Association between gut microbiota and anxiety symptoms: A large population-based study examining sex differences.

BACKGROUND: This study aimed to examine the association between anxiety symptoms and gut microbial composition and to infer their functional pathways. METHODS: In total, 605 participants were included in this study. Participants were categorized into anxious and non-anxious groups according to their Beck Anxiety Inventory scores, and their fecal microbiota was profiled using 16S ribosomal RNA gene sequencing. The microbial diversity and taxonomic profiles of the participants with anxiety symptoms were analyzed using generalized linear models. The function of the gut microbiota was inferred by comparing 16S rRNA data between the anxious and non-anxious groups. RESULTS: The gut microbiome of the anxious group showed lower alpha diversity than that of the non-anxious group, and there were prominent differences in the community structure of the gut microbiota between the two groups. Male participants with anxiety had lower relative abundances of the family Oscillospiraceae, fibrolytic bacteria including those of the family Monoglobaceae, and short-chain fatty acid-producing bacteria such as those of the genus Lachnospiraceae_NK4A136 than those without anxiety symptoms. Female participants with anxiety symptoms had a lower relative abundance of the genus Prevotella than those without anxiety symptoms. LIMITATION: The direction of causality between anxiety symptoms and the gut microbiota was unclear owing to the cross-sectional design of the study. CONCLUSION: Our results elucidate the association between anxiety symptoms and gut microbiota and provide insights for developing interventions to treat anxiety symptoms.

Identification of novel Carnobacterium maltaromaticum strains in bone marrow samples of patients with acute myeloid leukemia using a metagenomic binning approach.

The aim of this study aimed to examine the existence of a bacterial metagenome in the bone marrow of patients with acute myeloid leukemia (AML). We re-examined whole-genome sequencing data from the bone marrow samples of seven patients with AML, four of whom were remitted after treatment, for metagenomic analysis. After the removal of human reads, unmapped reads were used to profile the species-level composition. We used the metagenomic binning approach to confirm whether the identified taxon was a complete genome of known or novel strains. We observed a unique and novel microbial signature in which Carnobacterium maltaromaticum was the most abundant species in five patients with AML or remission. The complete genome of C. maltaromaticum "BMAML_KR01," which was observed in all samples, was 100% complete with 8.5% contamination and closely clustered with C. maltaromaticum strains DSM20730 and SF668 based on single nucleotide polymorphism variations. We identified five unique proteins that could contribute to cancer progression and 104 virulent factor proteins in the BMAML_KR01 genome. To our knowledge, this is the first report of a new strain of C. maltaromaticum in patients with AML. The presence of C. maltaromaticum and its new strain in patients indicates an urgent need to validate the existence of this bacterium and evaluate its pathophysiological role.

Machine learning-derived gut microbiome signature predicts fatty liver disease in the presence of insulin resistance.

A simple predictive biomarker for fatty liver disease is required for individuals with insulin resistance. Here, we developed a supervised machine learning-based classifier for fatty liver disease using fecal 16S rDNA sequencing data. Based on the Kangbuk Samsung Hospital cohort (n = 777), we generated a random forest classifier to predict fatty liver diseases in individuals with or without insulin resistance (n = 166 and n = 611, respectively). The model performance was evaluated based on metrics, including accuracy, area under receiver operating curve (AUROC), kappa, and F1-score. The developed classifier for fatty liver diseases performed better in individuals with insulin resistance (AUROC = 0.77). We further optimized the classifiers using genetic algorithm. The improved classifier for insulin resistance, consisting of ten microbial genera, presented an advanced classification (AUROC = 0.93), whereas the improved classifier for insulin-sensitive individuals failed to distinguish participants with fatty liver diseases from the healthy. The classifier for individuals with insulin resistance was comparable or superior to previous methods predicting fatty liver diseases (accuracy = 0.83, kappa = 0.50, F1-score = 0.89), such as the fatty liver index. We identified the ten genera as a core set from the human gut microbiome, which could be a diagnostic biomarker of fatty liver diseases for insulin resistant individuals. Collectively, these findings indicate that the machine learning classifier for fatty liver diseases in the presence of insulin resistance is comparable or superior to commonly used methods.

Sex-specific associations between gut microbiota and skeletal muscle mass in a population-based study.

