-024 -
Viruses Jul 2022is a common member of the human gut microbiome. We here describe the isolation and characterization of a putative virulent bacteriophage having as host. The...
is a common member of the human gut microbiome. We here describe the isolation and characterization of a putative virulent bacteriophage having as host. The double-layer agar method for isolating phages was adapted to anaerobic conditions for isolating bacteriophage PMBT5 from sewage on a strictly anaerobic strain of intestinal origin. For this, anaerobically grown cells were concentrated by centrifugation and used for a 24 h phage enrichment step. Subsequently, this suspension was added to anaerobically prepared top (soft) agar in Hungate tubes and further used in the double-layer agar method. Based on morphological characteristics observed by transmission electron microscopy, phage PMBT5 could be assigned to the phage family. It showed an isometric head with a flexible, noncontractile tail and a distinct single 45 nm tail fiber under the baseplate. Genome sequencing and assembly resulted in one contig of 30,930 bp and a mol% GC content of 51.3, consisting of 44 predicted protein-encoding genes. Phage-related proteins could be largely identified based on their amino acid sequence, and a comparison with metagenomes in the human virome database showed that the phage genome exhibits similarity to two distantly related phages.
Topics: Actinobacteria; Agar; Bacteriophages; DNA, Viral; Genome, Viral; Humans; Siphoviridae
PubMed: 35893664
DOI: 10.3390/v14081598 -
Science Advances Sep 2023Although the etiology of rheumatoid arthritis (RA) is unknown, a strong genetic predisposition and the presence of preclinical antibodies before the onset of symptoms is...
Although the etiology of rheumatoid arthritis (RA) is unknown, a strong genetic predisposition and the presence of preclinical antibodies before the onset of symptoms is documented. An expansion of is associated with severe disease in RA. Here, using a humanized mouse model of collagen-induced arthritis, we determined the impact of abundance on RA severity. Naïve mice gavaged with produce preclinical rheumatoid factor and, when induced for arthritis, develop severe disease. The augmented antibody response was much higher in female mice, and among patients with RA, women had higher average load of . Expansion of increased CXCL5 and CD4 T cells, and both interleukin-17- and interferon-γ-producing B cells. Further, gavage caused gut dysbiosis and decline in amino acids and nicotinamide adenine dinucleotide with an increase in microbe-dependent bile acids and succinyl carnitine causing systemic senescent-like inflammation.
Topics: Female; Animals; Mice; Arthritis, Rheumatoid; Actinobacteria; Inflammation; Autoantibodies
PubMed: 37656793
DOI: 10.1126/sciadv.adg1129 -
Microorganisms Jan 2022is an anaerobic, high GC, Gram-positive bacillus commonly found in the human digestive tract that belongs to the class Coriobacteriia of the phylum Actinobacteria. This...
is an anaerobic, high GC, Gram-positive bacillus commonly found in the human digestive tract that belongs to the class Coriobacteriia of the phylum Actinobacteria. This species has been of increasing interest as an important player in the metabolism of xenobiotics and dietary compounds. However, little is known regarding its susceptibility to bacteriophage predation and how this may influence its fitness. Here, we report the isolation of seven novel strains using cefotaxime and ceftriaxone as selective agents. We conducted comparative and pangenome analyses of these strains and those publicly available to investigate the diversity of prophages associated with this species. Prophage gene products represent a minimum of 5.8% of the pangenome, comprising at least ten distantly related prophage clades that display limited homology to currently known bacteriophages. All clades possess genes implicated in virion structure, lysis, lysogeny and, to a limited extent, DNA replication. Some prophages utilise tyrosine recombinases and diversity generating retroelements to generate phase variation among targeted genes. The prophages have differing levels of sensitivity to the CRISPR/cas systems of their hosts, with spacers from 44 isolates found to target only five out of the ten identified prophage clades. Furthermore, using a PCR-based approach targeting the prophage site, we were able to determine that several of these elements can excise from the host chromosome, thus supporting the notion that these are active prophages. The findings of this study provide further insights into the diversity of prophages infecting species of the phylum Actinobacteria.
PubMed: 35056644
DOI: 10.3390/microorganisms10010195 -
Current Neuropharmacology 2023Parkinson's disease (PD) is one of the most common neurodegenerative diseases, characterized by the reduction of dopamine neurons in the substantia nigra. Levodopa, as a... (Review)
Review
Parkinson's disease (PD) is one of the most common neurodegenerative diseases, characterized by the reduction of dopamine neurons in the substantia nigra. Levodopa, as a dopamine supplement, is the gold-standard therapeutic drug for PD. The metabolism of levodopa in the periphery not only decreases its bioavailability but also affects its efficacy. Thus, it is necessary to investigate how levodopa is metabolized. A growing number of studies have shown that intestinal bacteria, such as Enterococcus faecalis, Eggerthella lenta and Clostridium sporogenes, could metabolize levodopa in different ways. In addition, several pathways to reduce levodopa metabolism by gut microbiota were confirmed to improve levodopa efficacy. These pathways include aromatic amino acid decarboxylase (AADC) inhibitors, antibiotics, pH and (S)-α-fluoromethyltyrosine (AFMT). In this review, we have summarized the metabolic process of levodopa by intestinal bacteria and analyzed potential approaches to reduce the metabolism of levodopa by gut microbiota, thus improving the efficacy of levodopa.
Topics: Humans; Levodopa; Antiparkinson Agents; Parkinson Disease; Dopamine; Bacteria
PubMed: 36278467
DOI: 10.2174/1570159X21666221019115716