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Cited by 201Retinal Diseases and TreatmentsGut microbiota and healthOcular Diseases and Behçet’s Syndrome

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Gut microbiota influences pathological angiogenesis in obesity‐driven choroidal neovascularization

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Andriessen, Elisabeth MMA, Wilson, Ariel M, Mawambo, Gaelle, Dejda, Agnieszka, Miloudi, Khalil, Sennlaub, Florian, Sapieha, Przemyslaw·2016·EMBO Molecular Medicine
DOI 10.15252/emmm.201606531PMC PMC5167134
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Abstract

Age-related macular degeneration in its neovascular form (NV AMD) is the leading cause of vision loss among adults above the age of 60. Epidemiological data suggest that in men, overall abdominal obesity is the second most important environmental risk factor after smoking for progression to late-stage NV AMD To date, the mechanisms that underscore this observation remain ill-defined. Given the impact of high-fat diets on gut microbiota, we investigated whether commensal microbes influence the evolution of AMD Using mouse models of NV AMD, microbiotal transplants, and other paradigms that modify the gut microbiome, we uncoupled weight gain from confounding factors and demonstrate that high-fat diets exacerbate choroidal neovascularization (CNV) by altering gut microbiota. Gut dysbiosis leads to heightened intestinal permeability and chronic low-grade inflammation characteristic of inflammaging with elevated production of IL-6, IL-1β, TNF-α, and VEGF-A that ultimately aggravate pathological angiogenesis.

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Figure 1 High‐fat diet exacerbates CNV and influences gut microbiota ASchematic representation of experimental timeline where half of the mice start a high‐fat diet (HFD) at 6 weeks and later half of these receive neomycin (AB) treatment from the age of 9 weeks until killing at week 13. Control mice were fed a regular‐chow diet (RD). At the age of 11 weeks, mice are subjected to four laser burns per eye to perforate Bruch's membrane and recruit subretinal blood vessels from the choroid.B, CWeight gain (B) and area under the curve (C) of percentage weight gain of HFD‐fed mice compared to RD‐fed mice, treated with vehicle or antibiotic; n = 13 (RD), 17 (HFD), 16 (HFD+AB), 12 (RD+AB); CI 99.9%.DCompilation of compressed Z‐stack confocal image of FITC–dextran‐labeled CNV and single‐plane confocal image of isolectin B4‐stained choroidal flat mounts from RD‐ and HFD‐fed mice, with vehicle or antibiotic treatment.EQuantification of area of FITC–dextran‐labeled CNV over isolectin B4‐stained laser impact area fold RD; n = 11 (RD), 16 (HFD), 11 (HFD+AB), 12 (RD+AB), with 36 (RD), 32 (HFD), 33 (HFD+AB), 34 (RD+AB) burns total; CI 99%.F, GRepresentative circle charts of relative abundance of bacterial phyla, class, order, and family (from central to peripheral), in gut microbiota of RD‐fed mice with vehicle, HFD‐fed mice with vehicle, HFD‐fed mice with neomycin, and RD‐fed mice with neomycin (F) and relative proportion per group of different phyla; n = 7 (RD), 8 (HFD), 6 (HFD+AB), 7 (RD+AB); Bacteroidetes; CI 99.9%, Firmicutes; CI 99%, Proteobacteria; CI 99%, Actinobacteria and Spirochaetes (G). *n.d. = not detected.Data information: All comparisons between groups are analyzed using one‐way analysis of variance (ANOVA) and Tukey's multiple comparisons test; **P < 0.01, ***P < 0.001; error bars represent mean ± SEM. Each “n” represents one mouse per experimental group; CI, confidence interval. Scale bar: 100 μm.
