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Microbiology Spectrum Aug 2022Colorectal cancer (CRC) is the second leading cause of cancer mortality worldwide. The dysbiotic gut microbiota and its metabolite secretions play a significant role in... (Meta-Analysis)
Meta-Analysis
Colorectal cancer (CRC) is the second leading cause of cancer mortality worldwide. The dysbiotic gut microbiota and its metabolite secretions play a significant role in CRC development and progression. In this study, we identified microbial and metabolic biomarkers applicable to CRC using a meta-analysis of metagenomic datasets from diverse geographical regions. We used LEfSe, random forest (RF), and co-occurrence network methods to identify microbial biomarkers. Geographic dataset-specific markers were identified and evaluated using area under the ROC curve (AUC) scores and random effect size. Co-occurrence networks analysis showed a reduction in the overall microbial associations and the presence of oral pathogenic microbial clusters in CRC networks. Analysis of predicted metabolites from CRC datasets showed the enrichment of amino acids, cadaverine, and creatine in CRC, which were positively correlated with CRC-associated microbes (Peptostreptococcus stomatis, Gemella morbillorum, Bacteroides fragilis, spp., Fusobacterium nucleatum, Solobacterium moorei, and Clostridium symbiosum), and negatively correlated with control-associated microbes. Conversely, butyrate, nicotinamide, choline, tryptophan, and 2-hydroxybutanoic acid showed positive correlations with control-associated microbes ( < 0.05). Overall, our study identified a set of global CRC biomarkers that are reproducible across geographic regions. We also reported significant differential metabolites and microbe-metabolite interactions associated with CRC. This study provided significant insights for further investigations leading to the development of noninvasive CRC diagnostic tools and therapeutic interventions. Several studies showed associations between gut dysbiosis and CRC. Yet, the results are not conclusive due to cohort-specific associations that are influenced by genomic, dietary, and environmental stimuli and associated reproducibility issues with various analysis approaches. Emerging evidence suggests the role of microbial metabolites in modulating host inflammation and DNA damage in CRC. However, the experimental validations have been hindered by cost, resources, and cumbersome technical expertise required for metabolomic investigations. In this study, we performed a meta-analysis of CRC microbiota data from diverse geographical regions using multiple methods to achieve reproducible results. We used a computational approach to predict the metabolomic profiles using existing CRC metagenomic datasets. We identified a reliable set of CRC-specific biomarkers from this analysis, including microbial and metabolite markers. In addition, we revealed significant microbe-metabolite associations through correlation analysis and microbial gene families associated with dysregulated metabolic pathways in CRC, which are essential in understanding the vastly sporadic nature of CRC development and progression.
Topics: Biomarkers; Colorectal Neoplasms; Dysbiosis; Gastrointestinal Microbiome; Humans; Reproducibility of Results
PubMed: 35766483
DOI: 10.1128/spectrum.00013-22 -
Circulation Research Jul 2020The elderly experience profound systemic responses after stroke, which contribute to higher mortality and more severe long-term disability. Recent studies have revealed...
RATIONALE
The elderly experience profound systemic responses after stroke, which contribute to higher mortality and more severe long-term disability. Recent studies have revealed that stroke outcomes can be influenced by the composition of gut microbiome. However, the potential benefits of manipulating the gut microbiome after injury is unknown.
OBJECTIVE
To determine if restoring youthful gut microbiota after stroke aids in recovery in aged subjects, we altered the gut microbiome through young fecal transplant gavage in aged mice after experimental stroke. Further, the effect of direct enrichment of selective bacteria producing short-chain fatty acids (SCFAs) was tested as a more targeted and refined microbiome therapy.
METHODS AND RESULTS
Aged male mice (18-20 months) were subjected to ischemic stroke by middle cerebral artery occlusion. We performed fecal transplant gavage 3 days after middle cerebral artery occlusion using young donor biome (2-3 months) or aged biome (18-20 months). At day 14 after stroke, aged stroke mice receiving young fecal transplant gavage had less behavioral impairment, and reduced brain and gut inflammation. Based on data from microbial sequencing and metabolomics analysis demonstrating that young fecal transplants contained much higher SCFA levels and related bacterial strains, we selected 4 SCFA-producers (, , , and ) for transplantation. These SCFA-producers alleviated poststroke neurological deficits and inflammation, and elevated gut, brain and plasma SCFA concentrations in aged stroke mice.
