Black Raspberry Supplementation Alters the Gut Microbiome and Improves Alpha Diversity in a Mouse Model of Inflammation-Associated Colorectal Cancer

Abstract Objectives Anti-inflammatory bioactives in black raspberries (BRB) have been shown to have protective effects on the colon epithelium and may influence gut microbiome. The goal of this study was to determine the effects of dietary intervention with BRB on the dynamic composition of the gut microbiome composition in mice. Methods Using a 2 × 2 factorial design, C57BL/6J male mice were fed the standard AIN93G diet or the total Western diet (TWD) for 16 weeks with or without 10% (w/w) whole, freeze-dried BRB powder. The azoxymethane + dextran sodium sulfate model of inflammation-associated colorectal cancer was employed to assess the dynamic response of the gut microbiome to basal diet and BRB treatment prior to, during, and after active colitis and at the study end. Microbiome composition was determined using 16s rRNA sequencing followed by diversity analyses (alpha and beta) and identification of discriminating taxa by with linear discriminant analyses by effect size (lefse). Results Alpha diversity was markedly reduced during colitis for mice consuming either AIN93G or TWD, with some improvement noted by the recovery phase. Of note, consumption of BRB for two weeks significantly increased alpha diversity measures, and BRB improved alpha diversity in mice fed the AIN93G diet during colitis. Alternatively, BRB appeared less effective in mice fed TWD. Beta diversity was also significantly affected with notable clustering of microbiomes by BRB treatment during and after colitis. Consumption of BRB affected the relative abundance of several key taxa over the course of colitis and recovery from gut injury, including Erysipelotrichaceae, Bifidobacteriaceae, Streptococcaceae, Rikenellaceae, Ruminococcaceae and Akkermansiaceae, among others. Conclusions Dietary supplementation with BRB shifted the composition of the gut microbiome during colitis and recovery from gut injury, though the effects were inconsistent with respect to the basal diet consumed. Funding Sources USDA NIFA AFRI grant no. 2018-67017-27,516 and 2014-67017-21755.

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The Western Dietary Pattern Combined with Vancomycin-Mediated Changes to the Gut Microbiome Exacerbates Colitis Severity and Colon Tumorigenesis

Nutrients ◽

10.3390/nu13030881 ◽

2021 ◽

Vol 13 (3) ◽

pp. 881

Author(s):

Niklas D. Aardema ◽

Daphne M. Rodriguez ◽

Arnaud J. Van Wettere ◽

Abby D. Benninghoff ◽

Korry J. Hintze

Keyword(s):

Colorectal Cancer ◽

Gut Microbiome ◽

Tumor Development ◽

Alpha Diversity ◽

Basal Diet ◽

Plain Water ◽

Microbiome Composition ◽

Colon Tumorigenesis ◽

Induced Changes ◽

The Impact

Previous work by our group using a mouse model of inflammation-associated colorectal cancer (CAC) showed that the total Western diet (TWD) promoted colon tumor development. Others have also shown that vancomycin-mediated changes to the gut microbiome increased colorectal cancer (CRC). Therefore, the objective of this study was to determine the impact of vancomycin on colon tumorigenesis in the context of a standard mouse diet or the TWD. A 2 × 2 factorial design was used, in which C57Bl/6J mice were fed either the standard AIN93G diet or TWD and with vancomycin in the drinking water or not. While both the TWD and vancomycin treatments independently increased parameters associated with gut inflammation and tumorigenesis compared to AIN93G and plain water controls, mice fed the TWD and treated with vancomycin had significantly increased tumor multiplicity and burden relative to all other treatments. Vancomycin treatment significantly decreased alpha diversity and changed the abundance of several taxa at the phylum, family, and genus levels. Conversely, basal diet had relatively minor effects on the gut microbiome composition. These results support our previous research that the TWD promotes colon tumorigenesis and suggest that vancomycin-induced changes to the gut microbiome are associated with higher tumor rates.