BACKGROUND: A gut-muscle axis through which the microbiome influences skeletal muscle has been hypothesized. However, sex-specific association between the characteristics of gut microbiota and skeletal muscle mass has not yet been reported. Herein, we performed sex-specific analyses of faecal microbiota composition for the skeletal muscle mass in a population-based cohort. METHODS: We collected faecal samples of 1052 middle-aged participants (621 men and 431 women) who attended health screenings, and we analysed the intestinal microbiota using 16S rRNA gene sequencing. Relative muscle mass was calculated using a bioelectrical impedance analysis and presented as the skeletal muscle mass index [SMI (%) = total appendicular muscle mass (kg)/weight (kg) × 100]. We categorized the subjects into four groups by the quartile of the SMI. Association tests between gut microbiota and SMI were conducted according to the microbial diversity, taxonomic profiling and functional inference in a sex-stratified manner. RESULTS: The mean age and SMI of the total participants were 44.8 years (standard deviation [SD], 8.2) and 41.4% (SD, 3.9), respectively. After adjustments for possible covariates such as age, body mass index and regular physical activity, the highest quartile (Q4) group of SMI had higher alpha diversity than the lowest quartile (Q1) group in male participants (coefficient = 10.79, P < 0.05, linear regression model), whereas there was no difference in diversity among SMI groups in females. At the species level, Haemophilus parainfluenzae (coefficient = 1.910) and Roseburia faecis (coefficient = 1.536) were more abundant in the highest SMI (Q4) group than in the lowest SMI (Q1) group in males. However, no significant taxon was observed along the SMI groups in females. The gut microbiota of the lowest SMI group (Q1) was enriched with genes involved in biosynthesis of amino acids and energy generation compared with that of the highest SMI group (Q4) in both sexes, although the significance of the inferred pathways was weak (P < 0.05 but the false discovery rate q > 0.05). CONCLUSIONS: In this large sample of middle-aged individuals, this study highlights fundamental sex-specific differences in the microbial diversity, composition and metabolic pathways inferred from gut microbiota according to SMI. The gut microbiota may provide novel insights into the potential mechanisms underlying the sex dependence of skeletal muscle mass.

Association Between Gut Microbiota and Depressive Symptoms: A Cross-Sectional Population-Based Study in South Korea.

OBJECTIVE: This study aimed to investigate the association between gut microbiota and depressive symptoms in a large population cohort of Korean adults. METHODS: Overall, 1238 participants were included in the study. Participants were categorized into depressed or non-depressed groups, based on the depressive symptoms reported on the Center for Epidemiologic Studies Rating Scale for Depression, with a cutoff score of 16, and their fecal microbiota was profiled using 16S ribosomal RNA gene sequencing. Several alpha and beta diversity measures were also estimated. The association between depressive symptoms and gut microbiota was analyzed using generalized linear models. The inferred function of the metagenomes was compared between the two groups. RESULTS: There were no consistent differences in alpha and beta diversity between the depressed and non-depressed groups. However, the continuous measure of depressive symptoms was inversely associated with one of four measures of alpha diversity (Shannon's diversity, p = .021). We also found a substantial difference between the depressed and non-depressed groups in the Bray-Curtis dissimilarity among the four beta diversity indices ( p = .004). Participants whose depressive symptoms exceeded a clinical cutoff score had a lower relative abundance of the genus Faecalibacterium when compared with controls (coefficient = -0.025, q = 0.047). However, the depressed group had a significantly higher abundance of the genus Oscillospira than did the non-depressed group (coefficient = 0.002, q = 0.023). CONCLUSIONS: Our findings contribute to the identification of potential relationships between the gut microbiota and depressive symptoms and provide useful insights for developing microbiota-based interventions for patients with depressive symptoms.

Whole-Genome Sequencing Reveals Age-Specific Changes in the Human Blood Microbiota.

Based on several reports that indicate the presence of blood microbiota in patients with diseases, we became interested in identifying the presence of bacteria in the blood of healthy individuals. Using 37 samples from 5 families, we extracted sequences that were not mapped to the human reference genome and mapped them to the bacterial reference genome for characterization. Proteobacteria account for more than 95% of the blood microbiota. The results of clustering by means of principal component analysis showed similar patterns for each age group. We observed that the class Gammaproteobacteria was significantly higher in the elderly group (over 60 years old), whereas the arcsine square root-transformed relative abundance of the classes Alphaproteobacteria, Deltaproteobacteria, and Clostridia was significantly lower (p < 0.05). In addition, the diversity among the groups showed a significant difference (p < 0.05) in the elderly group. This result provides meaningful evidence of a consistent phenomenon that chronic diseases associated with aging are accompanied by metabolic endotoxemia and chronic inflammation.

Gut microbiota and the prevalence and incidence of renal stones.

