Characteristics Of Gut Microbiome Research Articles

Abstract LB208: Obesity is associated with lower tumor oxidative phosphorylation (OXPhos) in metastatic melanoma (MM)

Abstract Immune checkpoint inhibitors (ICI) and BRAF targeted therapies improve overall survival (OS) for patients (pts) with MM, but treatment responses are heterogeneous. Recent data strongly implicates host factors in response and resistance to these agents. We and others have shown that overweight/obese BMI [OW/OB: body mass index (BMI≥25)] is associated with improved OS with both ICI and BRAF targeted therapies in MM pts. The biologic basis for this association is unknown. Thus, we examined the molecular and immune correlates of BMI in MM. In melanoma TCGA regionally metastatic specimens with available BMI (n=202), BMI was not associated with DNA mutations or copy number variations, nor with protein expression. To assess for associations with gene expression, we performed a gene set enrichment analysis (GSEA) on pooled data for cohorts of MM patients with RNAseq and BMI data (TCGA, n=202; MDACC, n=61; MIA, n=68; UCLA, n=26). Following batch correction, GSEA identified downregulation of OXPHOS and adipogenesis in tumors from OW/OB pts compared to normal (NL) BMI (BMI<25). Mass spectrometry of 36 MM specimens from the TCGA cohort confirmed downregulation of the TCA cycle intermediates citrate (p=0.01) and succinate (p<0.05) in OW/OB MM. Immunohistochemistry for key immune cell populations and checkpoints in the MIA and MDACC cohorts did not identify significant differences by BMI, consistent with the lack of difference in inflammatory pathways by gene expression. Finally, we evaluated associations of BMI with gut microbiome features in MM pts (n=272). OW/OB was associated with lower microbial alpha diversity vs. NL BMI (p=0.02), but no significant differences were observed in the composition of individual species. As increased microbiome diversity has been associated with improved outcomes with ICI in MM, this finding supports that changes in the microbiome are unlikely to explain the improved outcomes seen with ICI in OW/OB pts. In sum, our findings suggest that host energy balance influences tumor metabolism in MM, with downregulation of OXPHOS in MM from OB/OW pts, which may influence outcomes with targeted and immune therapies. These hypothesis generating findings suggest one possible mechanism underlying the obesity paradox observed in MM pts. Citation Format: Andrew W. Hahn, Mingchu Xu, Jun Li, Lauren E. Haydu, M.A. Wadud Khan, Tuba N. Gide, Alexander M. Menzies, Courtney W. Hudgens, Theodore S. Nowicki, Jeffrey E. Gershenwald, Antoni Ribas, Michael T. Tetzlaff, Alexander J. Lazar, James Willmott, Jennifer Wargo, Andrew Futreal, Jianhua Zhang, Michael A. Davies, Jennifer L. McQuade. Obesity is associated with lower tumor oxidative phosphorylation (OXPhos) in metastatic melanoma (MM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB208.

Habitual Dietary Intake Affects the Altered Pattern of Gut Microbiome by Acarbose in Patients with Type 2 Diabetes.

The aim of this research was to reveal the characteristics of gut microbiome altered by acarbose intervention in Japanese patients with type 2 diabetes (T2D) and its possible association with habitual dietary intake. Eighteen patients with T2D were administered acarbose for four weeks. The abundances of two major phyla, namely Actinobacteria and Bacteroidetes, were reciprocally changed accompanied by the acarbose intervention. There were also significant changes in the abundances of ten genera, including the greater abundance of Bifidobacterium, Eubacterium, and Lactobacillus and the lower abundance of Bacteroides in the group after the intervention than that before the intervention. Hierarchical clustering of habitual dietary intake was performed based on the pattern of changes in the gut microbiota and were classified into distinct three clusters. Cluster I consisted of sucrose, cluster II mainly included fat intake, and cluster III mainly included carbohydrate intake. Moreover, the amount of change in Faecalibacterium was positively correlated with the intake of rice, but negatively correlated with the intake of bread. The intake of potato was negatively correlated with the amount of change in Akkermansia and Subdoligranulum. Acarbose altered the composition of gut microbiome in Japanese patients with T2D, which might be linked to the habitual dietary intake.

