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Nature Oct 2022Tobacco smoking is positively correlated with non-alcoholic fatty liver disease (NAFLD), but the underlying mechanism for this association is unclear. Here we report...
Tobacco smoking is positively correlated with non-alcoholic fatty liver disease (NAFLD), but the underlying mechanism for this association is unclear. Here we report that nicotine accumulates in the intestine during tobacco smoking and activates intestinal AMPKα. We identify the gut bacterium Bacteroides xylanisolvens as an effective nicotine degrader. Colonization of B. xylanisolvens reduces intestinal nicotine concentrations in nicotine-exposed mice, and it improves nicotine-exacerbated NAFLD progression. Mechanistically, AMPKα promotes the phosphorylation of sphingomyelin phosphodiesterase 3 (SMPD3), stabilizing the latter and therefore increasing intestinal ceramide formation, which contributes to NAFLD progression to non-alcoholic steatohepatitis (NASH). Our results establish a role for intestinal nicotine accumulation in NAFLD progression and reveal an endogenous bacterium in the human intestine with the ability to metabolize nicotine. These findings suggest a possible route to reduce tobacco smoking-exacerbated NAFLD progression.
Topics: Animals; Humans; Mice; Bacteria; Ceramides; Nicotine; Non-alcoholic Fatty Liver Disease; Sphingomyelin Phosphodiesterase; Tobacco Smoking; Intestines; AMP-Activated Protein Kinases; Disease Progression
PubMed: 36261549
DOI: 10.1038/s41586-022-05299-4 -
The Journal of Antimicrobial... May 2022We sought to characterize the carbapenem resistance mechanism of Bacteroides xylanisolvens 14880, an imipenem-resistant strain from Germany, and assess its prevalence.
OBJECTIVES
We sought to characterize the carbapenem resistance mechanism of Bacteroides xylanisolvens 14880, an imipenem-resistant strain from Germany, and assess its prevalence.
METHODS
Antimicrobial susceptibilities were determined using agar dilution or Etest methodology and specific imipenemase activity was detected. The genomic sequence of B. xylanisolvens 14880 was determined and analysed for antibiotic resistance genes and genomic islands. We also used gene transfer to a carbapenem susceptible host, along with 5'-RACE, conventional PCR with capillary sequencing and RT-PCR-based screening.
RESULTS
B. xylanisolvens 14880 displayed resistance to carbapenems and produced high specific imipenemase activity. Its genomic sequence was 6.1 Mbp and a class B1 β-lactamase gene (termed crxA) was detected in it. crxA was carried on a putative genomic island with insertion sequence (IS) elements and a putative GNAT (Gcn5-like acetyltransferase) toxin gene. Promoter localization by 5'-RACE and gene targeting to an imipenem-susceptible Bacteroides host indicated that it is activated by an IS1380-like IS element and it can confer carbapenem resistance. The PCR screening of Bacteroides strains showed that crxA was specific to B. xylanisolvens with a carriage rate of 16.7%.
CONCLUSIONS
B. xylanisolvens strains can harbour a carbapenem resistance gene, which has many similarities to the 'cfiA system': metallo-β-lactamase (MBL), IS element activation, carriage of a GNAT toxin gene, specific for a unique Bacteroides species with a significant prevalence.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Bacteroides; Bacteroides fragilis; Carbapenems; DNA Transposable Elements; Genomics; Imipenem; Microbial Sensitivity Tests; beta-Lactamases
PubMed: 35296904
DOI: 10.1093/jac/dkac088 -
Microbiome Apr 2021The gut phageome comprises a complex phage community of thousands of individual strains, with a few highly abundant bacteriophages. CrAss-like phages, which infect...
BACKGROUND
The gut phageome comprises a complex phage community of thousands of individual strains, with a few highly abundant bacteriophages. CrAss-like phages, which infect bacteria of the order Bacteroidales, are the most abundant bacteriophage family in the human gut and make an important contribution to an individual's core virome. Based on metagenomic data, crAss-like phages form a family, with four sub-families and ten candidate genera. To date, only three representatives isolated in pure culture have been reported: ΦcrAss001 and two closely related phages DAC15 and DAC17; all are members of the less abundant candidate genus VI. The persistence at high levels of both crAss-like phage and their Bacteroidales hosts in the human gut has not been explained mechanistically, and this phage-host relationship can only be properly studied with isolated phage-host pairs from as many genera as possible.
