Murine Gut Microbiome Meta-analysis Reveals Alterations in Carbohydrate Metabolism in Response to Aging

You, Xiaomeng; Dadwal, Ushashi C.; Lenburg, Marc E.; Kacena, Melissa A.; Charles, Julia F.

doi:10.1128/msystems.01248-21

Cited by 11 publications

(13 citation statements)

References 77 publications

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“…Relevant studies reanalyzing murine gut microbiome datasets have also described consistent microbial structure alterations in the setting of a known mouse model that induces obesity and metabolic alterations (the "high-fat diet" model) (Bisanz et al, 2019) and during aging (You et al, 2022). These meta-analyses have also revealed that each study has a marked influence on the microbial structure, but this did not seem to alter the reproducibility of the microbial alterations observed with the experimental model or variable of interest.…”

Section: Discussionmentioning

confidence: 92%

“…These findings raise an interesting aspect regarding the conserved ability of the LIP model to trigger shifts in periodontal microbial structure across studies, an aspect we could infer from the literature but, due to important differences in bioinformatic analyses, was difficult to ascertain and visualize. Relevant studies reanalyzing murine gut microbiome datasets have also described consistent microbial structure alterations in the setting of a known mouse model that induces obesity and metabolic alterations (the “high‐fat diet” model) (Bisanz et al., 2019) and during aging (You et al., 2022). These meta‐analyses have also revealed that each study has a marked influence on the microbial structure, but this did not seem to alter the reproducibility of the microbial alterations observed with the experimental model or variable of interest.…”

Section: Discussionmentioning

confidence: 97%

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A reappraisal of microbiome dysbiosis during experimental periodontitis

Arce

Endo

Dutzan

et al. 2022

Molecular Oral Microbiology

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Periodontitis is a chronic inflammatory disease associated with the presence of dysbiotic microbial communities. Several studies interrogating periodontitis pathogenesis have utilized the murine ligature-induced periodontitis (LIP) model and have further examined the ligature-associated microbiome relying on 16S rRNA-based sequencing techniques. However, it is often very challenging to compare microbial profiles across studies due to important differences in bioinformatic processing and databases used for taxonomic assignment. Thus, our study aim was to reanalyze microbiome sequencing datasets from studies utilizing the LIP model through a standardized bioinformatic analysis pipeline, generating a comprehensive overview of microbial dysbiosis during experimental periodontitis.We conducted a reanalysis of 16S rDNA gene sequencing datasets from nine published studies utilizing the LIP model. Reads were grouped according to the hypervariable region of the 16S rDNA gene amplified (V1-V3 and V4), preprocessed, binned into operational taxonomic units and classified utilizing relevant databases. Alpha-and beta-diversity analyses were conducted, along with relative abundance profiling of microbial communities.Our findings revealed similar microbial richness and diversity across studies and determined shifts in microbial community structure determined by periodontitis induction and study of origin. Clear variations in the relative abundance of bacterial taxa were observed starting on day 5 after ligation and onward, consistent with a distinct microbial composition during health and experimental periodontitis. We also uncovered differentially represented bacterial taxa across studies, dominating periodontal health and LIP-associated communities.Collectively, this reanalysis provides a unified overview of microbial dysbiosis during the LIP model, providing new insights that aim to inform further studies dedicated to unraveling oral host-microbial interactions.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 97%

A reappraisal of microbiome dysbiosis during experimental periodontitis

Arce

Endo

Dutzan

et al. 2022

Molecular Oral Microbiology

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“…The murine gut microbiome changes with aging and is associated with alterations in microbial carbohydrate metabolism, decreased fecal short-chain fatty acids and decreased cobalamin and biotin biosynthesis [ 60 , 61 ]. In the current study, we examined well-known gut-derived uremic toxins that are generated in the CKD milieu.…”