9-OR: Personalized Diets by Prediction of Glycemic Responses Improve Glycemic Control in Subjects with Newly Diagnosed T2D

Dietary modifications are crucial for the management of newly-diagnosed type-2 diabetes (T2D) and prevention of its health complications, but many patients fail to achieve clinical goals with diet alone. We previously developed a machine-learning algorithm for predicting personalized postprandial glucose responses (PPGR) to meals using clinical and gut microbiome features, and showed that dietary interventions based on this algorithm successfully lowered PPGRs in adults with prediabetes. Here, we sought to evaluate the clinical efficacy of our algorithm-based diet in subjects with newly-diagnosed T2D. We performed a short-term randomized controlled crossover trial and compared the effects of an algorithm-based personalized postprandial-targeting (PPT) diet, to those of a commonly used Mediterranean (MED) diet on glucose levels in 23 subjects with newly-diagnosed T2D. Average PPGR, glucose fluctuations, daily time of glucose levels >140 mg/dl and fructosamine levels decreased significantly more during the PPT intervention compared to the MED intervention. We further evaluated the long-term clinical effects of the PPT diet in 16 of the participants by an additional 6-month PPT intervention, and found significant improvements in multiple clinical parameters, including HbA1c (mean±SD, -0.39±0.48%, p<0.001), fasting glucose (-16.4±24.2 mg/dl, p=0.02), fasting insulin (-2.3±4.0 MCU/ml, p=0.04), triglycerides (-49±46 mg/dl, p<0.001), body weight (-3±3.5 kg, p=0.005), body fat% (-2.5±3%, p=0.005) and waist circumference (-4.7±3.7 cm, p=0.001). Importantly, 61% of the participants exhibited diabetes remission at the end of the intervention, as measured by HbA1c. Finally, some of the improvements in clinical outcomes were accompanied by significant alterations to the gut microbiome composition. These findings may be valuable for the design of future studies in larger cohorts and may have implications for dietary advice in clinical practice. Disclosure M. S. Rein: None. O. Ben-yacov: None. A. Godneva: None. S. Shilo: None. S. Zelber-sagi: None. E. Elinav: Consultant; Self; BiomX, DayTwo. E. Segal: Consultant; Self; DayTwo.

Comparative Population Genetics in the Human Gut Microbiome.

Genetic variation in the human gut microbiome is responsible for conferring a number of crucial phenotypes like the ability to digest food and metabolize drugs. Yet, our understanding of how this variation arises and is maintained remains relatively poor. Thus, the microbiome remains a largely untapped resource, as the large number of coexisting species in the microbiome presents a unique opportunity to compare and contrast evolutionary processes across species to identify universal trends and deviations. Here we outline features of the human gut microbiome that, while not unique in isolation, as an assemblage make it a system with unparalleled potential for comparative population genomics studies. We consciously take a broad view of comparative population genetics, emphasizing how sampling a large number of species allows researchers to identify universal evolutionary dynamics in addition to new genes, which can then be leveraged to identify exceptional species that deviate from general patterns. To highlight the potential power of comparative population genetics in the microbiome, we reanalyze patterns of purifying selection across ∼40 prevalent species in the human gut microbiome to identify intriguing trends which highlight functional categories in the microbiome that may be under more or less constraint.

OP0307 GUT MICROBIOTA AND ITS RELEVANCE TO PERIPHERAL LYMPHOCYTE SUBPOPULATION IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS

Background:Systemic lupus erythematosus (SLE) is an autoimmune disease with disturbance of lymphocyte subpopulations1. Growing experimental and clinical evidence suggests that chronic inflammatory response induced by gut microbiome critically contribute to the development of SLE2 3.Objectives:To investigate the characteristics of gut microbiome and the associations between flora and peripheral lymphocyte subpopulations in SLE patients.Methods:A total of 19 SLE patients who fulfilled the 2019 American college of Rheumatology (ACR) and European League Against Rheumatism (EULAR) classification criteria and 16 age- and sex- matched healthy controls (HC) were enrolled in this study. The peripheral T lymphocyte subsets of these participants were assessed by flow cytometry and the gut microbiota were investigated via 16s rRNA. Indicators of disease activity such as erythrocyte sedimentation rate (ESR), complement C3 and C4 were recorded at the same time. Mann-Whitney U test was applied to compare T lymphocyte subsets between SLE patients and HC. Spearman analysis was used for calculating correlation between T subsets and highly expressed differential flora as well as their correlation with disease activity indicators. All P-values reported herein were two-tailed and P-value<0.05 was taken as statistically significant.Results:SLE patients had higher proportions of Th17 cells (P=0.020) and γδT cells (P=0.018) but lower levels of Treg cells (P=0.001), Tfh cells (P=0.018) and Naïve CD4+T cells (P=0.004) (Figure 1a-e). The diversity and relative abundance of intestinal flora in patients with SLE were significantly different from those in HCs. Detailly, the α-diversity was decreased in SLE (P<0.05) (Figure 2a-c). Compared with HC, 11 species of flora were discovered to be distinctly different(P<0.05) (Figure 2d-e). Moreover, there was a significant positive correlation between Treg levels and Ruminococcus2 (P=0.042), Th17 and Megamonas (P=0.009), γδT and Streptococcus (P=0.004) as well as Megamonas (P=0.003), Tfh and Bacteroides (P=0.040). Whereas Th1 levels and Bifidobacterium were negatively correlated in these participants (P=0.005). As for clinical disease measures, there were negative correlations not only between ESR and Treg cells (P=0.031) but also C4 and the amount of Unclassified Ruminococcaceae (P=0.032).Conclusion:Abnormality of T cell subsets, especially the level of Naïve CD4+T, γδT, Tfh, Treg, and Th17 cells contributes to the occurrence and progression of SLE, which may be related to the disturbance of gut microbiota. Therefore it is necessary to attach importance to the alteration of gut microbiota to prevent the outbreak of inflammation and maybe they can be identified as biomarkers predicting disease activity.

Shotgun metagenomics reveals significant gut microbiome features in different grades of acute pancreatitis

BackgroundAcute pancreatitis (AP) has a broad spectrum of severity and is associated with considerable morbidity and mortality. Dysbiosis of gut microbiota may be associated with AP severity. AimsWe aimed to evaluate the composition and functional effects of gut microbiota in different grades of AP severity. MethodsWe carried out shotgun metagenomic sequencing on rectal swab samples from three patients with mild acute pancreatitis (MAP), three with moderately severe acute pancreatitis (MSAP), three with severe acute pancreatitis (SAP) and three normal control persons (NOR). Differences analysis in gut microbiota composition and functional enrichment was performed. ResultsGut microbiota in AP patients was characterized by decreased species richness. The most representative gut microbiota in mild acute pancreatitis (MAP), moderately severe acute pancreatitis (MSAP), and severe acute pancreatitis (SAP) was Streptococcus, Escherichia-coli, and Enterococcus, respectively. Each of the three AP-associated genera could differentiate AP from healthy control population. Representative pathways associated with the glutathione metabolism, lipopolysaccharide biosynthesis, and amino acid metabolism (valine, leucine and isoleucine degradation) were enriched in MAP, MSAP, and SAP, respectively. ConclusionsThe study shows a potential association of gut microbiome composition and function to the progression of AP severity.

Contribution of trace element exposure to gestational diabetes mellitus through disturbing the gut microbiome

BackgroundA healthy gut microbiome is critical for glucose metabolism during pregnancy. In vivo studies indicate that trace element affects the composition and function of the gut microbiome and potentially leads to metabolic disorders but their relationships are largely unknown. We aimed to investigate whether the gut microbiome plays a role in the relationship between trace element exposure and gestational diabetes mellitus (GDM). MethodsIn a prospective cohort study, serum levels of 22 trace elements and the fecal gut microbiome composition were assessed in 837 pregnant women in the second trimester between 22 and 24 weeks of pregnancy prior to GDM diagnosis. Regression and mediation analysis were used to explore the link between element exposure, the gut microbiome, and GDM. Results128 pregnant women (15.3%) were diagnosed with GDM. No individual trace elements were found significantly associated with GDM. In contrast, the composition of the gut microbiome was dramatically altered in women later diagnosed with GDM and characterized by lower alpha diversity and lower abundance of co-abundance groups (CAGs) composed of genera belonging to Ruminococcaceae, Coriobacteriales, and Lachnospiraceae. Rubidium (Rb) was positively associated with alpha diversity indices while mercury (Hg) and vanadium (V) showed negative associations. Elements including rubidium (Rb), thallium (Tl), arsenic (As), and antimony (Sb) were significantly correlated with GDM-related CAGs and mediation analysis revealed that Rb and Sb were inversely related to GDM risk by altering abundance levels of CAGs enriched for Lachnospiraceae, Coriobacteriales, and Ruminococcaceae. ConclusionOur study indicates that trace element exposure is associated with specific gut microbiome features that may contribute to GDM development, which could provide a new avenue for intervening in environmental exposure-related GDM.