CONCLUSIONS
This is the first study suggesting that the poor stroke recovery in aged mice can be reversed via poststroke bacteriotherapy following the replenishment of youthful gut microbiome via modulation of immunologic, microbial, and metabolomic profiles in the host.
Topics: Age Factors; Animals; Bifidobacterium longum; Brain Chemistry; Clostridium symbiosum; Faecalibacterium prausnitzii; Fatty Acids, Volatile; Fecal Microbiota Transplantation; Feces; Gastrointestinal Microbiome; Infarction, Middle Cerebral Artery; Interleukin-17; Intestines; Intraepithelial Lymphocytes; Ischemic Stroke; Limosilactobacillus fermentum; Male; Mice; Mucin-2; Mucin-4; T-Lymphocytes, Regulatory
PubMed: 32354259
DOI: 10.1161/CIRCRESAHA.119.316448 -
Journal of Cachexia, Sarcopenia and... Oct 2022Several studies have examined gut microbiota and sarcopenia using 16S ribosomal RNA amplicon sequencing; however, this technique may not be able to identify altered... (Observational Study)
Observational Study
BACKGROUND
Several studies have examined gut microbiota and sarcopenia using 16S ribosomal RNA amplicon sequencing; however, this technique may not be able to identify altered specific species and functional capacities of the microbes. We performed shotgun metagenomic sequencing to compare the gut microbiome composition and function between individuals with and without sarcopenia.
METHODS
Participants were from a community-based observational study conducted among the residents of rural areas in China. Appendicular skeletal muscle mass was assessed using direct segmental multi-frequency bioelectrical impedance and grip strength using a Jamar Hydraulic Hand dynamometer. Physical performance was evaluated using the Short Physical Performance Battery, 5-time chair stand test and gait speed with the 6 m walk test. Sarcopenia and its severity were diagnosed according to the Asian Working Group for Sarcopenia 2019 algorithm. The gut microbiome was profiled by shotgun metagenomic sequencing to determine the microbial composition and function. A gut microbiota-based model for classification of sarcopenia was constructed using the random forest model, and its performance was assessed using the area under receiver-operating characteristic curve (AUC).
RESULTS
The study sample included 1417 participants (women: 58.9%; mean age: 63.3 years; sarcopenia prevalence: 10.0%). β-diversity indicated by Bray-Curtis distance (genetic level: P = 0.004; taxonomic level of species: P = 0.020), but not α-diversity indicated by Shannon index (genetic level: P = 0.962; taxonomic level of species: P = 0.922), was significantly associated with prevalent sarcopenia. After adjusting for potential confounders, participants with sarcopenia had higher relative abundance of Desulfovibrio piger (P = 0.003, Q = 0.090), Clostridium symbiosum (P < 0.001, Q = 0.035), Hungatella effluvii (P = 0.003, Q = 0.090), Bacteroides fluxus (P = 0.002, Q = 0.089), Absiella innocuum (P = 0.002, Q = 0.072), Coprobacter secundus (P = 0.002, Q = 0.085) and Clostridium citroniae (P = 0.001, Q = 0.060) than those without sarcopenia. The relative abundance of six species (Desulfovibrio piger, Clostridium symbiosum, Hungatella effluvii, Bacteroides fluxus, Absiella innocuum, and Clostridium citroniae) was also positively associated with sarcopenia severity. A differential species-based model was constructed to separate participants with sarcopenia from controls. The value of the AUC was 0.852, suggesting that model has a decent discriminative performance. Desulfovibrio piger ranked the highest in this model. Functional annotation analysis revealed that the phenylalanine, tyrosine, and tryptophan biosynthesis were depleted (P = 0.006, Q = 0.071), while alpha-Linolenic acid metabolism (P = 0.008, Q = 0.094), furfural degradation (P = 0.001, Q = 0.029) and staurosporine biosynthesis (P = 0.006, Q = 0.072) were enriched in participants with sarcopenia. Desulfovibrio piger was significantly associated with staurosporine biosynthesis (P < 0.001).