Section: Discussionmentioning

confidence: 99%

Chronic kidney disease promotes cerebral microhemorrhage formation

Fang

Lau

Sun

et al. 2023

J Neuroinflammation

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Background Chronic kidney disease (CKD) is increasingly recognized as a stroke risk factor, but its exact relationship with cerebrovascular disease is not well-understood. We investigated the development of cerebral small vessel disease using in vivo and in vitro models of CKD. Methods CKD was produced in aged C57BL/6J mice using an adenine-induced tubulointerstitial nephritis model. We analyzed brain histology using Prussian blue staining to examine formation of cerebral microhemorrhage (CMH), the hemorrhagic component of small vessel disease and the neuropathological substrate of MRI-demonstrable cerebral microbleeds. In cell culture studies, we examined effects of serum from healthy or CKD patients and gut-derived uremic toxins on brain microvascular endothelial barrier. Results CKD was induced in aged C57BL/6J mice with significant increases in both serum creatinine and cystatin C levels (p < 0.0001) without elevation of systolic or diastolic blood pressure. CMH was significantly increased and positively correlated with serum creatinine level (Spearman r = 0.37, p < 0.01). Moreover, CKD significantly increased Iba-1-positive immunoreactivity by 51% (p < 0.001), induced a phenotypic switch from resting to activated microglia, and enhanced fibrinogen extravasation across the blood–brain barrier (BBB) by 34% (p < 0.05). On analysis stratified by sex, the increase in CMH number was more pronounced in male mice and this correlated with greater creatinine elevation in male compared with female mice. Microglial depletion with PLX3397 diet significantly decreased CMH formation in CKD mice without affecting serum creatinine levels. Incubation of CKD serum significantly reduced transendothelial electrical resistance (TEER) (p < 0.01) and increased sodium fluorescein permeability (p < 0.05) across the endothelial monolayer. Uremic toxins (i.e., indoxyl sulfate, p-cresyl sulfate, and trimethylamine-N-oxide) in combination with urea and lipopolysaccharide induced a marked drop in TEER compared with the control group (p < 0.0001). Conclusions CKD promotes the development of CMH in aged mice independent of blood pressure but directly proportional to the degree of renal impairment. These effects of CKD are likely mediated in part by microglia and are associated with BBB impairment. The latter is likely related to gut-derived bacteria-dependent toxins classically associated with CKD. Overall, these findings demonstrate an important role of CKD in the development of cerebral small vessel disease.

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“…Another study showed that the gut microbiota of the same genotype of mice from two different vendors differed in their gut microbiome profile (Hufeldt et al, 2010). Leveraging the use of publicly available 16S rRNA gene sequencing data, a study performed a meta-analysis on the effect of aging on the gut microbiome in mice (You et al, 2022). However, a significant limitation of this study was the differences in methods between the studies and the relatively small sample size (You et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

“…Leveraging the use of publicly available 16S rRNA gene sequencing data, a study performed a meta-analysis on the effect of aging on the gut microbiome in mice (You et al, 2022). However, a significant limitation of this study was the differences in methods between the studies and the relatively small sample size (You et al, 2022). Although important, these studies did not consider the multitude of other factors that, combined, may influence, and confound the gut microbiome in animal facilities.…”

Section: Introductionmentioning

confidence: 99%

The Influence of Angiotensin II on the Gut Microbiome of Mice: Findings from a Retrospective Study

Muralitharan

Nakai

Snelson

et al. 2023

Preprint

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Introduction: Gut microbiome studies often overlook experimental factors that could influence gut microbiome diversity and could impact findings. Large-scale studies investigating these experimental factors are lacking. Thus, we aimed to determine which experimental factors influence the gut microbiome diversity in pre-clinical animal model studies. Methods: We extracted DNA and sequenced the V4 region of the 16S rRNA gene of a total of 538 samples from various sections of the gastrointestinal tract of 303 young and aged male and female C57BL/6J mice of three different genotypes on five diets from three animal house facilities. As a proof-of-concept in a disease model, some mice were treated with sham or angiotensin II, a commonly studied agent used as a hypertension model. Some samples were sequenced twice as a matched-comparison group. Results: Using over 17 million sequencing reads, we found that experimental factors such as animal house facility, genotype, diet, age, sex, sampling site, and technical factor (i.e., sequencing batch) affected both α- and β-diversity (weighted and unweighted UniFrac), and were associated with compositional changes in the microbiome at varying magnitude, with diet and sampling site having the largest effect. After adjustment by these factors, treatment with angiotensin II had no impact on α-diversity and was only significant in unweighted UniFrac (presence/absence of bacteria) analyses. Conclusion: Our data identified several key experimental and technical factors that affect the gut microbiome in laboratory mice. Our findings support that not accounting or adjusting for these factors may lead to false-positive discoveries and non-biologically relevant findings in the gut microbiome field.

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Murine Gut Microbiome Meta-analysis Reveals Alterations in Carbohydrate Metabolism in Response to Aging

Abstract: Aging-associated microbial alteration is hypothesized to play an important role in host health and longevity. However, investigations regarding specific gut microbes or microbial functional alterations associated with aging have had inconsistent results.

Cited by 11 publications

References 77 publications

A reappraisal of microbiome dysbiosis during experimental periodontitis

A reappraisal of microbiome dysbiosis during experimental periodontitis

Chronic kidney disease promotes cerebral microhemorrhage formation

The Influence of Angiotensin II on the Gut Microbiome of Mice: Findings from a Retrospective Study

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