Figure 1 High‐fat diet exacerbates CNV and influences gut microbiota ASchematic representation of experimental timeline where half of the mice start a high‐fat diet (HFD) at 6 weeks and later half of these receive neomycin (AB) treatment from the age of 9 weeks until killing at week 13. Control mice were fed a regular‐chow diet (RD). At the age of 11 weeks, mice are subjected to four laser burns per eye to perforate Bruch's membrane and recruit subretinal blood vessels from the choroid.B, CWeight gain (B) and area under the curve (C) of percentage weight gain of HFD‐fed mice compared to RD‐fed mice, treated with vehicle or antibiotic; n = 13 (RD), 17 (HFD), 16 (HFD+AB), 12 (RD+AB); CI 99.9%.DCompilation of compressed Z‐stack confocal image of FITC–dextran‐labeled CNV and single‐plane confocal image of isolectin B4‐stained choroidal flat mounts from RD‐ and HFD‐fed mice, with vehicle or antibiotic treatment.EQuantification of area of FITC–dextran‐labeled CNV over isolectin B4‐stained laser impact area fold RD; n = 11 (RD), 16 (HFD), 11 (HFD+AB), 12 (RD+AB), with 36 (RD), 32 (HFD), 33 (HFD+AB), 34 (RD+AB) burns total; CI 99%.F, GRepresentative circle charts of relative abundance of bacterial phyla, class, order, and family (from central to peripheral), in gut microbiota of RD‐fed mice with vehicle, HFD‐fed mice with vehicle, HFD‐fed mice with neomycin, and RD‐fed mice with neomycin (F) and relative proportion per group of different phyla; n = 7 (RD), 8 (HFD), 6 (HFD+AB), 7 (RD+AB); Bacteroidetes; CI 99.9%, Firmicutes; CI 99%, Proteobacteria; CI 99%, Actinobacteria and Spirochaetes (G). *n.d. = not detected.Data information: All comparisons between groups are analyzed using one‐way analysis of variance (ANOVA) and Tukey's multiple comparisons test; **P < 0.01, ***P < 0.001; error bars represent mean ± SEM. Each “n” represents one mouse per experimental group; CI, confidence interval. Scale bar: 100 μm.CC BY · PubMed Central
Figure EV1 Mice on HFD have shifted ratios of commensal gut microbes Relative abundance of bacterial phyla in gut microbiota of RD‐fed mice with vehicle, HFD‐fed mice with vehicle, HFD‐fed mice with neomycin, and RD‐fed mice with neomycin, shown per sample; n = 7 (RD), 8 (HFD), 6 (HFD+AB), 7 (RD+AB).
Figure EV1 Mice on HFD have shifted ratios of commensal gut microbes Relative abundance of bacterial phyla in gut microbiota of RD‐fed mice with vehicle, HFD‐fed mice with vehicle, HFD‐fed mice with neomycin, and RD‐fed mice with neomycin, shown per sample; n = 7 (RD), 8 (HFD), 6 (HFD+AB), 7 (RD+AB).CC BY · PubMed Central
Figure 2 High‐fat diet increases recruitment of microglia and macrophages A–C3D rendering of Z‐stack confocal image showing isolectin B4‐stained laser burn with FITC–dextran‐labeled CNV and IBA‐1‐stained MPs.DRepresentative FACS plots of retinas and sclera–choroid–RPE cell complexes from regular‐chow diet (RD)‐fed mice without and 3, 7, and 14 days after laser burn.EQuantification of MPs (Ly6G−, F4/80+, CD11b+) at p3, p7, and p14; fold naïve (no burn); n = 5 (no burn), 5 (p3), 6 (p7), 5 (p14); CI 95%.F, GRepresentative FACS plots (F) and quantification of microglia (G) (Ly6G−, F4/80+, CD11b+, CX3CR1hi CD45lo) fold naïve; n = 5 (no burn), 4 (p3), 6 (p7), 5 (p14); CI 95%.HRepresentative FACS plots of retinas and sclera–choroid–RPE cell complexes from RD‐ and HFD‐fed mice, with vehicle or antibiotic treatment at p7.IQuantification of MPs at p7 fold RD; n = 6 (RD), 4 (HFD), 3 (HFD+AB), 4 (RD+AB); CI 95%.J, KRepresentative FACS plots (J) and quantification of microglia (K) (Ly6G−, F4/80+, CD11b+, CX3CR1hi CD45lo) fold RD; n = 5 (RD), 5 (HFD), 3 (HFD+AB), 4 (RD+AB); CI 95%.LRepresentative confocal images of IBA‐1‐stained MPs on choroidal flat mounts from RD‐ and HFD‐fed mice, treated with vehicle or with neomycin. Examples of labeled macrophages (white dots) are presented in side panels.MTotal number of MPs around laser impact area; n = 7 (RD), 9 (HFD), 4 (HFD+AB), 7 (RD+AB), with 23 (RD), 29 (HFD), 13 (HFD+AB), 23 (RD+AB) burns total; CI 99%.Data information: All comparisons between groups are analyzed using one‐way analysis of variance (ANOVA) and Tukey's multiple comparisons test; *P < 0.05, **P < 0.01, ***P < 0.001; error bars represent mean ± SEM. Each “n” represents one mouse per experimental group; CI, confidence interval. Scale bar: 100 μm.