Characteristics of the gut microbiome profile in obese patients with colorectal cancer.

Background and AimObesity affects the gut microbiome, which in turn increases the risk for colorectal cancer. Several studies have shown the mechanisms by which some bacteria may influence the development of colorectal cancer; however, gut microbiome characteristics in obese patients with colorectal cancer remain unclear. Therefore, this study evaluated their gut microbiome profile and its relationship with metabolic markers.MethodsThe study assessed fecal samples from 36 consecutive patients with colorectal cancer and 38 controls without colorectal cancer. To identify microbiotic variations between patients with colorectal cancer and controls, as well as between nonobese and obese individuals, 16S rRNA gene amplicon sequencing was performed.ResultsPrincipal coordinate analysis showed significant differences in the overall structure of the microbiome among the study groups. The α‐diversity, assessed by the Chao1 index or Shannon index, was higher in patients with colorectal cancer versus controls. The relative abundance of the genera Enterococcus, Capnocytophaga, and Polaribacter was significantly altered in obese patients with colorectal cancer, whose serum low‐density lipoprotein concentrations were positively correlated with the abundance of the genus Enterococcus; among the most abundant species was Enterococcus faecalis, observed at lower levels in obese versus nonobese patients.ConclusionsThis study demonstrated several compositional alterations of the gut microbiome in patients with colorectal cancer and showed that a reduced presence of E. faecalis may be associated with obesity‐related colorectal cancer development. The gut microbiome may provide novel insights into the potential mechanisms in obesity‐related colorectal carcinogenesis.

Gut Microbiome Alterations in Patients With Thyroid Nodules.

Thyroid nodules are found in nearly half of the adult population. Accumulating evidence suggests that the gut microbiota plays an important role in thyroid metabolism, yet the association between gut microbiota capacity, thyroid nodules, and thyroid function has not been studied comprehensively. We performed a gut microbiome genome-wide association study in 196 patients with thyroid nodules and 283 controls by using whole-genome shotgun sequencing. We found that participants with high-grade thyroid nodules have decreased number of gut microbial species and gene families compared with those with lower grade nodules and controls. There are also significant alterations in the overall microbial composition in participants with high-grade thyroid nodules. The gut microbiome in participants with high-grade thyroid nodules is characterized by greater amino acid degradation and lower butyrate production. The relative abundances of multiple butyrate producing microbes are reduced in patients with high-grade thyroid nodules and the relative abundances of L-histidine metabolism pathways are associated with thyrotropin-releasing hormone. Our study describes the gut microbiome characteristics in thyroid nodules and a gut-thyroid link and highlight specific gut microbiota as a potential therapeutic target to regulate thyroid metabolism.

The Fecal Microbiota Is Already Altered in Normoglycemic Individuals Who Go on to Have Type 2 Diabetes

ObjectiveMounting evidence has suggested a link between gut microbiome characteristics and type 2 diabetes (T2D). To determine whether these alterations occur before the impairment of glucose regulation, we characterize gut microbiota in normoglycemic individuals who go on to develop T2D.MethodsWe designed a nested case-control study, and enrolled individuals with a similar living environment. A total of 341 normoglycemic individuals were followed for 4 years, including 30 who developed T2D, 33 who developed prediabetes, and their matched controls. Fecal samples (developed T2D, developed prediabetes and controls: n=30, 33, and 63, respectively) collected at baseline underwent metagenomics sequencing.ResultsCompared with matched controls, individuals who went on to develop T2D had lower abundances of Bifidobacterium longum, Coprobacillus unclassified, and Veillonella dispar and higher abundances of Roseburia hominis, Porphyromonas bennonis, and Paraprevotella unclassified. The abundance of Bifidobacterium longum was negatively correlated with follow-up blood glucose levels. Moreover, the microbial Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of carbohydrate metabolism, methane metabolism, amino acid metabolism, fatty acid metabolism, and membrane transport were changed between the two groups.ConclusionsWe found that fecal microbiota of healthy individuals who go on to develop T2D had already changed when they still were normoglycemic. These alterations of fecal microbiota might provide insights into the development of T2D and a new perspective for identifying individuals at risk of developing T2D.