The role of the gut microbiome in the development of renal stone diseases has not been well characterized. This study focused on the taxonomic and functional profiles of gut microbiomes according to the prevalence and incidence of nephrolithiasis. Stool samples from 915 Korean adults were collected at baseline. Participants were followed for a median of 4.0 years. We evaluated the biodiversity of the gut microbiota and taxonomic profiles associated with nephrolithiasis status, using 16S rRNA gene sequencing. Nephrolithiasis status was categorized into three groups: control (no-stone at both baseline and follow-up visits), incidental nephrolithiasis, and prevalent nephrolithiasis. Compared to the control and incidental nephrolithiasis, the prevalent nephrolithiasis showed a reduced evenness in alpha diversity. Nephrolithiasis was associated with a reduced abundance of some key taxa involved in short-chain fatty acid production. Moreover, the abundance of Bifidobacterium, which possess oxalate-degrading ability, was higher in the control. Conversely, there was no significant difference in the bacterial composition between the incidental and prevalent nephrolithiasis. In our study with repeated nephrolithiasis measurements, prevalent renal stones were associated with an altered gut microbiota composition compared to the control. Besides the known oxalate degradation pathway, other functional pathways inferred in this study require further investigation.

Correlation between Gut Microbiota and Six Facets of Neuroticism in Korean Adults.

A person high in neuroticism is more likely to experience anxiety, stress, worry, fear, anger, and depression. Previous studies have shown that the gut microbiota can influence personality and mental disorders, including stress, anxiety, and depression, through the gut-brain axis. Here, we investigated the correlations between the sub-facet of neuroticism and gut microbiota using the Revised NEO Personality Inventory and the 16S rRNA gene sequencing data 784 adults. We found that the high anxiety and vulnerability group showed significantly lower richness in microbial diversity than a group with low anxiety and vulnerability. In beta diversity, there was a significant difference between the low and high groups of anxiety, self-consciousness, impulsiveness, and vulnerability. In taxonomic compositions, Haemophilus belonging to Gammaproteobacteria was correlated with the Neuroticism domain as well as N1 anxiety and N6 vulnerability facets. The high N1 anxiety and N6 vulnerability group was correlated with a low abundance of Christensenellaceae belonging to Firmicutes Clostridia. High N4 self-consciousness was correlated with a low abundance of Alistipes and Sudoligranulum. N5 impulsiveness was correlated with a low abundance of Oscillospirales. Our findings will contribute to uncovering the potential link between the gut microbiota and neuroticism, and the elucidation of the correlations of the microbiome-gut-brain axis with behavioral changes and psychiatric cases in the general population.

Gut Microbiota Composition across Normal Range Prostate-Specific Antigen Levels.

Animal studies have shown the interaction between androgens and the gut microbiome directly and indirectly; however, limited evidence from human studies is available. To evaluate the association between prostate-specific antigen (PSA) levels within the normal range, reflective of androgen receptor activity, and the gut microbiota composition, a cross-sectional analysis was performed in 759 Korean men aged between 25 and 78 years with normal PSA levels of ≤4.0 ng/mL. We evaluated the biodiversity of gut microbiota as well as the taxonomic and functional signatures associated with PSA levels using 16S rRNA gene sequencing data. PSA levels within the normal range were categorized into three groups: lowest quartile (G1), interquartile range (G2, reference), and highest quartile (G3). The G3 group had higher microbial richness than the G2 group, although it was dominated by a few bacteria. An increase in Escherichia/Shigella abundance and a reduction in Megamonas abundance in the G3 group were also detected. A U-shaped relationship was observed between the three groups across most analyses, including biodiversity, taxonomic composition, and inferred pathways in the gut microbiota. This study showed different microbiota patterns across PSA levels within the normal range. Further studies are required to elucidate the role of microbiota in regulating PSA levels.

Reversion of Gut Microbiota during the Recovery Phase in Patients with Asymptomatic or Mild COVID-19: Longitudinal Study.

Patients with COVID-19 have been reported to experience gastrointestinal symptoms as well as respiratory symptoms, but the effects of COVID-19 on the gut microbiota are poorly understood. We explored gut microbiome profiles associated with the respiratory infection of SARS-CoV-2 during the recovery phase in patients with asymptomatic or mild COVID-19. A longitudinal analysis was performed using the same patients to determine whether the gut microbiota changed after recovery from COVID-19. We applied 16S rRNA amplicon sequencing to analyze two paired fecal samples from 12 patients with asymptomatic or mild COVID-19. Fecal samples were selected at two time points: during SARS-CoV-2 infection (infected state) and after negative conversion of the viral RNA (recovered state). We also compared the microbiome data with those from 36 healthy controls. Microbial evenness of the recovered state was significantly increased compared with the infected state. SARS-CoV-2 infection induced the depletion of Bacteroidetes, while an abundance was observed with a tendency to rapidly reverse in the recovered state. The Firmicutes/Bacteroidetes ratio in the infected state was markedly higher than that in the recovered state. Gut dysbiosis was observed after infection even in patients with asymptomatic or mild COVID-19, while the composition of the gut microbiota was recovered after negative conversion of SARS-CoV-2 RNA. Modifying intestinal microbes in response to COVID-19 might be a useful therapeutic alternative.