Figure 2 High‐fat diet increases recruitment of microglia and macrophages A–C3D rendering of Z‐stack confocal image showing isolectin B4‐stained laser burn with FITC–dextran‐labeled CNV and IBA‐1‐stained MPs.DRepresentative FACS plots of retinas and sclera–choroid–RPE cell complexes from regular‐chow diet (RD)‐fed mice without and 3, 7, and 14 days after laser burn.EQuantification of MPs (Ly6G−, F4/80+, CD11b+) at p3, p7, and p14; fold naïve (no burn); n = 5 (no burn), 5 (p3), 6 (p7), 5 (p14); CI 95%.F, GRepresentative FACS plots (F) and quantification of microglia (G) (Ly6G−, F4/80+, CD11b+, CX3CR1hi CD45lo) fold naïve; n = 5 (no burn), 4 (p3), 6 (p7), 5 (p14); CI 95%.HRepresentative FACS plots of retinas and sclera–choroid–RPE cell complexes from RD‐ and HFD‐fed mice, with vehicle or antibiotic treatment at p7.IQuantification of MPs at p7 fold RD; n = 6 (RD), 4 (HFD), 3 (HFD+AB), 4 (RD+AB); CI 95%.J, KRepresentative FACS plots (J) and quantification of microglia (K) (Ly6G−, F4/80+, CD11b+, CX3CR1hi CD45lo) fold RD; n = 5 (RD), 5 (HFD), 3 (HFD+AB), 4 (RD+AB); CI 95%.LRepresentative confocal images of IBA‐1‐stained MPs on choroidal flat mounts from RD‐ and HFD‐fed mice, treated with vehicle or with neomycin. Examples of labeled macrophages (white dots) are presented in side panels.MTotal number of MPs around laser impact area; n = 7 (RD), 9 (HFD), 4 (HFD+AB), 7 (RD+AB), with 23 (RD), 29 (HFD), 13 (HFD+AB), 23 (RD+AB) burns total; CI 99%.Data information: All comparisons between groups are analyzed using one‐way analysis of variance (ANOVA) and Tukey's multiple comparisons test; *P < 0.05, **P < 0.01, ***P < 0.001; error bars represent mean ± SEM. Each “n” represents one mouse per experimental group; CI, confidence interval. Scale bar: 100 μm.CC BY · PubMed Central
Figure EV2 FACS gating scheme and relative expression of MPs Gating scheme explaining the identification of the Ly6G−, F4/80+, CD11b+ mononuclear phagocytes and the Ly6G−, F4/80+, CD11b+, CX3CR1hi CD45lo microglia in retinas and sclera–choroid–RPE cell complexes. The gating scheme was as follows: gating of live cells, removal of doublets, selection of viable cells, exclusion of neutrophils, gating of mononuclear macrophages, and gating of microglia. Quantification of overall proportion of microglia within the MP population; n = 6 (no burn), 4 (p3), 6 (p7), 5 (p14). Error bars represent mean ± SEM. Each “n” represents one mouse.