Gut microbiome associations with outcome following co-infection with porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV2) in pigs immunized with a PRRS modified live virus vaccine

Porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV2) are two of the most significant pathogens affecting swine. Co-infections are common and result in respiratory disease and reduced weight gain in growing pigs. Although PRRS modified live virus (MLV) vaccines are widely used to decrease PRRS-associated losses, they are generally considered inadequate for disease control. The gut microbiome provides an alternative strategy to enhance vaccine efficacy and improve PRRS control. The objective of this study was to identify gut microbiome characteristics associated with improved outcome in pigs immunized with a PRRS MLV and co-challenged with PRRSV and PCV2b. Twenty-eight days after vaccination and prior to co-challenge, fecal samples were collected from an experimental population of 50 nursery pigs. At 42 days post-challenge, 20 pigs were retrospectively identified as having high or low growth outcomes during the post-challenge period. Gut microbiomes of the two outcome groups were compared using the Lawrence Livermore Microbial Detection Array (LLMDA) and 16S rDNA sequencing. High growth outcomes were associated with several gut microbiome characteristics, such as increased bacterial diversity, increased Bacteroides pectinophilus, decreased Mycoplasmataceae species diversity, higher Firmicutes:Bacteroidetes ratios, increased relative abundance of the phylum Spirochaetes, reduced relative abundance of the family Lachnospiraceae, and increased Lachnospiraceae species C6A11 and P6B14. Overall, this study identifies gut microbiomes associated with improved outcomes in PRRS vaccinated pigs following a polymicrobial respiratory challenge and provides evidence towards the gut microbiome playing a role in PRRS vaccine efficacy.

Association of the Gut Microbiome and Metabolome with Wheeze Frequency in Childhood Asthma

While the gut microbiome has an established role in asthma development, less is known about its contribution to morbidity in children with asthma. In this ancillary study of the Vitamin D Antenatal Asthma Reduction Trial (VDAART), we analyzed the gut microbiome and metabolome of wheeze frequency in children with asthma. Microbiome profiling by 16S rRNA gene sequencing and metabolomic profiling by mass spectrometry were performed on fecal samples collected from 3 year-olds with parent-reported doctor-diagnosed asthma. We tabulated the proportion of quarterly questionnaires in which parents/guardians reported wheeze between months 39 and 63 of life (“wheeze proportion”). Associations of bacterial taxa with wheeze proportion were tested in negative binomial regression models including potential confounders and associations of metabolites with wheeze proportion were tested in correlation, linear regression and pathway analyses. Microbe-metabolite and microbial correlation networks were constructed. In 111 children with asthma, several bacterial taxa were associated with wheeze proportion. Among those with higher wheeze proportion, Veillonella spp. were enriched (log2FoldChanges: 3.1 for V dispar (FDR = 0.01); 3.2 for V parvula (FDR = 0.01); 3.1 for unidentified Veillonella spp. (FDR = 0.02)) and Bifidobacterium longum was depleted (log2FoldChange -2.1, FDR = 0.01). Histidine pathway metabolites were enriched in those with higher wheeze proportion (p < 0.05 using two different pathway analysis methods). V dispar and V uniformis correlated with each other and with numerous metabolites. Gut microbiome features are associated with wheeze frequency in children with asthma, suggesting an impact of the gut microbiome on morbidity in childhood asthma.

Gut Microbiome Features of Chinese Patients Newly Diagnosed with Alzheimer's Disease or Mild Cognitive Impairment.

Patients with Alzheimer's disease (AD) have gut microbiome alterations compared with healthy controls. However, previous studies often assess AD patients who have been on medications or other interventions for the disease. Also, simultaneous determination of gut microbiome in patients with mild cognitive impairment (MCI) or AD in a study is rare. To determine whether there was a gut microbiome alteration in patients newly diagnosed with AD or MCI and whether the degree of gut microbiome alteration was more severe in patients with AD than patients with MCI. Fecal samples of 18 patients with AD, 20 patients with MCI, and 18 age-matched healthy controls were collected in the morning for 16S ribosomal RNA sequencing. No patient had medications or interventions for AD or MCI before the samples were collected. Although there was no difference in the microbial α-diversity among the three groups, patients with AD or MCI had increased β-diversity compared with healthy controls. Patients with AD had decreased Bacteroides, Lachnospira, and Ruminiclostridium_9 and increased Prevotella at the genus level compared with healthy controls. The changing direction of these genera in patients with MCI was the same as patients with AD. However, Lachnospira was the only genus whose abundance in patients with MCI was statistically significantly lower than healthy controls. Bacteroides, Lachnospira, and Ruminiclostridium_9 were positively associated with better cognitive functions whereas Prevotella was on the contrary when subjects of all three groups were considered. The negative correlation of Prevotella with cognitive functions remained among patients with MCI. Patients newly diagnosed with AD or MCI have gut dysbiosis that includes the decrease of potentially protective microbiome, such as Bacteroides, and the increase of microbiome that can promote inflammation, such as Prevotella. Our results support a novel idea that the degree of gut dysbiosis is worsened with the disease stage from MCI to AD.