Variants in NEB and RIF1 genes on chr2q23 are associated with skeletal muscle index in Koreans: genome-wide association study.

Although skeletal muscle plays a crucial role in metabolism and influences aging and chronic diseases, little is known about the genetic variations with skeletal muscle, especially in the Asian population. We performed a genome-wide association study in 2,046 participants drawn from a population-based study. Appendicular skeletal muscle mass was estimated based on appendicular lean soft tissue measured with a multi-frequency bioelectrical impedance analyzer and divided by height squared to derive the skeletal muscle index (SMI). After conducting quality control and imputing the genotypes, we analyzed 6,391,983 autosomal SNPs. A genome-wide significant association was found for the intronic variant rs138684936 in the NEB and RIF1 genes (ß = 0.217, p = 6.83 × 10-9). These two genes are next to each other and are partially overlapped on chr2q23. We conducted extensive functional annotations to gain insight into the directional biological implication of significant genetic variants. A gene-based analysis identified the significant TNFSF9 gene and confirmed the suggestive association of the NEB gene. Pathway analyses showed the significant association of regulation of multicellular organism growth gene-set and the suggestive associations of pathways related to skeletal system development or skeleton morphogenesis with SMI. In conclusion, we identified a new genetic locus on chromosome 2 for SMI with genome-wide significance. These results enhance the biological understanding of skeletal muscle mass and provide specific leads for functional experiments.

Gut microbiota and metabolic health among overweight and obese individuals.

Although obesity is associated with numerous diseases, the risks of disease may depend on metabolic health. Associations between the gut microbiota, obesity, and metabolic syndrome have been reported, but differences in microbiomes according to metabolic health in the obese population have not been explored in previous studies. Here, we investigated the composition of gut microbiota according to metabolic health status in obese and overweight subjects. A total of 747 overweight or obese adults were categorized by metabolic health status, and their fecal microbiota were profiled using 16S ribosomal RNA gene sequencing. We classified these adults into a metabolically healthy group (MH, N = 317) without any components of metabolic syndrome or a metabolically unhealthy group (MU, N = 430) defined as having at least one metabolic abnormality. The phylogenetic and non-phylogenetic alpha diversity for gut microbiota were lower in the MU group than the MH group, and there were significant differences in gut microbiota bacterial composition between the two groups. We found that the genus Oscillospira and the family Coriobacteriaceae were associated with good metabolic health in the overweight and obese populations. This is the first report to describe gut microbial diversity and composition in metabolically healthy and unhealthy overweight and obese individuals. Modulation of the gut microbiome may help prevent metabolic abnormalities in the obese population.

Polygenic analysis of the effect of common and low-frequency genetic variants on serum uric acid levels in Korean individuals.

Increased serum uric acid (SUA) levels cause gout and are associated with multiple diseases, including chronic kidney disease. Previous genome-wide association studies (GWAS) have identified more than 180 loci that contribute to SUA levels. Here, we investigated genetic determinants of SUA level in the Korean population. We conducted a GWAS for SUA in 6,881 Korean individuals, calculated polygenic risk scores (PRSs) for common variants, and validated the association of low-frequency variants and PRS with SUA levels in 3,194 individuals. We identified two low-frequency and six common independent variants associated with SUA. Despite the overall similar effect sizes of variants in Korean and European populations, the proportion of variance for SUA levels explained by the variants was greater in the Korean population. A rare, nonsense variant SLC22A12 p.W258X showed the most significant association with reduced SUA levels, and PRSs of common variants associated with SUA levels were significant in multiple Korean cohorts. Interestingly, an East Asian-specific missense variant (rs671) in ALDH2 displayed a significant association on chromosome 12 with the SUA level. Further genetic epidemiological studies on SUA are needed in ethnically diverse cohorts to investigate rare or low-frequency variants and determine the influence of genetic and environmental factors on SUA.

Differentially Abundant Bacterial Taxa Associated with Prognostic Variables of Crohn's Disease: Results from the IMPACT Study.

