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Functional Characteristics of the Gut Microbiome in C57BL/6 Mice Differentially Susceptible to Plasmodium yoelii

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ABSTRACT

C57BL/6 mice are widely used for in vivo studies of immune function and metabolism in mammals. In a previous study, it was observed that when C57BL/6 mice purchased from different vendors were infected with Plasmodium yoelii, a causative agent of murine malaria, they exhibited both differential immune responses and significantly different parasite burdens: these patterns were reproducible when gut contents were transplanted into gnotobiotic mice. To gain insight into the mechanism of resistance, we removed whole ceca from mice purchased from two vendors, Taconic Biosciences (low parasitemia) and Charles River Laboratories (high parasitemia), to determine the combined host and microflora metabolome and metatranscriptome. With the exception of two Charles River samples, we observed ≥90% similarity in overall bacterial gene expression within vendors and ≤80% similarity between vendors. In total 33 bacterial genes were differentially expressed in Charles River mice (p-value < 0.05) relative to the mice purchased from Taconic. Included among these, fliC, ureABC, and six members of the nuo gene family were overrepresented in microbiomes susceptible to more severe malaria. Moreover, 38 mouse genes were differentially expressed in these purported genetically identical mice. Differentially expressed genes included basigin, a cell surface receptor required for P. falciparum invasion of red blood cells. Differences in metabolite pools were detected, though their relevance to malaria infection, microbial community activity, or host response is not yet understood. Our data have provided new targets that may connect gut microbial activity to malaria resistance and susceptibility phenotypes in the C57BL/6 model organism.

No MeSH data available.


Volcano plot showing degree of differential expression of bacterially derived genes in Charles River Laboratories mice compared to Taconic Biosciences. Log-transformed fold change in expression is plotted on the x-axis and log-transformed false discovery rate-adjusted p-values plotted on the y-axis. The red horizontal line represents the 0.1 p-value cutoff. Empty triangle: fliC (Flagellin).
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Figure 5: Volcano plot showing degree of differential expression of bacterially derived genes in Charles River Laboratories mice compared to Taconic Biosciences. Log-transformed fold change in expression is plotted on the x-axis and log-transformed false discovery rate-adjusted p-values plotted on the y-axis. The red horizontal line represents the 0.1 p-value cutoff. Empty triangle: fliC (Flagellin).

Mentions: To determine whether specific transcripts significantly differed in expression between the resistant and susceptible phenotypes, statistical analysis of differential gene expression of bacterially derived transcripts was performed using the edgeR Bioconductor package. A total of 60 bacterial genes were differentially expressed (p ≤ 0.1), 33 of which with false discovery rate (FDR) adjusted p-values less than 0.05 and 11 with p-values less than 0.001 (Figure 5). Of these, 51 of 60 genes were overrepresented in Charles River mice compared to Taconic. The majority of differentially expressed genes are involved in energy, amino acid, and carbon metabolisms. Overexpressed in Charles River mice were transcripts encoding FliC, the flagellar body protein, which is heavily proinflammatory. Only three genes were determined to be significantly overrepresented in resistant mice purchased from Taconic Biosciences. All statistically significant bacterial genes, with the exception of three, exhibited an effect size greater than 0.8, the value typically used as the cutoff for a strong effect.


Functional Characteristics of the Gut Microbiome in C57BL/6 Mice Differentially Susceptible to Plasmodium yoelii
Volcano plot showing degree of differential expression of bacterially derived genes in Charles River Laboratories mice compared to Taconic Biosciences. Log-transformed fold change in expression is plotted on the x-axis and log-transformed false discovery rate-adjusted p-values plotted on the y-axis. The red horizontal line represents the 0.1 p-value cutoff. Empty triangle: fliC (Flagellin).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037233&req=5

Figure 5: Volcano plot showing degree of differential expression of bacterially derived genes in Charles River Laboratories mice compared to Taconic Biosciences. Log-transformed fold change in expression is plotted on the x-axis and log-transformed false discovery rate-adjusted p-values plotted on the y-axis. The red horizontal line represents the 0.1 p-value cutoff. Empty triangle: fliC (Flagellin).
Mentions: To determine whether specific transcripts significantly differed in expression between the resistant and susceptible phenotypes, statistical analysis of differential gene expression of bacterially derived transcripts was performed using the edgeR Bioconductor package. A total of 60 bacterial genes were differentially expressed (p ≤ 0.1), 33 of which with false discovery rate (FDR) adjusted p-values less than 0.05 and 11 with p-values less than 0.001 (Figure 5). Of these, 51 of 60 genes were overrepresented in Charles River mice compared to Taconic. The majority of differentially expressed genes are involved in energy, amino acid, and carbon metabolisms. Overexpressed in Charles River mice were transcripts encoding FliC, the flagellar body protein, which is heavily proinflammatory. Only three genes were determined to be significantly overrepresented in resistant mice purchased from Taconic Biosciences. All statistically significant bacterial genes, with the exception of three, exhibited an effect size greater than 0.8, the value typically used as the cutoff for a strong effect.

View Article: PubMed Central - PubMed

ABSTRACT

C57BL/6 mice are widely used for in vivo studies of immune function and metabolism in mammals. In a previous study, it was observed that when C57BL/6 mice purchased from different vendors were infected with Plasmodium yoelii, a causative agent of murine malaria, they exhibited both differential immune responses and significantly different parasite burdens: these patterns were reproducible when gut contents were transplanted into gnotobiotic mice. To gain insight into the mechanism of resistance, we removed whole ceca from mice purchased from two vendors, Taconic Biosciences (low parasitemia) and Charles River Laboratories (high parasitemia), to determine the combined host and microflora metabolome and metatranscriptome. With the exception of two Charles River samples, we observed ≥90% similarity in overall bacterial gene expression within vendors and ≤80% similarity between vendors. In total 33 bacterial genes were differentially expressed in Charles River mice (p-value < 0.05) relative to the mice purchased from Taconic. Included among these, fliC, ureABC, and six members of the nuo gene family were overrepresented in microbiomes susceptible to more severe malaria. Moreover, 38 mouse genes were differentially expressed in these purported genetically identical mice. Differentially expressed genes included basigin, a cell surface receptor required for P. falciparum invasion of red blood cells. Differences in metabolite pools were detected, though their relevance to malaria infection, microbial community activity, or host response is not yet understood. Our data have provided new targets that may connect gut microbial activity to malaria resistance and susceptibility phenotypes in the C57BL/6 model organism.

No MeSH data available.