The Gut Microbiota and Its Relevance to Peripheral Lymphocyte Subpopulations and Cytokines in Patients with Rheumatoid Arthritis.

Growing experimental and clinical evidence suggests that a chronic inflammatory response induced by gut microbiome critically contribute to the development of rheumatoid arthritis (RA). Previous studies demonstrated the disturbance of lymphocyte subpopulations in RA patients. The purpose of this study was to explore the characteristics of gut microbiome and the associations between bacterium and lymphocyte subpopulations as well as cytokines in patients with RA. Fecal samples from 205 RA patients and 199 healthy controls (HCs) were collected for bacterial DNA extraction and 16S ribosomal RNA (rRNA) gene sequencing. The levels of peripheral lymphocyte subpopulation such as T, B, CD4+T, CD8+T, NK, T helper 1 (Th1), Th2, Th17, and regulatory T cells (Tregs) of these subjects were detected by flow cytometry combined with standard absolute counting beads. The serum levels of cytokines interleukin-2 (IL-2), IL-4, IL-6, IL-10, IL-17, tumour necrosis factor-α (TNF-α), and interferon-γ (INF-γ) were tested by flow cytometric bead array (CBA). Alpha and beta diversity of gut microbiome were explored by bioinformatics analysis. Spearman rank correlation test was used to explore the relationships between gut microbiome and lymphocyte subsets as well as serum cytokines. The diversity and relative abundance of intestinal microbiota in patients with RA were significantly different from those in HCs. Detailly, the abundant of phylum Proteobacteria in RA patients was more than that in HCs, while Firmicutes was less than in HCs. There was increased relative abundance of genus Clostridium_XlVa as well as genus Blautia, more abundance of Ruminococcus2 in patients with lower levels of T, B, CD4+T, and Tregs. In addition, the relative abundances of Pelagibacterium, Oxalobacter, ClostridiumXlVb, and ClostridiumXVIII were correlated with cytokines. Gut microbiome of RA patients was clearly different from that of HCs. Abnormal bacteria communities are associated with the altered levels of lymphocyte subpopulation and cytokines, which might be one of the pathogenesis of RA.

1206. Association of Aging, Frailty and Place of Residence with Skin, Oral and Gut Microbiome Characteristics and Pathogenicity Reservoirs

BackgroundDespite their elevated risk for morbidity and mortality from infections, the microbiota of older adults remain understudied. While colonization resistance from resident microflora is a promising means to prevent infections, little is known about pathogenicity reservoirs and colonization resistance in this vulnerable population. Here we study the skin, oral, and gut microbiome dynamics of older adults in both community and Skilled Nursing Facility (SNF) settings, investigating relationships between age, frailty, environment, microbiota, and pathogenicity reservoirs.MethodsWe conducted a longitudinal metagenome survey of 47 adults age 65+ years of age; 22 residents of 3 different SNFs and 25 community dwelling individuals. We performed metagenomic whole genome shotgun sequencing on stool, oral, and skin samples from 8 sites, 1421 total. To correlate clinical and behavioral variables, we measured frailty, collected medical records, and interviewed participants on diet and lifestyle. We also draw comparisons with previous younger cohorts.Results• Compared to younger adults, the skin microbiota of older adults was characterized by ◦ High heterogeneity ◦ Decreased stability over time, suggesting increased susceptibility to colonization and pathogenicity ◦ Compositional differences including significantly lower levels of Cutibacterium acnes, with reciprocal increases in Staphylococci, Corynebacteria, and Malassezia• In older adults, Frailty (Rockwood) was found to have linear correlation with relative abundance of species relevant to infection risk including acnes, staphylococci, streptococci, E. coli, Akkermansia mucinophila, and Enterococcus faecalis.• The skin, oral, and gut microbiota of SNF residents had substantially elevated virulence factor and antibiotic resistance genes.ConclusionTo the best of our knowledge, this is largest report to date of the skin metagenome in older adults. We demonstrate distinct and significant differences between cohorts with clinically relevant implications. We believe these results may inform infection control and prevention by increasing our understanding of colonization resistance and pathogenicity reservoirs, as well as advance our knowledge of the relationship between aging, the microbiome, and infections.Disclosures All Authors: No reported disclosures