Limited studies have examined the intestinal microbiota composition in relation to Crohn's disease (CD) prognosis. We analyzed the differences in microbial communities and relevant metabolic pathways associated with prognostic variables in patients with CD. We applied 16S rRNA gene sequencing to analyze a cohort of 1110 CD and healthy control (HC) fecal samples. We categorized patients with CD into good (CD-G), intermediate (CD-I) and poor (CD-P) prognosis groups, according to the history of using biologics and intestinal resection. Microbiota α-diversity decreased more in CD-P than CD-G and CD-I. Microbiota ß-diversity in CD-P differed from that in CD-G and CD-I. Thirteen genera and 10 species showed differential abundance between CD-G and CD-P groups. Escherichia coli (p = 0.001) and species Producta (p = 0.01) and genera Lactobacillus (p = 0.003) and Coprococcus (p = 0.01) consistently showed differences between CD-G and CD-P groups after adjusting for confounding variables. Functional profiling suggested that the microbial catabolic pathways and pathways related to enterobacterial common antigen and lipopolysaccharide biosynthesis were better represented in the CD-P group than in the CD-G group, and E. coli were the top contributors to these pathways. CD prognosis is associated with altered microbiota composition and decreased diversity, and E. coli might be causally involved in CD progression, and may have adapted to live in inflammatory environments.

Major Lipids, Apolipoproteins, and Alterations of Gut Microbiota.

The gut microbiota has been linked to blood lipids. However, the relationship between the gut microbiome and other lipid markers like apolipoproteins A1 (apoA1) and B (apoB) as well as classical lipid markers in Asians remain unclear. Here, we examined the associations between gut microbial diversity and taxonomic compositions with both apolipoproteins and lipid markers in a large number of Korean patients. The fecal 16S rRNA gene sequencing data from 1141 subjects were analyzed and subjects were categorized into control group (G0) or abnormal group (G1) according to blood lipid measurements. The microbial diversity and several taxa of the gut microbiota were significantly associated with triglyceride, apoA1, and apoB levels, but not with total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels. The alpha diversity of the gut microbiota was inversely associated with high triglyceride level. Interestingly, G1 of apoA1 showed increased microbial richness and distinct microbial community compared with G0 of apoA1. A high abundance of Fusobacteria and low abundance of Oscillospira were found in the hypertriglyceridemia group. In this large-scale study, we identified associations of gut microbiota with apolipoproteins and classical lipid markers, indicating that the gut microbiota may be an important target for regulating blood lipids.

Comprehensive molecular characterization of mitochondrial genomes in human cancers.

Mitochondria are essential cellular organelles that play critical roles in cancer. Here, as part of the International Cancer Genome Consortium/The Cancer Genome Atlas Pan-Cancer Analysis of Whole Genomes Consortium, which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we performed a multidimensional, integrated characterization of mitochondrial genomes and related RNA sequencing data. Our analysis presents the most definitive mutational landscape of mitochondrial genomes and identifies several hypermutated cases. Truncating mutations are markedly enriched in kidney, colorectal and thyroid cancers, suggesting oncogenic effects with the activation of signaling pathways. We find frequent somatic nuclear transfers of mitochondrial DNA, some of which disrupt therapeutic target genes. Mitochondrial copy number varies greatly within and across cancers and correlates with clinical variables. Co-expression analysis highlights the function of mitochondrial genes in oxidative phosphorylation, DNA repair and the cell cycle, and shows their connections with clinically actionable genes. Our study lays a foundation for translating mitochondrial biology into clinical applications.

Physiologic intestinal 18F-FDG uptake is associated with alteration of gut microbiota and proinflammatory cytokine levels in breast cancer.

The clinical significance of physiologic Fluorine-18-fluorodeoxyglucose (18F-FDG) intestinal uptake (IU) based on the predicted link with gut microbiota dysbiosis and inflammatory cytokine production was investigated in a cohort of breast cancer patients. A total of 114 patients were visually classified into the lower or higher IU group. The maximum and mean standardized uptake values of total bowel (TB SUVmax and TB SUVmean) were measured. The gut microbial abundance of the Citrobacter genus of the Enterobacteriaceae family showed a significant positive correlation with TB SUVmax and TB SUVmean (q = 0.021 and q = 0.010). The unclassified Ruminococcaceae showed a significant negative correlation with TB SUVmax (q = 0.010). The level of tumor necrosis factor alpha (TNF-α) was significantly increased in the high IU group (p = 0.017). The TNF-α levels showed a significant positive correlation with TB SUVmax (rho = 0.220 and p = 0.018) and TB SUVmean (rho = 0.250 and p = 0.007). Therefore, our findings suggest that the physiologic intestinal uptake may reflect subclinical inflammation and differences in the composition of the gut microbiome in breast cancer patients.