CONCLUSIONS
This large population-based observational study provided empirical evidence that alterations in the gut microbiome composition and function were observed among individuals with sarcopenia.
Topics: Bacteroides; Clostridiaceae; Clostridiales; Desulfovibrio; Female; Furaldehyde; Gastrointestinal Microbiome; Humans; Middle Aged; Phenylalanine; RNA, Ribosomal, 16S; Sarcopenia; Staurosporine; Tryptophan; Tyrosine; alpha-Linolenic Acid
PubMed: 35851765
DOI: 10.1002/jcsm.13037 -
Science (New York, N.Y.) Feb 2016Undernourished children exhibit impaired development of their gut microbiota. Transplanting microbiota from 6- and 18-month-old healthy or undernourished Malawian donors...
Undernourished children exhibit impaired development of their gut microbiota. Transplanting microbiota from 6- and 18-month-old healthy or undernourished Malawian donors into young germ-free mice that were fed a Malawian diet revealed that immature microbiota from undernourished infants and children transmit impaired growth phenotypes. The representation of several age-discriminatory taxa in recipient animals correlated with lean body mass gain; liver, muscle, and brain metabolism; and bone morphology. Mice were cohoused shortly after receiving microbiota from healthy or severely stunted and underweight infants; age- and growth-discriminatory taxa from the microbiota of the former were able to invade that of the latter, which prevented growth impairments in recipient animals. Adding two invasive species, Ruminococcus gnavus and Clostridium symbiosum, to the microbiota from undernourished donors also ameliorated growth and metabolic abnormalities in recipient animals. These results provide evidence that microbiota immaturity is causally related to undernutrition and reveal potential therapeutic targets and agents.
Topics: Animals; Bacteria; Bifidobacterium; Body Weight; Bone Development; Clostridiales; Disease Models, Animal; Feces; Femur; Gastrointestinal Microbiome; Germ-Free Life; Humans; Infant; Infant Nutrition Disorders; Malawi; Male; Mice; Mice, Inbred C57BL
PubMed: 26912898
DOI: 10.1126/science.aad3311 -
EBioMedicine Nov 2017Current non-invasive early detection of colorectal cancer (CRC) requires improvement. We aimed to identified a fecal Clostridium symbiosum-based biomarker for early and... (Clinical Trial)
Clinical Trial
OBJECTIVE
Current non-invasive early detection of colorectal cancer (CRC) requires improvement. We aimed to identified a fecal Clostridium symbiosum-based biomarker for early and advanced colorectal cancer detection.
DESIGN
In the test stage, the relative abundance of Clostridium symbiosum (C. symbiosum) was measured by qPCR in 781 cases including 242 controls, 212 colorectal adenoma (CRA) patients, 109 early CRC (tumor restricted to the submucosa) patients, 218 advanced CRC patients. The prediction accuracy was compared to Fusobacterium nucleatum (F. nucleatum), fecal immunochemical test (FIT) and CEA (carcinoembryonic antigen) and validated in an independent cohort of 256 subjects. Current status of the trial:ongoing/still enrolling. Primary endpoint:June, 2017 (Clinicaltrials.gov Identifier NCT02845973).
RESULTS
Significant stepwise increase of C. symbiosum abundance was found in CRA, early CRC and advanced CRC (P<0.01). C. symbiosum outperformed all the other markers in early CRC prediction performance. The combination of C. symbiosum and FIT achieved better performance (0.803 for test cohort and 0.707 for validation cohort). For overall discrimination of CRCs, the combination of all above markers achieved the performance of 0.876.
CONCLUSIONS
Fecal C. symbiosum is a promising biomarker for early and noninvasive detection of colorectal cancer, being more effective than F. nucleatum, FIT and CEA. Combining C. symbiosum and FIT or CEA may improve the diagnosis power.
Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Clostridium symbiosum; Colonoscopy; Colorectal Neoplasms; Early Detection of Cancer; Feces; Female; Fusobacterium nucleatum; Gastrointestinal Microbiome; Humans; Male; Middle Aged; Occult Blood; Predictive Value of Tests
PubMed: 29033369
DOI: 10.1016/j.ebiom.2017.10.005 -
World Journal of Gastroenterology Oct 2023The small intestine is known to play a crucial role in the development and remission of diabetes mellitus (DM). However, the exact mechanism by which mid-small...
BACKGROUND
The small intestine is known to play a crucial role in the development and remission of diabetes mellitus (DM). However, the exact mechanism by which mid-small intestinal bypass improves glucose metabolism in diabetic rats is not fully understood.
AIM
To elucidate the mechanisms by which mid-small intestinal bypass improves glucose metabolism.
METHODS
Streptozotocin (STZ) was used to induce DM in Sprague-Dawley (SD) rats at a dose of 60 mg/kg. The rats were then randomly divided into two groups: The mid-small intestine bypass (MSIB) group and the sham group (underwent switch laparotomy). Following a 6-wk recovery period post-surgery, the rats underwent various assessments, including metabolic parameter testing, analysis of liver glycogen levels, measurement of key gluconeogenic enzyme activity, characterization of the gut microbiota composition, evaluation of hormone levels, determination of bile acid concentrations, and assessment of the expression of the intestinal receptors Takeda G protein-coupled receptor 5 and farnesoid X receptor.
RESULTS
The MSIB group of rats demonstrated improved glucose metabolism and lipid metabolism, along with increased hepatic glycogen content. Furthermore, there was a decrease in the expression of the key gluconeogenic enzymes phosphoenolpyruvate carboxykinase 1 and glucose-6-phosphatase. Importantly, the MSIB group exhibited a substantial increase in the abundances of intestinal , , , and . Moreover, higher levels of secondary bile acids, such as intestinal lithocholic acid, were observed in this group. Remarkably, the changes in the gut microbiota showed a significant correlation with the expression of key gluconeogenic enzymes and glucagon-like peptide 1 (GLP-1) at 6 wk postoperatively, highlighting their potential role in glucose regulation. These findings highlight the beneficial effects of mid-small intestine bypass on glucose metabolism and the associated modulation of the gut microbiota.
CONCLUSION
The findings of this study demonstrate that the introduction of postoperative intestinal in the mid-small intestine contributes to the enhancement of glucose metabolism in nonobese diabetic rats. This improvement is attributed to the increased inhibition of hepatic gluconeogenesis mediated by GLP-1, resulting in a favorable modulation of glucose homeostasis.
Topics: Rats; Animals; Gluconeogenesis; Glucagon-Like Peptide 1; Clostridium symbiosum; Jejunoileal Bypass; Diabetes Mellitus, Experimental; Rats, Sprague-Dawley; Gastric Bypass; Glucose; Homeostasis; Blood Glucose
PubMed: 37900993
DOI: 10.3748/wjg.v29.i39.5471 -
Microorganisms Aug 2023Globally, colorectal cancer (CRC) is the second most common cause of mortality worldwide. Considerable evidence indicates that dysbiosis of the gut microbial community... (Review)
Review
Globally, colorectal cancer (CRC) is the second most common cause of mortality worldwide. Considerable evidence indicates that dysbiosis of the gut microbial community and its metabolite secretions play a fundamental role in advanced adenoma (ADA) and CRC development and progression. This study is a systematic review that aims to assess the clinical association between gut microbial markers and/or gut and circulating metabolites with ADA and CRC. Five electronic databases were searched by four independent reviewers. Only controlled trials that compared ADA and/or CRC with healthy control (HC) using either untargeted (16s rRNA gene or whole genome sequencing) or targeted (gene-based real-time PCR) identification methods for gut microbiome profile, or untargeted or targeted metabolite profiling approaches from the gut or serum/plasma, were eligible. Three independent reviewers evaluated the quality of the studies using the . Twenty-four studies were eligible. We identified strong evidence of two microbial markers and for ADA vs. CRC, and nine microbial markers -Lachnoclostridium, -Ruminococcus, spp., , Enterobacteriaceae, spp., Bacteroides, -, spp.-, , and for CRC vs. HC. The remaining metabolite marker evidence between the various groups, including ADA vs. HC, ADA vs. HC, and CRC vs. HC, was not of sufficient quality to support additional findings. The identified gut microbial markers can be used in a panel for diagnosing ADA and/or CRC. Further research in the metabolite markers area is needed to evaluate the possibility to use in diagnostic or prognostic markers for colorectal cancer.