Metabolic modeling predicts specific gut bacteria as key determinants for Candida albicans colonization levels

Candida albicans is a leading cause of life-threatening hospital-acquired infections and can lead to Candidemia with sepsis-like symptoms and high mortality rates. We reconstructed a genome-scale C. albicans metabolic model to investigate bacterial-fungal metabolic interactions in the gut as determinants of fungal abundance. We optimized the predictive capacity of our model using wild type and mutant C. albicans growth data and used it for in silico metabolic interaction predictions. Our analysis of more than 900 paired fungal–bacterial metabolic models predicted key gut bacterial species modulating C. albicans colonization levels. Among the studied microbes, Alistipes putredinis was predicted to negatively affect C. albicans levels. We confirmed these findings by metagenomic sequencing of stool samples from 24 human subjects and by fungal growth experiments in bacterial spent media. Furthermore, our pairwise simulations guided us to specific metabolites with promoting or inhibitory effect to the fungus when exposed in defined media under carbon and nitrogen limitation. Our study demonstrates that in silico metabolic prediction can lead to the identification of gut microbiome features that can significantly affect potentially harmful levels of C. albicans.

Interpretable Machine Learning Framework Reveals Robust Gut Microbiome Features Associated With Type 2 Diabetes.

OBJECTIVETo identify the core gut microbial features associated with type 2 diabetes risk and potential demographic, adiposity, and dietary factors associated with these features.RESEARCH DESIGN AND METHODSWe used an interpretable machine learning framework to identify the type 2 diabetes–related gut microbiome features in the cross-sectional analyses of three Chinese cohorts: one discovery cohort (n = 1,832, 270 cases of type 2 diabetes) and two validation cohorts (cohort 1: n = 203, 48 cases; cohort 2: n = 7,009, 608 cases). We constructed a microbiome risk score (MRS) with the identified features. We examined the prospective association of the MRS with glucose increment in 249 participants without type 2 diabetes and assessed the correlation between the MRS and host blood metabolites (n = 1,016). We transferred human fecal samples with different MRS levels to germ-free mice to confirm the MRS–type 2 diabetes relationship. We then examined the prospective association of demographic, adiposity, and dietary factors with the MRS (n = 1,832).RESULTSThe MRS (including 14 microbial features) consistently associated with type 2 diabetes, with risk ratio for per 1-unit change in MRS 1.28 (95% CI 1.23–1.33), 1.23 (1.13–1.34), and 1.12 (1.06–1.18) across three cohorts. The MRS was positively associated with future glucose increment (P < 0.05) and was correlated with a variety of gut microbiota–derived blood metabolites. Animal study further confirmed the MRS–type 2 diabetes relationship. Body fat distribution was found to be a key factor modulating the gut microbiome–type 2 diabetes relationship.CONCLUSIONSOur results reveal a core set of gut microbiome features associated with type 2 diabetes risk and future glucose increment.

350 Enhancing the nutritional value of red meats through genetic and feeding strategies

Abstract Consumption of red meats contributes substantially to the intake of several essential nutrients in the human diet, including protein, essential fatty acids, and several vitamins and trace minerals. Despite concerns regarding potential negative impacts on human health and the environment, demand for red meats continues to increase worldwide, particularly in developing countries. Enhancing the nutritional value of meats is essential to provide consumers with competitive products that meet their nutrient requirements and address their health concerns. Different nutrients in red meats vary in their responsiveness to dietary and genetic manipulations. The fat content and fatty acid composition of meats can be easily modified through animal nutrition. Similarly, iodine, selenium and fat-soluble vitamin content can be significantly manipulated using dietary strategies. In contrast, amino acids, copper, iron, zinc, and water-soluble vitamins are less responsive to dietary manipulations. Feeding studies (i.e. supplements, additives, production systems, life period, nutritional regimes and duration) are relatively abundant and have shown substantial changes to nutritional value in many scenarios. Traditional breeding, including genetic selection for specific traits, has been used to influence multiple carcass and meat quality attributes relevant to nutritional value of meat, including leanness. The use of molecular genetics (i.e. GWAS, identification of genetic variants, gene expression profiles) in the past decade has offered alternative genetic perspectives on improving the nutritional value of meats. Recent studies have also shown influence of rumen or gut microbiome features on nutrient bioavailability and utilization. However, a limited number of studies have combined feeding strategies for specific genetic potential. Given the nutrient composition of meat can be influenced by a dynamic interaction of genetics and environment, the fields of phenomics, nutrigenomics, integrative diet-host-microbiome, and systems biology may bring further insight to better understand the manipulation of red meat composition under both experimental and commercial conditions.