RESULTS
Faeces from a healthy donor with high levels of crAss-like phage was used to initiate a faecal fermentation in a chemostat, with selected antibiotics chosen to inhibit rapidly growing bacteria and selectively enrich for Gram-negative Bacteroidales. This had the objective of promoting the simultaneous expansion of crAss-like phages on their native hosts. The levels of seven different crAss-like phages expanded during the fermentation, indicating that their hosts were also present in the fermenter. The enriched supernatant was then tested against individual Bacteroidales strains isolated from the same faecal sample. This resulted in the isolation of a previously uncharacterised crAss-like phage of candidate genus IV of the proposed Alphacrassvirinae sub-family, ΦcrAss002, that infects the gut commensal Bacteroides xylanisolvens. ΦcrAss002 does not form plaques or spots on lawns of sensitive cells, nor does it lyse liquid cultures, even at high titres. In keeping with the co-abundance of phage and host in the human gut, ΦcrAss002 and Bacteroides xylanisolvens can also co-exist at high levels when co-cultured in laboratory media.
CONCLUSIONS
We report the isolation and characterisation of ΦcrAss002, the first representative of the proposed Alphacrassvirinae sub-family of crAss-like phages. ΦcrAss002 cannot form plaques or spots on bacterial lawns but can co-exist with its host, Bacteroides xylanisolvens, at very high levels in liquid culture without impacting on bacterial numbers. Video abstract.
Topics: Bacteriophages; Bacteroides; Gastrointestinal Microbiome; Humans; Phylogeny
PubMed: 33845877
DOI: 10.1186/s40168-021-01036-7 -
Frontiers in Microbiology 2023Hyperuricemia is widespread in humans and birds which is a necessary physiological factor leading to gout. Studies have shown an inextricable relationship between gut...
INTRODUCTION
Hyperuricemia is widespread in humans and birds which is a necessary physiological factor leading to gout. Studies have shown an inextricable relationship between gut microbiota and hyperuricemia. This study explored the association between intestinal flora and hyperuricemia in Goslings.
METHODS AND RESULTS
The hyperuricemia model was established in gosling by a high protein diet (HPD). 16S rDNA sequencing showed that the cecal microbiota differed significantly between the HPD and control groups (fed with the normal protein). The abundance of was higher in the HPD group, while the were lower than in controls. To investigate the role of intestinal flora in hyperuricemia, the cecum microbiotas from the HPD group and the control group were transplanted to the newly born goslings by gavage. The serum uric acid levels of the goslings that transplanted the cecal microbiota of the HPD group were significantly higher than the goslings that transplanted the cecal microbiota of the controls. Furthermore, the transplantation of cecal microbiota also affects the production and excretion of uric acid in goslings. Then we identify the gut bacterium as an effective anti-hyperuricemia in the Goslings. reduces serum uric acid concentrations in hyperuricemia in the Goslings' model, and it can up-regulation ABCG2 mRNA expression in the kidney and down-regulation XDH mRNA expression in the liver.
DISCUSSION
The intestinal flora acts as a novel target for the therapeutic approach to hyperuricemia and gout, suggest is a possible route to therapy for hyperuricemia and gout in goslings.
PubMed: 37455728
DOI: 10.3389/fmicb.2023.1173856 -
Nutrients Mar 2023Alginate has been documented to prevent the development and progression of ulcerative colitis by modulating the gut microbiota. However, the bacterium that may mediate...
Alginate has been documented to prevent the development and progression of ulcerative colitis by modulating the gut microbiota. However, the bacterium that may mediate the anti-colitis effect of alginate has not been fully characterized. We hypothesized that alginate-degrading bacteria might play a role here since these bacteria could utilize alginate as a carbon source. To test this hypothesis, we isolated 296 strains of alginate-degrading bacteria from the human gut. AY11-1 was observed to have the best capability for alginate degradation. The degradation and fermentation of alginate by AY11-1 produced significant amounts of oligosaccharides and short-chain fatty acids. Further studies indicated that AY11-1 could alleviate body weight loss and contraction of colon length, reduce the incidences of bleeding and attenuate mucosal damage in dextran sulfate sodium (DSS)-fed mice. Mechanistically, AY11-1 improved gut dysbiosis and promoted the growth of probiotic bacteria, including spp. And , in diseased mice. Additionally, AY11-1 showed no oral toxicity and was well-tolerated in male and female mice. Altogether, we illustrate for the first time an anti-colitis effect of the alginate-degrading bacterium AY11-1. Our study paves the way for the development of AY11-1 as a next-generation probiotic bacterium.