PubMed: 37630597
DOI: 10.3390/microorganisms11082037 -
BMC Cancer Jun 2022The effects of diet on the interaction between microbes and host health have been widely studied. However, its effects on the gut microbiota of patients with colorectal...
BACKGROUND
The effects of diet on the interaction between microbes and host health have been widely studied. However, its effects on the gut microbiota of patients with colorectal cancer (CRC) have not been elucidated. This study aimed to investigate the association between diet and the overall diversity and different taxa levels of the gut microbiota in CRC patients via the nutrition-wide association approach.
METHODS
This hospital-based study utilized data of 115 CRC patients who underwent CRC surgery in Department of Surgery, Seoul National University Hospital. Spearman correlation analyses were conducted for 216 dietary features and three alpha-diversity indices, Firmicutes/Bacteroidetes ratio, and relative abundance of 439 gut microbial taxonomy. To identify main enterotypes of the gut microbiota, we performed the principal coordinate analysis based on the β-diversity index. Finally, we performed linear regression to examine the association between dietary intake and main microbiome features, and linear discriminant analysis effect size (LEfSe) to identify bacterial taxa phylogenetically enriched in the low and high diet consumption groups.
RESULTS
Several bacteria were enriched in patients with higher consumption of mature pumpkin/pumpkin juice (ρ, 0.31 to 0.41) but lower intake of eggs (ρ, -0.32 to -0.26). We observed negative correlations between Bacteroides fragilis abundance and intake of pork (belly), beef soup with vegetables, animal fat, and fatty acids (ρ, -0.34 to -0.27); an inverse correlation was also observed between Clostridium symbiosum abundance and intake of some fatty acids, amines, and amino acids (ρ, -0.30 to -0.24). Furthermore, high intake of seaweed was associated with a 6% (95% CI, 2% to 11%) and 7% (95% CI, 2% to 11%) lower abundance of Rikenellaceae and Alistipes, respectively, whereas overall beverage consumption was associated with an 10% (95% CI, 2% to 18%) higher abundance of Bacteroidetes, Bacteroidia, and Bacteroidales, compared to that in the low intake group. LEfSe analysis identified phylogenetically enriched taxa associated with the intake of sugars and sweets, legumes, mushrooms, eggs, oils and fats, plant fat, carbohydrates, and monounsaturated fatty acids.
CONCLUSIONS
Our data elucidates the diet-microbe interactions in CRC patients. Additional research is needed to understand the significance of these results in CRC prognosis.
Topics: Animals; Bacteria; Cattle; Colorectal Neoplasms; Diet; Fatty Acids; Feces; Gastrointestinal Microbiome; Humans
PubMed: 35701733
DOI: 10.1186/s12885-022-09735-6 -
Scientific Reports Apr 2022In the present study, we elucidated the effect of grain-based (GB) diet containing both soluble and insoluble fibers and purified ingredients-based (PIB) diet containing...