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Basal Diet Determined Long-Term Composition of the Gut Microbiome and Mouse Phenotype to a Greater Extent than Fecal Microbiome Transfer from Lean or Obese Human Donors

Nutrients ◽

10.3390/nu11071630 ◽

2019 ◽

Vol 11 (7) ◽

pp. 1630 ◽

Cited By ~ 6

Author(s):

Daphne M. Rodriguez ◽

Abby D. Benninghoff ◽

Niklas D.J. Aardema ◽

Sumira Phatak ◽

Korry J. Hintze

Keyword(s):

Gut Microbiome ◽

Basal Diet ◽

Body Type ◽

Human Donor ◽

Final Body Weight ◽

Linear Discriminant ◽

Fecal Microbiome ◽

Microbiome Composition ◽

Diet Induced Obesity ◽

Obese Human

The Western dietary pattern can alter the gut microbiome and cause obesity and metabolic disorders. To examine the interactions between diet, the microbiome, and obesity, we transplanted gut microbiota from lean or obese human donors into mice fed one of three diets for 22 weeks: (1) a control AIN93G diet; (2) the total Western diet (TWD), which mimics the American diet; or (3) a 45% high-fat diet-induced obesity (DIO) diet. We hypothesized that a fecal microbiome transfer (FMT) from obese donors would lead to an obese phenotype and aberrant glucose metabolism in recipient mice that would be exacerbated by consumption of the TWD or DIO diets. Prior to the FMT, the native microbiome was depleted using an established broad-spectrum antibiotic protocol. Interestingly, the human donor body type microbiome did not significantly affect final body weight or body composition in mice fed any of the experimental diets. Beta diversity analysis and linear discriminant analysis with effect size (LEfSe) showed that mice that received an FMT from obese donors had a significantly different microbiome compared to mice that received an FMT from lean donors. However, after 22 weeks, diet influenced the microbiome composition irrespective of donor body type, suggesting that diet is a key variable in the shaping of the gut microbiome after FMT.

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Changes in Microbial Community Composition Related to Sex and Colon Cancer by Nrf2 Knockout

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.636808 ◽

2021 ◽

Vol 11 ◽

Author(s):

Chin-Hee Song ◽

Nayoung Kim ◽

Ryoung Hee Nam ◽

Soo In Choi ◽

Jeong Eun Yu ◽

...

Keyword(s):

Gut Microbiome ◽

Microbial Community Composition ◽

Alpha Diversity ◽

16S Rrna Gene Sequencing ◽

Rrna Gene ◽

Related Factor ◽

Invasive Adenocarcinoma ◽

Linear Discriminant ◽

Microbiome Composition ◽

Male Control

The frequency of azoxymethane/dextran sulfate sodium (AOM/DSS)-induced carcinogenesis in male mice is higher than that in female mice. Previous studies have reported that 17β-estradiol inhibits tumorigenesis in males by modulating nuclear factor-erythroid 2-related factor 2 (Nrf2). This study aimed to investigate the changes in mouse gut microbiome composition based on sex, AOM/DSS-induced colorectal cancer (CRC), and Nrf2 genotype. The gut microbiome composition was determined by 16S rRNA gene sequencing fecal samples obtained at week 16 post-AOM administration. In terms of sex differences, our results showed that the wild-type (WT) male control mice had higher alpha diversity (i.e. Chao1, Shannon, and Simpson) than the WT female control mice. The linear discriminant analysis effect size (LEfSe) results revealed that the abundances of Akkermansia muciniphila and Lactobacillus murinus were higher in WT male control mice than in WT female controls. In terms of colon tumorigenesis, the alpha diversity of the male CRC group was lower than that of the male controls in both WT and Nrf2 KO, but did not show such changes in females. Furthermore, the abundance of A. muciniphila was higher in male CRC groups than in male controls in both WT and Nrf2 KO. The abundance of Bacteroides vulgatus was higher in WT CRC groups than in WT controls in both males and females. However, the abundance of L. murinus was lower in WT female CRC and Nrf2 KO male CRC groups than in its controls. The abundance of A. muciniphila was not altered by Nrf2 KO. In contrast, the abundances of L. murinus and B. vulgatus were changed differently by Nrf2 KO depending on sex and CRC. Interestingly, L. murinus showed negative correlation with tumor numbers in the whole colon. In addition, B. vulgatus showed positive correlation with inflammatory markers (i.e. myeloperoxidase and IL-1β levels), tumor numbers, and high-grade adenoma, especially, developed mucosal and submucosal invasive adenocarcinoma at the distal part of the colon. In conclusion, Nrf2 differentially alters the gut microbiota composition depending on sex and CRC induction.