Topics: Humans; Male; Female; Animals; Mice; Alginates; Gastrointestinal Microbiome; Colitis; Colon; Bacteria; Probiotics; Dextran Sulfate; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 36986080
DOI: 10.3390/nu15061352 -
Clinical and Experimental Rheumatology Sep 2022Gout, the most common inflammatory arthritis worldwide, is an auto-inflammatory metabolic disease that leads to monosodium urate crystal deposition. Hyperuricaemia is a... (Review)
Review
Gout, the most common inflammatory arthritis worldwide, is an auto-inflammatory metabolic disease that leads to monosodium urate crystal deposition. Hyperuricaemia is a significant risk factor for the development of gout; however, hyperuricaemia alone is not sufficient to induce gout.Gout flares have circadian rhythms. Gout flares vary during the day and have strong seasonality, with flares being more common in the spring. The reasons for the predominance of flares in the spring are unclear since serum urate (SU) levels show seasonal variation; however, SU levels are highest in the summer.Immune function varies significantly throughout the year, with enhanced immune responses increasing during the winter. In addition, chronic disruption of circadian rhythms is associated with metabolic syndrome and diseases driven by metabolism. The most telling example relates to Xanthine oxidase (XOD/XDH). The analysis of XOD/XDH established its circadian regulation and demonstrated that inhibition of the activity of XOD is characterised by distinct, crossregulating diurnal/seasonal patterns of activity.The gastrointestinal microbiota of gout patients is highly distinct from healthy individuals. In a small series of gout patients, Bacteroides caccae and Bacteroides xylanisolvens were found to be enriched. Bacteroidales levels were highest during the spring and summer, and loading values were highest in the spring.Our review discusses gout's circadian rhythm and seasonality, possible influences of the microbiome on gout due to our new knowledge that Bacteroidales levels were highest during spring when gout is most common, and potential opportunities for treatment based on our current understanding of this interaction.
Topics: Arthritis, Gouty; Gout; Gout Suppressants; Humans; Hyperuricemia; Microbiota; Symptom Flare Up; Uric Acid; Xanthine Oxidase
PubMed: 35383564
DOI: 10.55563/clinexprheumatol/hdtge7 -
Polymers Apr 2023Heparinase I (Hep I), which specifically degrades heparin to oligosaccharide or unsaturated disaccharide, has an important role in the production of low molecular weight...
Heparinase I (Hep I), which specifically degrades heparin to oligosaccharide or unsaturated disaccharide, has an important role in the production of low molecular weight heparin (LMWH). However, low productivity and stability of heparinase I hinders its applications. Here, a novel heparinase I (BxHep-I) was cloned from and overexpressed in soluble form in . The expression conditions of BxHep-I were optimized for an activity of 7144 U/L. BxHep-I had a specific activity of 57.6 U/mg at the optimal temperature and pH of 30 °C and pH 7.5, with the and of 0.79 mg/mL and 124.58 U/mg, respectively. BxHep-I catalytic activity could be enhanced by Ca and Mg, while strongly inhibited by Zn and Co. Purified BxHep-I displayed an outstanding thermostability with half-lives of 597 and 158 min at 30 and 37 °C, respectively, which are the highest half-lives ever reported for heparinases I. After storage at 4 °C for one week, BxHep-I retained 73% of its initial activity. Molecular docking revealed that the amino acids Asn25, Gln27, Arg88, Lys116, His156, Arg161, Gln228, Tyr356, Lys358, and Tyr362 form 13 hydrogen bonds with the substrate heparin disaccharides in the substrate binding domain and are mainly involved in the substrate binding of BxHep-I. These results suggest that the BxHep-I with high stability could be a candidate catalyst for the industrial production of LMWH.
PubMed: 37050390
DOI: 10.3390/polym15071776 -
Oncoimmunology 2022The microbiome is now regarded as one of the hallmarks of cancer and several strategies to modify the gut microbiota to improve immune checkpoint inhibitor (ICI)...
The microbiome is now regarded as one of the hallmarks of cancer and several strategies to modify the gut microbiota to improve immune checkpoint inhibitor (ICI) activity are being evaluated in clinical trials. Preliminary data regarding the upper gastro-intestinal microbiota indicated that seropositivity was associated with a negative prognosis in patients amenable to ICI. In 97 patients with advanced melanoma treated with ICI, we assessed the impact of on outcomes and microbiome composition. We performed serology and profiled the fecal microbiome with metagenomics sequencing. Among the 97 patients, 22% were positive (Pos). Pos patients had a significantly shorter overall survival () compared to negative (Neg) patients. In addition, objective response rate and progression-free survival were decreased in Pos patients. Metagenomics sequencing did not reveal any difference in diversity indexes between the groups. At the taxa level, , and were increased in the Pos group, while and were over-represented in the Neg group. In a second independent cohort of patients with NSCLC, diversity indexes were similar in both groups and was increased in Neg patients. Our results demonstrated that the negative impact of on outcomes seem to be independent from the fecal microbiome composition. These findings warrant further validation and development of therapeutic strategies to eradicate in immuno-oncology arena.