Figure EV2 FACS gating scheme and relative expression of MPs Gating scheme explaining the identification of the Ly6G−, F4/80+, CD11b+ mononuclear phagocytes and the Ly6G−, F4/80+, CD11b+, CX3CR1hi CD45lo microglia in retinas and sclera–choroid–RPE cell complexes. The gating scheme was as follows: gating of live cells, removal of doublets, selection of viable cells, exclusion of neutrophils, gating of mononuclear macrophages, and gating of microglia. Quantification of overall proportion of microglia within the MP population; n = 6 (no burn), 4 (p3), 6 (p7), 5 (p14). Error bars represent mean ± SEM. Each “n” represents one mouse.CC BY · PubMed Central
Figure 3 High‐fat diet augments gut permeability, metabolic endotoxemia, and systemic inflammation Concentration of gut‐absorbed Evans Blue in serum 24 h after oral administration in regular‐chow diet (RD)‐ and high‐fat diet (HFD)‐fed mice, treated with vehicle or with antibiotic; n = 6 (RD), 5 (HFD), 5 (HFD+AB), 5 (RD+AB); CI 99%.Activation of PRRs induced by stimulation with serum isolated from mice fed RD or HFD for 7 weeks and receiving vehicle or neomycin for 3 weeks; fold RD; n = 3 for all groups; CI 99%.Serum cytokine profiles determined by Bio‐Plex assay (Bio‐Rad) of IL‐1β, n = 11 (RD), 12 (HFD), 12 (HFD+AB), 11 (RD+AB); CI 95%; IL‐6, n = 11 (RD), 12 (HFD), 12 (HFD+AB), 11 (RD+AB), CI 99.9%; TNF‐α, n = 11 for all groups, CI 99%; IL‐17A, n = 11 (RD), 12 (HFD), 12 (HFD+AB), 11 (RD+AB), CI 95%; and IFN‐γ, n = 12 for all groups, CI 95%. *n.d. = not detected.mRNA expression of Il1b, n = 5 (RD), 7 (HFD), 7 (HFD+AB), 3 (RD+AB), CI 95%; Il6, n = 5 (RD), 5 (HFD), 4 (HFD+AB), 4 (RD+AB), CI 95%; Tnfa, n = 6 (RD), 9 (HFD), 4 (HFD+AB), 5 (RD+AB), CI 95%; and Vegfa, n = 6 (RD), 5 (HFD), 5 (HFD+AB), 6 (RD+AB), CI 95% in choroids. Data information: All comparisons between groups are analyzed using one‐way analysis of variance (ANOVA) and Tukey's multiple comparisons test; *P < 0.05, **P < 0.01, ***P < 0.001; error bars represent mean ± SEM. Each “n” represents one mouse; CI: confidence interval.
Figure 3 High‐fat diet augments gut permeability, metabolic endotoxemia, and systemic inflammation Concentration of gut‐absorbed Evans Blue in serum 24 h after oral administration in regular‐chow diet (RD)‐ and high‐fat diet (HFD)‐fed mice, treated with vehicle or with antibiotic; n = 6 (RD), 5 (HFD), 5 (HFD+AB), 5 (RD+AB); CI 99%.Activation of PRRs induced by stimulation with serum isolated from mice fed RD or HFD for 7 weeks and receiving vehicle or neomycin for 3 weeks; fold RD; n = 3 for all groups; CI 99%.Serum cytokine profiles determined by Bio‐Plex assay (Bio‐Rad) of IL‐1β, n = 11 (RD), 12 (HFD), 12 (HFD+AB), 11 (RD+AB); CI 95%; IL‐6, n = 11 (RD), 12 (HFD), 12 (HFD+AB), 11 (RD+AB), CI 99.9%; TNF‐α, n = 11 for all groups, CI 99%; IL‐17A, n = 11 (RD), 12 (HFD), 12 (HFD+AB), 11 (RD+AB), CI 95%; and IFN‐γ, n = 12 for all groups, CI 95%. *n.d. = not detected.mRNA expression of Il1b, n = 5 (RD), 7 (HFD), 7 (HFD+AB), 3 (RD+AB), CI 95%; Il6, n = 5 (RD), 5 (HFD), 4 (HFD+AB), 4 (RD+AB), CI 95%; Tnfa, n = 6 (RD), 9 (HFD), 4 (HFD+AB), 5 (RD+AB), CI 95%; and Vegfa, n = 6 (RD), 5 (HFD), 5 (HFD+AB), 6 (RD+AB), CI 95% in choroids. Data information: All comparisons between groups are analyzed using one‐way analysis of variance (ANOVA) and Tukey's multiple comparisons test; *P < 0.05, **P < 0.01, ***P < 0.001; error bars represent mean ± SEM. Each “n” represents one mouse; CI: confidence interval.CC BY · PubMed Central
Figure EV3 Serum IL‐10 is induced with HFD and neomycin treatment in HFD mice improves glucose tolerance Serum IL‐10 profile; n = 12 for all groups; CI 95%.Blood glucose (mg/dl) following intraperitoneal injection of glucose (2 mg/kg) in RD, HFD, HFD+AB, and RD+AB mice. n = 5 (RD), 6 (HFD), 5 (HFD+AB), 10 (RD+AB); CI 95%. Area under the curve (AUC) of the same groups as in (B). Data information: All comparisons between groups are analyzed using one‐way analysis of variance (ANOVA) and Tukey's multiple comparisons test; *P < 0.05, **P < 0.01, ***P < 0.001; error bars represent mean ± SEM. Each “n” represents one mouse; CI, confidence interval.
