Metagenomic biomarker discovery and explanation

Segata, Nicola; Izard, Jacques; Waldron, Levi; Gevers, Dirk; Miropolsky, Larisa; Garrett, Wendy S.; Huttenhower, Curtis

doi:10.1186/gb-2011-12-6-r60

Cited by 12,111 publications

(9,232 citation statements)

References 107 publications

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“…Principal-coordinates beta-diversity visualizations were created with Emperor as packaged in QIIME 26 . The Linear Discriminant Analysis Effect Size (LEfSe) Galaxy module (http://huttenhower.sph.harvard.edu/galaxy/) was used for additional statistical analyses 27 .…”

Section: Methodsmentioning

confidence: 99%

Moving beyond microbiome-wide associations to causal microbe identification

Surana

Kasper

2017

Nature

219

177

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Microbiome-wide association studies have established that numerous diseases are associated with changes in the microbiota1,2. These studies typically generate a long list of commensals implicated as biomarkers of disease, with no clear relevance to disease pathogenesis1–5. If the field is to move beyond correlations and begin to address causation, an effective system is needed for refining this catalog of differentially abundant microbes and allow for subsequent mechanistic studies1,4. Herein, we demonstrate that triangulation of microbe–phenotype relationships is an effective method for reducing the noise inherent in microbiota studies and enabling identification of causal microbes. We found that gnotobiotic mice harboring different microbial communities exhibited differential survival in a colitis model. Co-housing of these mice generated animals that had hybrid microbiotas and displayed intermediate susceptibility to colitis. Mapping of microbe–phenotype relationships in parental mouse strains and in mice with hybrid microbiotas identified the bacterial family Lachnospiraceae as a correlate for protection from disease. Using directed microbial culture techniques, we discovered Clostridium immunis, a previously unknown bacterial species from this family, that—when administered to colitis-prone mice—protected them against colitis-associated death. To demonstrate the generalizability of our approach, we used it to identify several commensal organisms that induce intestinal expression of an antimicrobial peptide. Thus, we have used microbe–phenotype triangulation to move beyond the standard correlative microbiome study and identify causal microbes for two completely distinct phenotypes. Identification of disease-modulating commensals by microbe–phenotype triangulation may be more broadly applicable to human microbiome studies.

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Section: Methodsmentioning

confidence: 99%

Moving beyond microbiome-wide associations to causal microbe identification

Surana

Kasper

2017

Nature

219

177

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“…69 Comparisons were made with “Sample Type” as the main categorical variable (“Class”). Alpha levels of 0.01 were used for both the Kruskal–Wallis and pairwise Wilcoxon tests.…”

Section: Methodsmentioning

confidence: 99%

“…Relative abundances of predicted functional genes were multiplied by 1 million and formatted. 69 Comparisons were made with “Group” as the main categorical variable (“Class”). Alpha levels of 0.05 were used for both the Kruskal–Wallis and pairwise Wilcoxon tests.…”

Section: Methodsmentioning

confidence: 99%

Prenatal androgen exposure causes hypertension and gut microbiota dysbiosis

et al. 2018

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Background: Conditions of excess androgen in women, such as polycystic ovary syndrome (PCOS), often exhibit intergenerational transmission. One way in which the risk for PCOS may be increased in daughters of affected women is through exposure to elevated androgens in utero. Hyperandrogenemic conditions have serious health consequences, including increased risk for hypertension and cardiovascular disease. Recently, gut dysbiosis has been found to induce hypertension in rats, such that blood pressure can be normalized through fecal microbial transplant. Therefore, we hypothesized that the hypertension seen in PCOS has early origins in gut dysbiosis caused by in utero exposure to excess androgen. We investigated this hypothesis with a model of prenatal androgen (PNA) exposure and maternal hyperandrogenemia by single-injection of testosterone cypionate or sesame oil vehicle (VEH) to pregnant dams in late gestation. We then completed a gut microbiota and cardiometabolic profile of the adult female offspring. Results: The metabolic assessment revealed that adult PNA rats had increased body weight and increased mRNA expression of adipokines: adipocyte binding protein 2, adiponectin, and leptin in inguinal white adipose tissue. Radiotelemetry analysis revealed hypertension with decreased heart rate in PNA animals. The fecal microbiota profile of PNA animals contained higher relative abundance of bacteria associated with steroid hormone synthesis, Nocardiaceae and Clostridiaceae, and lower abundance of Akkermansia, Bacteroides, Lactobacillus, Clostridium. The PNA animals also had an increased relative abundance of bacteria associated with biosynthesis and elongation of unsaturated short chain fatty acids (SCFAs). Conclusions: We found that prenatal exposure to excess androgen negatively impacted cardiovascular function by increasing systolic and diastolic blood pressure and decreasing heart rate. Prenatal androgen was also associated with gut microbial dysbiosis and altered abundance of bacteria involved in metabolite production of short chain fatty acids. These results suggest that early-life exposure to hyperandrogenemia in daughters of women with PCOS may lead to long-term alterations in gut microbiota and cardiometabolic function.

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“…Linear discriminant analysis (LDA) effect size (LEfSe)40 was used to evaluate differentially abundant bacterial taxa between the animal groups.…”

Section: Methodsmentioning

confidence: 99%

Effect of an extruded animal protein‐free diet on fecal microbiota of dogs with food‐responsive enteropathy

Bresciani

Minamoto

Suchodolski

et al. 2018

Veterinary Internal Medicne

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BackgroundDietary interventions are thought to modify gut microbial communities in healthy individuals. In dogs with chronic enteropathies, resolution of dysbiosis, along with remission of clinical signs, is expected with treatment.Hypothesis/ObjectiveTo evaluate changes in the fecal microbiota in dogs with food‐responsive chronic enteropathy (FRE) and in healthy control (HC) dogs before and after an elimination dietary trial with an animal protein‐free diet (APFD).AnimalsDogs with FRE (n = 10) and HC (n = 14).MethodsDogs were fed the APFD for 60 days. Fecal microbiota was analyzed by Illumina 16S rRNA sequencing and quantitative polymerase chain reaction (PCR).ResultsA significantly lower bacterial alpha‐diversity was observed in dogs with FRE compared with HC dogs at baseline, and compared with FRE dogs after the trial. Distinct microbial communities were observed in dogs with FRE at baseline compared with HC dogs at baseline and compared with dogs with FRE after the trial. Microbial communities still were different in FRE dogs after the trial compared with HC dogs at baseline. In HC dogs, the fecal microbiota did not show a significant modification after administration of the APFD.Conclusion and Clinical ImportanceOur results suggest that, in FRE dogs, treatment with the APFD led to a partial recovery of the fecal microbiota by significantly increasing microbiota richness, which was significantly closer to a healthy microbiota after the treatment. In contrast, no changes were detected in the fecal microbiota of HC dogs fed the same APFD.

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Metagenomic biomarker discovery and explanation

Cited by 12,111 publications

References 107 publications

Moving beyond microbiome-wide associations to causal microbe identification

Moving beyond microbiome-wide associations to causal microbe identification

Prenatal androgen exposure causes hypertension and gut microbiota dysbiosis

Effect of an extruded animal protein‐free diet on fecal microbiota of dogs with food‐responsive enteropathy

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