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Interaction between Host MicroRNAs and the Gut Microbiota in Colorectal Cancer

mSystems ◽

10.1128/msystems.00205-17 ◽

2018 ◽

Vol 3 (3) ◽

Cited By ~ 35

Author(s):

Ce Yuan ◽

Michael B. Burns ◽

Subbaya Subramanian ◽

Ran Blekhman

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Gut Microbiota ◽

Mirna Expression ◽

Gut Microbiome ◽

Noncoding Rna ◽

Microbial Community Composition ◽

Host Cells ◽

Microbiome Composition ◽

Small Noncoding Rna

ABSTRACT Although variation in gut microbiome composition has been linked with colorectal cancer (CRC), the factors that mediate the interactions between CRC tumors and the microbiome are poorly understood. MicroRNAs (miRNAs) are known to regulate CRC progression and are associated with patient survival outcomes. In addition, recent studies suggested that host miRNAs can also regulate bacterial growth and influence the composition of the gut microbiome. Here, we investigated the association between miRNA expression and microbiome composition in human CRC tumor and normal tissues. We identified 76 miRNAs as differentially expressed (DE) in tissue from CRC tumors and normal tissue, including the known oncogenic miRNAs miR-182, miR-503, and mir-17~92 cluster. These DE miRNAs were correlated with the relative abundances of several bacterial taxa, including Firmicutes , Bacteroidetes , and Proteobacteria . Bacteria correlated with DE miRNAs were enriched with distinct predicted metabolic categories. Additionally, we found that miRNAs that correlated with CRC-associated bacteria are predicted to regulate targets that are relevant for host-microbiome interactions and highlight a possible role for miRNA-driven glycan production in the recruitment of pathogenic microbial taxa. Our work characterized a global relationship between microbial community composition and miRNA expression in human CRC tissues. IMPORTANCE Recent studies have found an association between colorectal cancer (CRC) and the gut microbiota. One potential mechanism by which the microbiota can influence host physiology is through affecting gene expression in host cells. MicroRNAs (miRNAs) are small noncoding RNA molecules that can regulate gene expression and have important roles in cancer development. Here, we investigated the link between the gut microbiota and the expression of miRNA in CRC. We found that dozens of miRNAs are differentially regulated in CRC tumors and adjacent normal colon and that these miRNAs are correlated with the abundance of microbes in the tumor microenvironment. Moreover, we found that microbes that have been previously associated with CRC are correlated with miRNAs that regulate genes related to interactions with microbes. Notably, these miRNAs likely regulate glycan production, which is important for the recruitment of pathogenic microbial taxa to the tumor. This work provides a first systems-level map of the association between microbes and host miRNAs in the context of CRC and provides targets for further experimental validation and potential interventions.

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Immune Gene Expression Covaries with Gut Microbiome Composition in Stickleback

mBio ◽

10.1128/mbio.00145-21 ◽

2021 ◽

Vol 12 (3) ◽

Author(s):

Lauren E. Fuess ◽

Stijn den Haan ◽

Fei Ling ◽

Jesse N. Weber ◽

Natalie C. Steinel ◽

...

Keyword(s):

Gene Expression ◽

Microbial Communities ◽

Gut Microbiome ◽

Alpha Diversity ◽

Host Immunity ◽

Host Gene ◽

Microbiota Composition ◽

Host Gene Expression ◽

Microbiome Composition ◽

Immune Genes

ABSTRACT Commensal microbial communities have immense effects on their vertebrate hosts, contributing to a number of physiological functions, as well as host fitness. In particular, host immunity is strongly linked to microbiota composition through poorly understood bi-directional links. Gene expression may be a potential mediator of these links between microbial communities and host function. However, few studies have investigated connections between microbiota composition and expression of host immune genes in complex systems. Here, we leverage a large study of laboratory-raised fish from the species Gasterosteus aculeatus (three-spined stickleback) to document correlations between gene expression and microbiome composition. First, we examined correlations between microbiome alpha diversity and gene expression. Our results demonstrate robust positive associations between microbial alpha diversity and expression of host immune genes. Next, we examined correlations between host gene expression and abundance of microbial taxa. We identified 15 microbial families that were highly correlated with host gene expression. These families were all tightly correlated with host expression of immune genes and processes, falling into one of three categories—those positively correlated, negatively correlated, and neutrally related to immune processes. Furthermore, we highlight several important immune processes that are commonly associated with the abundance of these taxa, including both macrophage and B cell functions. Further functional characterization of microbial taxa will help disentangle the mechanisms of the correlations described here. In sum, our study supports prevailing hypotheses of intimate links between host immunity and gut microbiome composition. IMPORTANCE Here, we document associations between host gene expression and gut microbiome composition in a nonmammalian vertebrate species. We highlight associations between expression of immune genes and both microbiome diversity and abundance of specific microbial taxa. These findings support other findings from model systems which have suggested that gut microbiome composition and host immunity are intimately linked. Furthermore, we demonstrate that these correlations are truly systemic; the gene expression detailed here was collected from an important fish immune organ (the head kidney) that is anatomically distant from the gut. This emphasizes the systemic impact of connections between gut microbiota and host immune function. Our work is a significant advancement in the understanding of immune-microbiome links in nonmodel, natural systems.