Figure EV3 Serum IL‐10 is induced with HFD and neomycin treatment in HFD mice improves glucose tolerance Serum IL‐10 profile; n = 12 for all groups; CI 95%.Blood glucose (mg/dl) following intraperitoneal injection of glucose (2 mg/kg) in RD, HFD, HFD+AB, and RD+AB mice. n = 5 (RD), 6 (HFD), 5 (HFD+AB), 10 (RD+AB); CI 95%. Area under the curve (AUC) of the same groups as in (B). Data information: All comparisons between groups are analyzed using one‐way analysis of variance (ANOVA) and Tukey's multiple comparisons test; *P < 0.05, **P < 0.01, ***P < 0.001; error bars represent mean ± SEM. Each “n” represents one mouse; CI, confidence interval.CC BY · PubMed Central
Figure 4 High‐fat diet exacerbates CNV through gut microbiota ASchematic representation of microbiotal transfer experiments where recipient mice are gavaged with a suspension of fecal pellets in PBS from donor mice that are fed either a regular‐chow diet (RD) or a high‐fat diet (HFD).BExperimental timeline describing preparation of mice for microbiotal transfers where mice receive 5 days of antibiotics (neomycin and ampicillin) at 6 weeks of age. Starting at 7 weeks of life, RDxRDT and HFDxRDT mice receive weekly microbiotal transplants from RD donor mice and HFDxHFDT mice receive weekly microbiotal transplants from HFD donor mice until killing at week 13. At the age of 11 weeks, mice are subjected to four laser burns per eye.C, DWeight gain (C) and area under the curve (D) of percentage weight gain of RDxRDT, HFDxRDT, and HFDxHFDT mice; n = 13 (RDxRDT), 12 (HFDxHFDT), 14 (HFDxRDT); CI 99%.ERepresentative circle charts of relative abundance of bacterial phyla in gut microbiota of RD‐fed mice receiving a RD transfer and HFD‐fed mice receiving a HFD or RD transfer.FRelative proportion per experimental group of different phyla; n = 5 (RDxRDT), 5 (HFDxHFDT), 4 (HFDxRDT); Bacteroidetes; CI 99%, Firmicutes; CI 95%, Proteobacteria; CI 95%, Actinobacteria and Spirochaetes.GCompilation of compressed Z‐stack confocal images of FITC–dextran‐labeled CNV and single‐plane confocal images of isolectin B4‐stained choroidal flat mounts from RDxRDT, HFDxRDT, and HFDxHFDT mice.HQuantification of area of FITC–dextran‐labeled CNV over area of isolectin B4‐stained laser impact area fold RDxRDT; n = 6 (RDxRDT), 9 (HFDxHFDT), 9 (HFDxRDT), with 15 (RDxRDT), 21 (HFDxHFDT), 16 (HFDxRDT) burns total; CI 95%.IConcentration of gut‐absorbed Evans Blue in serum 24 h after oral administration in RD‐ and HFD‐fed mice, after RD or HFD microbiotal transplant; n = 3 (RDxRDT), 3 (HFDxHFDT), 4 (HFDxRDT); CI 95%.JmRNA expression of Il1b: n = 5 (RDxRDT), 4 (HFDxHFDT), 5 (HFDxRDT); Il6: n = 5 (RDxRDT), 4 (HFDxHFDT), 4 (HFDxRDT), CI 99%; Tnfa: n = 5 (RDxRDT), 4 (HFDxHFDT), 4 (HFDxRDT), CI 95%; and Vegfa: n = 5 (RDxRDT), 4 (HFDxHFDT), 5 (HFDxRDT), CI 95% in choroids.Data information: All comparisons between groups are analyzed using one‐way analysis of variance (ANOVA) and Tukey's multiple comparisons test; *P < 0.05, **P < 0.01, ***P < 0.001; error bars represent mean ± SEM. Each “n” represents one mouse per experimental group; in (I), both eyes were used for mRNA extraction, giving two data points per mouse; CI, confidence interval. Scale bar, 100 μm.