The interplay between host genetics and the gut microbiome reveals common and distinct microbiome features for complex human diseases

BackgroundInterest in the interplay between host genetics and the gut microbiome in complex human diseases is increasing, with prior evidence mainly being derived from animal models. In addition, the shared and distinct microbiome features among complex human diseases remain largely unclear.ResultsThis analysis was based on a Chinese population with 1475 participants. We estimated the SNP-based heritability, which suggested that Desulfovibrionaceae and Odoribacter had significant heritability estimates (0.456 and 0.476, respectively). We performed a microbiome genome-wide association study to identify host genetic variants associated with the gut microbiome. We then conducted bidirectional Mendelian randomization analyses to examine the potential causal associations between the gut microbiome and complex human diseases. We found that Saccharibacteria could potentially decrease the concentration of serum creatinine and increase the estimated glomerular filtration rate. On the other hand, atrial fibrillation, chronic kidney disease and prostate cancer, as predicted by host genetics, had potential causal effects on the abundance of some specific gut microbiota. For example, atrial fibrillation increased the abundance of Burkholderiales and Alcaligenaceae and decreased the abundance of Lachnobacterium, Bacteroides coprophilus, Barnesiellaceae, an undefined genus in the family Veillonellaceae and Mitsuokella. Further disease-microbiome feature analysis suggested that systemic lupus erythematosus and chronic myeloid leukaemia shared common gut microbiome features.ConclusionsThese results suggest that different complex human diseases share common and distinct gut microbiome features, which may help reshape our understanding of disease aetiology in humans.D8HH2e9efBg_dUkabV_mryVideo

Dysbiosis of Gut Microbiota and Short-Chain Fatty Acids in Encephalitis: A Chinese Pilot Study.

BackgroundEncephalitis, the inflammation of the brain, may be caused by an infection or an autoimmune reaction. However, few researches were focused on the gut microbiome characteristics in encephalitis patients.MethodsA prospective observational study was conducted in an academic hospital in Guangzhou from February 2017 to February 2018. Patients with encephalitis were recruited. Fecal and serum samples were collected at admission. Healthy volunteers were enrolled from a community. Disease severity scores were recorded by specialized physicians, including Glasgow Coma Scale (GCS), Sequential Organ Failure Assessment (SOFA), and Acute Physiology and Chronic Health Evaluation-II (APACHE-II). 16S rRNA sequence was performed to analyze the gut microbiome, then the α-diversities and β-diversities were estimated. Short-chain fatty acids (SCFAs) were extracted from fecal samples and determined by gas chromatography-mass spectrometry. Serum D-lactate (D-LA), intestinal fatty acid-binding protein (iFABP), lipopolysaccharide (LPS), and lipopolysaccharide-binding protein (LBP) were measured by enzyme-linked immunosorbent assay (ELISA). The associations among microbial indexes and clinical parameters were evaluated by Spearman correlation analysis.ResultsIn total, twenty-eight patients were recruited for analysis (median age 46 years; 82.1% male; median GCS 6.5; median SOFA 6.5; median APACHE-II 14.5). Twenty-eight age- and sex-matched healthy subjects were selected as controls. The β-diversities between patients and healthy subjects were significantly different. The α-diversities did not show significant differences between these two groups. In the patient group, the abundances of Bacteroidetes, Proteobacteria, and Bacilli were significantly enriched. Accordingly, fecal SCFA levels were decreased in the patient group, whereas serum D-LA, iFABP, LPS, and LBP levels were increased compared with those in healthy subjects. Correlation analyses showed that disease severity had positive correlations with Proteobacteria and Akkermansia but negative correlations with Firmicutes, Clostridia, and Ruminococcaceae abundances. The cerebrospinal fluid albumin-to-serum albumin ratio (CSAR) was positively related to the α-diversity but negatively correlated with the fecal butyrate concentration.ConclusionGut microbiota disruption was observed in encephalitis patients, which manifested as pathogen dominance and health-promoting commensal depletion. Disease severity and brain damage may have associations with the gut microbiota or its metabolites. The causal relationship should be further explored in future studies.