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Abstract 18: Gut Microbiome Modifies the Protective Effects of a Mediterranean Dietary Pattern Against Diabetes Mellitus in US Hispanics/ Latinos: The Hispanic Community Health Study/ Study of Latinos (HCHS/SOL)

Circulation ◽

10.1161/circ.141.suppl_1.18 ◽

2020 ◽

Vol 141 (Suppl_1) ◽

Cited By ~ 1

Author(s):

Dong Wang ◽

Qibin Qi ◽

Zheng Wang ◽

Mykhaylo Usyk ◽

Daniela Sotres-Alvarez ◽

...

Keyword(s):

Diabetes Mellitus ◽

Relative Abundance ◽

Gut Microbiome ◽

16S Rrna Gene Sequencing ◽

Health Study ◽

Rrna Gene ◽

Inverse Association ◽

Protective Effects ◽

Acid Fermentation ◽

Microbiome Composition

Introduction: Little is known about whether the effect of a healthy diet on diabetes mellitus (DM) is modified by the gut microbiome in human. Hypothesis: We hypothesize that the gut microbiome modifies the inverse association between the Mediterranean diet (MedDiet) and risk of DM. Methods: This study included 543 DM cases, 805 with impaired glucose tolerance (IGT) and 394 with normal glucose regulation (NGR) in adults 23-83yrs old from the HCHS/SOL. Fecal samples were profiled using 16s rRNA gene sequencing. We applied QIIME 2 to cluster sequences into OTUs and assign taxonomies, and PICRUSt to predict metagenomic gene functions. Adherence to the MedDiet was evaluated by a MedDiet index using the average of two 24-hr dietary recalls. We applied MaAsLin2 to quantify associations between the MedDiet index and microbial features with adjustment for confounding factors listed in the caption of Fig. 1. Results: MedDiet was associated with phylogenetically diverse, rare, and abundant gut microbes (Fig. 1a). For example, a higher MedDiet index was associated with a higher relative abundance of Faecalibacterium Prausnitzii [FDR-adjusted p (q) =0.002], but a lower relative abundance of Collinsella aerofaciens ( q =0.009). We found that several microbial functions related to plant-derived polysaccharide degradation such as fructuronate reductase ( q =0.02), and short-chain fatty acid fermentation such as butyryl-CoA dehydrogenase ( q =0.002) were enriched in participants with higher MedDiet index. We found that the inverse association between MedDiet and risk of DM was more pronounced in participants with greater abundance of Prevotella copri , but weaker in participants whose gut microbial communities were dominated by Bacteroides ( P interaction =0.02 for IGT/DM vs NGR, Fig. 1b). Conclusions: Adherence to the MedDiet is associated with diverse gut microorganisms and microbial functions. The inverse association between MedDiet and risk of DM might be modified by gut microbiome composition. 1

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Cruciferous Vegetable Intake Results in Differentially Modified Gut Microbiome Composition of Mice Fed a High Fat Diet or a Western Diet

Current Developments in Nutrition ◽

10.1093/cdn/nzaa062_052 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1595-1595

Author(s):

Sabrina Trudo ◽

Rosa Moreno ◽

Jeong Hoon Pan ◽

Daniel Gallaher ◽

Jae Kyeom Kim ◽

...

Keyword(s):