Topics: Carcinoma, Non-Small-Cell Lung; Helicobacter Infections; Helicobacter pylori; Humans; Immune Checkpoint Inhibitors; Lung Neoplasms; Melanoma; Syndrome
PubMed: 35832043
DOI: 10.1080/2162402X.2022.2096535 -
MSystems Feb 2022Symbiotic bacteria are responsible for the majority of complex carbohydrate digestion in the human colon. Since the identities and amounts of dietary polysaccharides...
Symbiotic bacteria are responsible for the majority of complex carbohydrate digestion in the human colon. Since the identities and amounts of dietary polysaccharides directly impact the gut microbiota, determining which microorganisms consume specific nutrients is central for defining the relationship between diet and gut microbial ecology. Using a custom phenotyping array, we determined carbohydrate utilization profiles for 354 members of the , a dominant saccharolytic phylum. There was wide variation in the numbers and types of substrates degraded by individual bacteria, but phenotype-based clustering grouped members of the same species indicating that each species performs characteristic roles. The ability to utilize dietary polysaccharides and endogenous mucin glycans was negatively correlated, suggesting exclusion between these niches. By analyzing related Bacteroides ovatusBacteroides xylanisolvens strains that vary in their ability to utilize mucin glycans, we addressed whether gene clusters that confer this complex, multilocus trait are being gained or lost in individual strains. Pangenome reconstruction of these strains revealed a remarkably mosaic architecture in which genes involved in polysaccharide metabolism are highly variable and bioinformatics data provide evidence of interspecies gene transfer that might explain this genomic heterogeneity. Global transcriptomic analyses suggest that the ability to utilize mucin has been lost in some lineages of and , which harbor residual gene clusters that are involved in mucin utilization by strains that still actively express this phenotype. Our data provide insight into the breadth and complexity of carbohydrate metabolism in the microbiome and the underlying genomic events that shape these behaviors. Nonharmful bacteria are the primary microbial symbionts that inhabit the human gastrointestinal tract. These bacteria play many beneficial roles and in some cases can modify disease states, making it important to understand which nutrients sustain specific lineages. This knowledge will in turn lead to strategies to intentionally manipulate the gut microbial ecosystem. We designed a scalable, high-throughput platform for measuring the ability of gut bacteria to utilize polysaccharides, of which many are derived from dietary fiber sources that can be manipulated easily. Our results provide paths to expand phenotypic surveys of more diverse gut bacteria to understand their functions and also to leverage dietary fibers to alter the physiology of the gut microbial community.
Topics: Humans; Polysaccharides; Bacteria; Dietary Carbohydrates; Microbiota; Dietary Fiber; Genomics; Mucins
PubMed: 35166563
DOI: 10.1128/msystems.00947-21 -
Frontiers in Cellular and Infection... 2023The wide application of immune checkpoint inhibitors has significantly improved the survival expectation of cancer patients. While immunotherapy brings benefits to...
INTRODUCTION
The wide application of immune checkpoint inhibitors has significantly improved the survival expectation of cancer patients. While immunotherapy brings benefits to patients, it also results in a series of immune-related adverse events (irAEs). Increasing evidence suggests that the gut microbiome is critical for immunotherapy response and the development of irAEs.
METHODS
In this prospective study, we recruited 95 patients with advanced/unresectable gastrointestinal cancers treated with immunotherapy and report a comprehensive analysis of the association of the gut microbiome with irAEs. Metagenome sequencing was used to analyze the differences in bacterial composition and metabolic pathways of baseline fecal samples.
RESULTS
In summary, we identified bacterial species and metabolic pathways that might be associated with the occurrence of irAEs in gastric, esophageal, and colon cancers. Ruminococcus callidus and Bacteroides xylanisolvens were enriched in patients without severe irAEs. Several microbial metabolic pathways involved in the urea cycle, including citrulline and arginine biosynthesis, were associated with irAEs. We also found that irAEs in different cancer types and toxicity in specific organs and the endocrine system were associated with different gut microbiota profiles. These findings provide the basis for future mechanistic exploration.
Topics: Humans; Immune Checkpoint Inhibitors; Gastrointestinal Microbiome; Prospective Studies; Neoplasms; Gastrointestinal Neoplasms; Colonic Neoplasms; Immunotherapy
PubMed: 37051296
DOI: 10.3389/fcimb.2023.1099063