In the present study, we elucidated the effect of grain-based (GB) diet containing both soluble and insoluble fibers and purified ingredients-based (PIB) diet containing only insoluble fiber, namely cellulose on mice gut microbiome using whole shotgun based metagenomic sequencing. Although the fiber content in both diet types is the same (5%) the presence of soluble fiber only in the GB diet differentiates it from the PIB diet. The taxonomic analysis of sequenced reads reveals a significantly higher enrichment of probiotic Lactobacilli in the GB group as compared to the PIB group. Further, the enhancement of energy expensive cellular processes namely, cell cycle control, cell division, chromosome partitioning, and transcription is observed in the GB group which could be due to the metabolization of the soluble fiber for faster energy production. In contrast, a higher abundance of cellulolytic bacterial community namely, the members of family Lachnospiraceae and Ruminococcaceae and the metabolism functions are found in the PIB group. The PIB group shows a significant increase in host-derived oligosaccharide metabolism functions indicating that they might first target the host-derived oligosaccharides and self-stored glycogen in addition to utilising the available cellulose. In addition to the beneficial microbial community variations, both the groups also exhibited an increased abundance of opportunistic pathobionts which could be due to an overall low amount of fiber in the diet. Furthermore, backtracing analysis identified probiotic members of Lactobacillus, viz., L. crispatus ST1, L. fermentum CECT 5716, L. gasseri ATCC 33323, L. johnsonii NCC 533 and L. reuteri 100-23 in the GB group, while Bilophila wadsworthia 3_1_6, Desulfovibrio piger ATCC 29098, Clostridium symbiosum WAL-14163, and Ruminococcaceae bacterium D16 in the PIB group. These data suggest that Lactobacilli, a probiotic community of microorganisms, are the predominant functional contributors in the gut of GB diet-fed mice, whereas pathobionts too coexisted with commensals in the gut microbiome of the PIB group. Thus at 5% fiber, GB modifies the gut microbial ecology more effectively than PIB and the inclusion of soluble fiber in the GB diet may be one of the primary factors responsible for this impact.
Topics: Animals; Cellulose; Diet; Dietary Fiber; Edible Grain; Lactobacillus; Metagenome; Metagenomics; Mice; Prebiotics
PubMed: 35468931
DOI: 10.1038/s41598-022-10762-3 -
Frontiers in Microbiology 2023Gut microbiota plays an important role in colorectal cancer (CRC) pathogenesis through microbes and their metabolites, while oral pathogens are the major components of...
OBJECTIVE
Gut microbiota plays an important role in colorectal cancer (CRC) pathogenesis through microbes and their metabolites, while oral pathogens are the major components of CRC-associated microbes. Multiple studies have identified gut and fecal microbiome-derived biomarkers for precursors lesions of CRC detection. However, few studies have used salivary samples to predict colorectal polyps. Therefore, in order to find new noninvasive colorectal polyp biomarkers, we searched into the differences in fecal and salivary microbiota between patients with colorectal polyps and healthy controls.
METHODS
In this case-control study, we collected salivary and fecal samples from 33 patients with colorectal polyps (CP) and 22 healthy controls (HC) between May 2021 and November 2022. All samples were sequenced using full-length 16S rRNA sequencing and compared with the Nucleotide Sequence Database. The salivary and fecal microbiota signature of colorectal polyps was established by alpha and beta diversity, Linear discriminant analysis Effect Size (LEfSe) and random forest model analysis. In addition, the possibility of microbiota in identifying colorectal polyps was assessed by Receiver Operating Characteristic Curve (ROC).
RESULTS
In comparison to the HC group, the CP group's microbial diversity increased in saliva and decreased in feces ( < 0.05), but there was no significantly difference in microbiota richness ( > 0.05). The principal coordinate analysis revealed significant differences in β-diversity of salivary and fecal microbiota between the CP and HC groups. Moreover, LEfSe analysis at the species level identified and as the major contributors to the salivary microbiota, and and to the fecal microbiota of patients with polyps. Salivary and fecal bacterial biomarkers showed Area Under ROC Curve of 0.8167 and 0.8051, respectively, which determined the potential of diagnostic markers in distinguishing patients with colorectal polyps from controls, and it increased to 0.8217 when salivary and fecal biomarkers were combined.
CONCLUSION
The composition and diversity of the salivary and fecal microbiota were significantly different in colorectal polyp patients compared to healthy controls, with an increased abundance of harmful bacteria and a decreased abundance of beneficial bacteria. A promising non-invasive tool for the detection of colorectal polyps can be provided by potential biomarkers based on the microbiota of the saliva and feces.
PubMed: 37655344
DOI: 10.3389/fmicb.2023.1182346