Gut Microbiome ◽

Vegetable Intake ◽

Body Weight Gain ◽

Alpha Diversity ◽

Western Diet ◽

Index Number ◽

Standard Diet ◽

Jaccard Distance ◽

Microbiome Composition ◽

Distinct Cluster

Abstract Objectives Cruciferous (CRU; rich in glucosinolates) and apiaceous (API; rich in furanocoumarins) vegetable intake decrease colon cancer risk markers, likely through different mechanisms. Previous reports suggest background diets influence efficacy of bioactives. Here, we determined the effects on the composition of the gut microbiome of CRU and API supplementation to different background diets, diet-induced obesity (DIO) and the total western diet (TWD). Methods C57BL/6J male mice were fed standard diet (AIN93G), DIO, DIO with 21% (w/w) CRU (DIO + CRU), DIO with 21% (w/w) API (DIO + API), TWD, TWD with CRU (TWD + CRU), or TWD with API (TWD + API). After 12 weeks, cecal contents were collected for 16S rRNA sequencing and data analyzed by mothur. Results There were no differences in body weight gain except mice fed DIO + CRU gained more than mice fed AIN-93G or TWD. Lachnospiraceae was increased by CRU supplementation to both DIO and TWD and by API supplementation to TWD. CRU increased alpha diversity [Shannon Index, number of observed Operational Taxonomic Unit (OTUs)] compared to DIO and TWD. Regarding beta diversity, DIO + CRU showed distinct cluster compared to DIO (Bray-Curtis, ANOSIM, R = 0.35, P < 0.001; Jaccard distance, R = 0.47, P < 0.001). TWD + CRU showed distinct cluster compared to TWD (Bray-Curtis, R = 0.59, P < 0.001; Jaccard distance, R = 0.62, P < 0.001). API did not change alpha diversity, but did affect beta diversities with distinct clusters between API groups and their basal diet groups (Jaccard distance, R = 0.36 and 0.31 for DIO and TWD, respectively, P < 0.05). Among top 25 discriminating features between DIO and TWD and their supplementation of API and CRU, there were 9 shared OTUs including Lachnospiraceae, Clostridium XlVa, Clostridiales, Eisenbergiella, and Clostridium IV. Akkermansia were decreased in DIO + CRU compared with DIO. In TWD panel, Bifidobacterium and Erysipelotrichaceae decreased in TWD + CRU, while Turicibacter were identified as TWD + CRU signature. Erysipelotrichaceae and Bifidobacterium differentiated AIN-93G, DIO, and TWD. Conclusions CRU supplementation of DIO and TWD altered gut microbiome composition with some differences based on background diet. API also altered composition, albeit to a lesser extent. Funding Sources University of Arkansas, Fulbright Nicaragua Fellow.

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Safety and Modulatory Effects of Humanized Galacto-Oligosaccharides on the Gut Microbiome

Frontiers in Nutrition ◽

10.3389/fnut.2021.640100 ◽

2021 ◽

Vol 8 ◽

Author(s):

Jason W. Arnold ◽

Hunter D. Whittington ◽

Suzanne F. Dagher ◽

Jeffery Roach ◽

M. Andrea Azcarate-Peril ◽

...

Keyword(s):

Gut Microbiome ◽

Alpha Diversity ◽

Biological Synthesis ◽

Glycosyl Hydrolases ◽

Microbiome Composition ◽

Metabolic Substrates ◽

Beneficial Impact ◽

Infant Gut Microbiome ◽

Membrane Bound

Complex dietary carbohydrate structures including β(1–4) galacto-oligosaccharides (GOS) are resistant to digestion in the upper gastrointestinal (GI) tract and arrive intact to the colon where they benefit the host by selectively stimulating microbial growth. Studies have reported the beneficial impact of GOS (alone or in combination with other prebiotics) by serving as metabolic substrates for modulating the assembly of the infant gut microbiome while reducing GI infections. N-Acetyl-D-lactosamine (LacNAc, Galβ1,4GlcNAc) is found in breast milk as a free disaccharide. This compound is also found as a component of human milk oligosaccharides (HMOs), which have repeating and variably branched lactose and/or LacNAc units, often attached to sialic acid and fucose monosaccharides. Human glycosyl-hydrolases do not degrade most HMOs, indicating that these structures have evolved as natural prebiotics to drive the proper assembly of the infant healthy gut microbiota. Here, we sought to develop a novel enzymatic method for generating LacNAc-enriched GOS, which we refer to as humanized GOS (hGOS). We showed that the membrane-bound β-hexosyl transferase (rBHT) from Hamamotoa (Sporobolomyces) singularis was able to generate GOS and hGOS from lactose and N-Acetyl-glucosamine (GlcNAc). The enzyme catalyzed the regio-selective, repeated addition of galactose from lactose to GlcNAc forming the β-galactosyl linkage at the 4-position of the GlcNAc and at the 1-position of D-galactose generating, in addition to GOS, LacNAc, and Galactosyl-LacNAc trisaccharides which were produced by two sequential transgalactosylations. Humanized GOS is chemically distinct from HMOs, and its effects in vivo have yet to be determined. Thus, we evaluated its safety and demonstrated the prebiotic's ability to modulate the gut microbiome in 6-week-old C57BL/6J mice. Longitudinal analysis of gut microbiome composition of stool samples collected from mice fed a diet containing hGOS for 5 weeks showed a transient reduction in alpha diversity. Differences in microbiome community composition mostly within the Firmicutes phylum were observed between hGOS and GOS, compared to control-fed animals. In sum, our study demonstrated the biological synthesis of hGOS, and signaled its safety and ability to modulate the gut microbiome in vivo, promoting the growth of beneficial microorganisms, including Bifidobacterium and Akkermansia.