Figure 4 High‐fat diet exacerbates CNV through gut microbiota ASchematic representation of microbiotal transfer experiments where recipient mice are gavaged with a suspension of fecal pellets in PBS from donor mice that are fed either a regular‐chow diet (RD) or a high‐fat diet (HFD).BExperimental timeline describing preparation of mice for microbiotal transfers where mice receive 5 days of antibiotics (neomycin and ampicillin) at 6 weeks of age. Starting at 7 weeks of life, RDxRDT and HFDxRDT mice receive weekly microbiotal transplants from RD donor mice and HFDxHFDT mice receive weekly microbiotal transplants from HFD donor mice until killing at week 13. At the age of 11 weeks, mice are subjected to four laser burns per eye.C, DWeight gain (C) and area under the curve (D) of percentage weight gain of RDxRDT, HFDxRDT, and HFDxHFDT mice; n = 13 (RDxRDT), 12 (HFDxHFDT), 14 (HFDxRDT); CI 99%.ERepresentative circle charts of relative abundance of bacterial phyla in gut microbiota of RD‐fed mice receiving a RD transfer and HFD‐fed mice receiving a HFD or RD transfer.FRelative proportion per experimental group of different phyla; n = 5 (RDxRDT), 5 (HFDxHFDT), 4 (HFDxRDT); Bacteroidetes; CI 99%, Firmicutes; CI 95%, Proteobacteria; CI 95%, Actinobacteria and Spirochaetes.GCompilation of compressed Z‐stack confocal images of FITC–dextran‐labeled CNV and single‐plane confocal images of isolectin B4‐stained choroidal flat mounts from RDxRDT, HFDxRDT, and HFDxHFDT mice.HQuantification of area of FITC–dextran‐labeled CNV over area of isolectin B4‐stained laser impact area fold RDxRDT; n = 6 (RDxRDT), 9 (HFDxHFDT), 9 (HFDxRDT), with 15 (RDxRDT), 21 (HFDxHFDT), 16 (HFDxRDT) burns total; CI 95%.IConcentration of gut‐absorbed Evans Blue in serum 24 h after oral administration in RD‐ and HFD‐fed mice, after RD or HFD microbiotal transplant; n = 3 (RDxRDT), 3 (HFDxHFDT), 4 (HFDxRDT); CI 95%.JmRNA expression of Il1b: n = 5 (RDxRDT), 4 (HFDxHFDT), 5 (HFDxRDT); Il6: n = 5 (RDxRDT), 4 (HFDxHFDT), 4 (HFDxRDT), CI 99%; Tnfa: n = 5 (RDxRDT), 4 (HFDxHFDT), 4 (HFDxRDT), CI 95%; and Vegfa: n = 5 (RDxRDT), 4 (HFDxHFDT), 5 (HFDxRDT), CI 95% in choroids.Data information: All comparisons between groups are analyzed using one‐way analysis of variance (ANOVA) and Tukey's multiple comparisons test; *P < 0.05, **P < 0.01, ***P < 0.001; error bars represent mean ± SEM. Each “n” represents one mouse per experimental group; in (I), both eyes were used for mRNA extraction, giving two data points per mouse; CI, confidence interval. Scale bar, 100 μm.CC BY · PubMed Central
Figure EV4 Transplantation of RD feces into HFD mice rebalances gut microbiota and improves glucose tolerance Relative abundance of bacterial phyla in gut microbiota of RDxRDT, HFDxHFDT, and HFDxRDT mice, shown per sample; n = 5 (RDxRDT), 5 (HFDxHFDT), 4 (HFDxRDT).Blood glucose (mg/dl) following intraperitoneal injection of glucose (2 mg/kg) in RDxRDT, HFDxHFDT, and HFDxRDT mice. n = 3 (RDxRDT), 2 (HFDxHFDT), 4 (HFDxRDT); CI 95%.Area under the curve (AUC) of the same groups as in (B). All comparisons between groups are analyzed using one‐way analysis of variance (ANOVA) and Tukey's multiple comparisons test; *P < 0.05; error bars represent mean ± SEM. Each “n” represents one mouse; CI, confidence interval.
