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. 2017 Oct 24;7(1):13950.
doi: 10.1038/s41598-017-14260-9.

Periodontal pathogenic bacteria, Aggregatibacter actinomycetemcomitans affect non-alcoholic fatty liver disease by altering gut microbiota and glucose metabolism

Rina Komazaki  1 , Sayaka Katagiri  2 , Hirokazu Takahashi  3 , Shogo Maekawa  1 , Takahiko Shiba  1 , Yasuo Takeuchi  1 , Yoichiro Kitajima  4   5 , Anri Ohtsu  1 , Sayuri Udagawa  1 , Naoki Sasaki  1 , Kazuki Watanabe  1 , Noriko Sato  6 , Naoyuki Miyasaka  7 , Yuichiro Eguchi  8 , Keizo Anzai  4 , Yuichi Izumi  1
Affiliations

Periodontal pathogenic bacteria, Aggregatibacter actinomycetemcomitans affect non-alcoholic fatty liver disease by altering gut microbiota and glucose metabolism

Rina Komazaki et al. Sci Rep. .

Erratum in

Abstract

Increasing evidence indicates that periodontitis affects non-alcoholic fatty liver disease (NAFLD). We examined the relationship between periodontal bacterial infection and clinical/biochemical parameters in 52 NAFLD patients. Anti-Aggregatibacter actinomycetemcomitans (Aa) antibody titers correlated positively with visceral fat, fasting plasma insulin, and HOMA-IR; and negatively with the liver/spleen ratio. C57BL/6J mice (8-weeks-old) were given Aa or saline (control) for 6 weeks, and were fed either normal chow (NCAa, NCco) or high-fat diet (HFAa and HFco). NCAa and HFAa mice presented impaired glucose tolerance and insulin resistance compared to control mice. HFAa mice showed higher hepatic steatosis than HFco animals. Liver microarray analysis revealed that 266 genes were differentially expressed between NCAa and NCco mice. Upregulated genes in Aa-administrated mice were enriched for glucagon signaling pathway, adipocytokine signaling pathway and insulin resistance. Consistently, plasma glucagon concentration was higher in NCAa mice. In addition, Akt phosphorylation was lower in the liver of NCAa/HFAa than in NCco/HFco mice. Based on 16S rRNA sequencing, Aa administration changed composition of the gut microbiota. Metagenome prediction in gut microbiota showed upregulation of fatty acid biosynthesis and downregulation of fatty acid degradation in Aa-administered mice. Thus, infection with Aa affects NAFLD by altering the gut microbiota and glucose metabolism.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Correlations between IgG antibody titers to periodontal pathogen and clinical/biochemical parameters in NAFLD patients (n = 52). Correlation between total fat area and (A) anti-Aa IgG antibody titer, (B) anti-Fn IgG antibody titer, (C) anti-Pg IgG antibody titer. Correlation between visceral fat area and (D) anti-Aa IgG antibody titer, (E) anti-Fn IgG antibody titer, (F) anti-Pg IgG antibody titer. Correlation between anti-Aa IgG antibody titer and (G) fasting plasma insulin, (H) HOMA-IR, (I) AST, (J) ALT, (K) γ-GTP, (L) L/S ratio.
Figure 2
Figure 2
Comparison of body weight, body fat, glucose tolerance and insulin resistance among NCco, NCAa, HFco and HFAa mice. (A) Photographs of Micro-CT imaging. Yellow region represents visceral fat area and orange region represents subcutaneous fat area; (B) Body weight. (C) The volume of fat area, (D) the volume of visceral fat area and (E) the volume of subcutaneous fat area evaluated by Micro-CT imaging (n = 5). *P < 0.05, **P < 0.01. (F) OGTT (1 g/kg) and (G) ITT (1 U/kg) performed 6 h fasting at 6 weeks (n = 9–12). *P < 0.05, **P < 0.01 NCco vs NCAa, †P < 0.05, ††P < 0.01 HFco vs HFAa.
Figure 3
Figure 3
Evaluation of liver steatosis. (A) HE staining of liver tissue from NCco6w, NCAa6w, HFco6w, HFAa6w, NCco12w, NCAa12w, HFco12w and HFAa12w mice (row magnification × 200, Black bar = 100 μm), and (B) lipid area (%). (C) Acc1 mRNA expressions; (D) Glck mRNA expressions; (E) Tnfα mRNA expressions; (F) Il6 mRNA expressions; (G) Il1β mRNA expressions among NCco, NCAa, HFco and HFAa mice at 6 weeks (n = 9–12). *P < 0.05, **P < 0.01.
Figure 4
Figure 4
Microarray analysis in liver between NCco and NCAa mice (n = 4). (A) Volcano plots. (B) Gene Ontology in DEGs. (C) KEGG pathway (P < 0.05) in upregulated DEGs. Analysis of gene expressions in liver in (D) Ppargc1a mRNA expressions; (E) Slc2a1 mRNA expressions; (F) Plcb1 mRNA expressions; (G) Sik1 mRNA; (H) Ppp3cc mRNA expressions; (I) Acsl1 mRNA expressions; (J) Ppp2r4 mRNA expressions among NCco, NCAa, HFco and HFAa mice at 6 weeks. *P < 0.05, **P < 0.01.
Figure 5
Figure 5
Analysis of glucose metabolism and insulin resistance among NCco, NCAa, HFco and HFAa mice (n = 6–8). (A) Concentration of fasting plasma glucagon. Analysis of gene expressions in liver in (B) Prkaca mRNA expressions, (C) Prkacb mRNA expressions. (D) Total Akt and pAkt expressions, (E) total Erk and pErk expressions in liver. *P < 0.05, **P < 0.01.
Figure 6
Figure 6
Evaluation of gut microbiome compositions based on 16S rRNA sequences between NCco and NCAa mice (n = 4). (A) rarefaction curve, (B) number of OTUs, (C) Shannon index, (D) Chao1 between NCco and NCAa mice. (E) Microbial composition at a Phylum level. (F) Microbial composition at a Genus level, dendrogram and heatmap constructed based on read abundance. (G) Rank distributions of the spices between NCco and NCAa mice (>0.1% relative abundance). The species name or 16S ribosomal RNA database ID in DDBJ is shown. *P < 0.05 between NCco and NCAa mice.
Figure 7
Figure 7
Metagenome prediction between NCco and NCAa mice. (A) Metagenome prediction of level-2 subsystem. *P < 0.05 between NCco and NCAa mice. (B) Dendrogram and heatmap constructed based on metagenome prediction. (C) Predicted KEGG pathways present in any of samples for NCco (upper figure) and NCAa (lower figure). Middle figure shows significantly enriched pathway. Blue: NCco. Red: NCAa.
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