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Distinct Colon Mucosa Microbiomes associated with Tubular Adenomas and Serrated Polyps

10.1101/2021.07.20.453135 ◽

2021 ◽

Author(s):

Julio Avelar-Barragan ◽

Lauren DeDecker ◽

Zachary Lu ◽

Bretton Coppedge ◽

William Karnes ◽

...

Keyword(s):

Colorectal Cancer ◽

Gut Microbiome ◽

Microbial Community Composition ◽

Tubular Adenoma ◽

Colon Mucosa ◽

Fecal Samples ◽

Serrated Polyps ◽

Microbiome Composition ◽

Serrated Polyp ◽

Mechanisms Of Carcinogenesis

Background: Colorectal cancer is the second most deadly and third most common cancer in the world. Its development is heterogenous, with multiple mechanisms of carcinogenesis. Two distinct mechanisms include the adenoma-carcinoma sequence and the serrated pathway. The gut microbiome has been identified as a key player in the adenoma-carcinoma sequence, but its role in serrated carcinogenesis is unclear. In this study, we characterized the gut microbiome of 140 polyp-free and polyp-bearing individuals using colon mucosa and fecal samples to determine if microbiome composition was associated with each of the two key pathways. Results: We discovered significant differences between colon mucosa and fecal samples, explaining 14% of the variation observed in the microbiome. Multiple mucosal samples were collected from each individual to investigate the gut microbiome for differences between polyp and healthy intestinal tissue, but no such differences were found. Colon mucosa sampling revealed that the microbiomes of individuals with tubular adenomas and serrated polyps were significantly different from each other and polyp-free individuals, explaining 2-10% of the variance in the microbiome. Further analysis revealed differential abundances of Eggerthella lenta, Clostridium scindens, and three microbial genes across tubular adenoma, serrated polyp, and polyp-free cases. Conclusion: By directly sampling the colon mucosa and distinguishing between the different developmental pathways of colorectal cancer, this study helps characterize potential mechanistic targets and diagnostic biomarkers for serrated carcinogenesis. This research also provides insight into multiple microbiome sampling strategies by assessing each methods practicality and effect on microbial community composition.

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An online atlas of human plasma metabolite signatures of gut microbiome composition

10.1101/2021.12.23.21268179 ◽

2021 ◽

Author(s):

Koen F. Dekkers ◽

Sergi Sayols-Baixeras ◽

Gabriel Baldanzi ◽

Christoph Nowak ◽

Ulf Hammar ◽

...

Keyword(s):

Gut Microbiota ◽

Gut Microbiome ◽

High Performance ◽

Alpha Diversity ◽

Plasma Metabolites ◽

Uremic Toxin ◽

Metagenomic Sequencing ◽

Microbiome Composition ◽

Plasma Metabolite

The human gut microbiota produces a variety of small compounds, some of which enter the bloodstream and impact host health. Conversely, various exogenous nutritional and pharmaceutical compounds affect the gut microbiome composition before entering circulation. Characterization of the gut microbiota—host plasma metabolite interactions is an important step towards understanding the effects of the gut microbiota on human health. However, studies involving large and deeply phenotyped cohorts that would reveal such meaningful interactions are scarce. Here, we used deep metagenomic sequencing and ultra-high-performance liquid chromatography linked to mass spectrometry for detailed characterization of the fecal microbiota and plasma metabolome, respectively, of 8,584 participants invited at age 50 to 64 of the Swedish CArdioPulmonary bioImage Study (SCAPIS). After adjusting for multiple comparisons, we identified 1,008 associations between species alpha diversity and plasma metabolites, and 318,944 associations between specific gut metagenomic species and plasma metabolites. The gut microbiota explained up to 50% of the variance of individual plasma metabolites (mean of 4.7%). We present all results as the searchable association atlas "GUTSY" as a rich resource for mining associations, and exemplify the potential of the atlas by presenting novel associations between oral medication and the gut microbiome, and microbiota species strongly associated with levels of the uremic toxin p-cresol sulfate. The association atlas can be used as the basis for targeted studies of perturbation of specific bacteria and for identification of candidate plasma biomarkers of gut flora composition.

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