Figure EV4 Transplantation of RD feces into HFD mice rebalances gut microbiota and improves glucose tolerance Relative abundance of bacterial phyla in gut microbiota of RDxRDT, HFDxHFDT, and HFDxRDT mice, shown per sample; n = 5 (RDxRDT), 5 (HFDxHFDT), 4 (HFDxRDT).Blood glucose (mg/dl) following intraperitoneal injection of glucose (2 mg/kg) in RDxRDT, HFDxHFDT, and HFDxRDT mice. n = 3 (RDxRDT), 2 (HFDxHFDT), 4 (HFDxRDT); CI 95%.Area under the curve (AUC) of the same groups as in (B). All comparisons between groups are analyzed using one‐way analysis of variance (ANOVA) and Tukey's multiple comparisons test; *P < 0.05; error bars represent mean ± SEM. Each “n” represents one mouse; CI, confidence interval.CC BY · PubMed Central
Figure 5 High‐fat diet‐induced dysbiosis increases intestinal permeability, metabolic endotoxemia, and systemic and local inflammation and ultimately contributes to CNV The ratio of Bacteroidetes and Firmicutes, the two dominant phyla in intestinal flora, decreases significantly in high‐fat diet (HFD)‐fed mice compared to regular‐chow diet (RD)‐fed mice, with a relative increase in Firmicutes in HFD‐fed mice and decrease in Bacteroidetes. This dysbiosis is accompanied by heightened intestinal permeability, which allows increased translocation of pathogen‐associated molecular patterns (PAMPs) (endotoxemia). Recognition of these microbe‐specific molecules by pattern recognition receptors (PRRs) present on innate immune cells triggers synthesis and excretion of cytokines causing chronic systemic low‐grade inflammation. Ultimately, this exacerbates CNV.
Figure 5 High‐fat diet‐induced dysbiosis increases intestinal permeability, metabolic endotoxemia, and systemic and local inflammation and ultimately contributes to CNV The ratio of Bacteroidetes and Firmicutes, the two dominant phyla in intestinal flora, decreases significantly in high‐fat diet (HFD)‐fed mice compared to regular‐chow diet (RD)‐fed mice, with a relative increase in Firmicutes in HFD‐fed mice and decrease in Bacteroidetes. This dysbiosis is accompanied by heightened intestinal permeability, which allows increased translocation of pathogen‐associated molecular patterns (PAMPs) (endotoxemia). Recognition of these microbe‐specific molecules by pattern recognition receptors (PRRs) present on innate immune cells triggers synthesis and excretion of cytokines causing chronic systemic low‐grade inflammation. Ultimately, this exacerbates CNV.CC BY · PubMed Central

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  1. Combadière C, Feumi C, Raoul W, Keller N, Rodéro M, Pézard A, Lavalette S, Houssier M, Jonet L, Picard E et al (2007) CX3CR1‐dependent subretinal microglia cell accumulation is associated with cardinal features of age‐related macular degeneration. J Clin Invest 117: 2920–2928 · DOI · Paper page

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Authors
Andriessen, E. M., Wilson, A. M., Mawambo, G., Dejda, A., Miloudi, K., Sennlaub, F., & Sapieha, P.
Affiliations
  • Hôpital Maisonneuve-Rosemont (CA)
  • Polytechnique Montréal (CA)
  • McGill University (CA)
  • Centre National de la Recherche Scientifique (FR)
Corresponding author
Sapieha, Przemyslaw
ORCID
Venue
EMBO Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2016-11-15
Volume
8
Issue
12
Pages
1366-1379
ISSN
  • 1757-4676 (ISSN-L)
  • 1757-4684
DOI
10.15252/emmm.201606531
PMC
PMC5167134
OpenAlex
W2552235278
Cited by
201
References
70
Citations by year
2026: 23 · 2025: 16 · 2024: 26 · 2023: 32 · 2022: 35 · 2021: 28 · 2020: 18 · 2019: 8 · 2018: 10 · 2017: 4 · 2016: 1
FWCI
8.14
Type
journal article
Language
en
Open access
Licence
Locations
  • EMBO Molecular Medicine (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PolyPublie (École Polytechnique de Montréal) (submittedVersion, cc-by)
  • HAL (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Foundation Fighting Blindness Canada
  • Canadian Institutes of Health Research (324573)
  • Canadian Diabetes Association (OG‐3‐11‐3329‐PS)
  • Natural Sciences and Engineering Research Council of Canada (418637)
  • Fondation de l'Avenir pour la Recherche Médicale Appliquée (RMA‐2015‐010)
Topics
  • Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
Keywords
gut microbiota, choroidal neovascularization, age-related macular degeneration, obesity, abdominal obesity, high-fat diet, gut dysbiosis, intestinal permeability, inflammaging, pathological angiogenesis, VEGF-A, low-grade inflammation, microbiota transplantation
MeSH terms
Gastrointestinal Microbiome, Fecal Microbiota Transplantation, Animals, Disease Models, Animal, Inflammation, Macular Degeneration, Neovascularization, Pathologic, Obesity, Cytokines, Choroidal Neovascularization, Gastrointestinal Tract, Mice, Diet, High-Fat, Dysbiosis

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