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. 2018 Feb 1;148(2):209-219.
doi: 10.1093/jn/nxx027.

Blueberry Supplementation Influences the Gut Microbiota, Inflammation, and Insulin Resistance in High-Fat-Diet-Fed Rats

Sunhye Lee  1 , Katherine I Keirsey  1 , Rebecca Kirkland  1 , Zachary I Grunewald  1 , Joan G Fischer  1 , Claire B de La Serre  1
Affiliations

Blueberry Supplementation Influences the Gut Microbiota, Inflammation, and Insulin Resistance in High-Fat-Diet-Fed Rats

Sunhye Lee et al. J Nutr. .

Abstract

Background: Gut microbiota dysbiosis has been linked to obesity-associated chronic inflammation. Microbiota manipulation may therefore affect obesity-related comorbidities. Blueberries are rich in anthocyanins, which have anti-inflammatory properties and may alter the gut microbiota.

Objective: We hypothesized that blueberry supplementation would alter the gut microbiota, reduce systemic inflammation, and improve insulin resistance in high-fat (HF)-diet-fed rats.

Methods: Twenty-four male Wistar rats (260-270 g; n = 8/group) were fed low-fat (LF; 10% fat), HF (45% fat), or HF with 10% by weight blueberry powder (HF_BB) diets for 8 wk. LF rats were fed ad libitum, whereas HF and HF_BB rats were pair-fed with diets matched for fiber and sugar contents. Glucose tolerance, microbiota composition (16S ribosomal RNA sequencing), intestinal integrity [villus height, gene expression of mucin 2 (Muc2) and β-defensin 2 (Defb2)], and inflammation (gene expression of proinflammatory cytokines) were assessed.

Results: Blueberry altered microbiota composition with an increase in Gammaproteobacteria abundance (P < 0.001) compared with LF and HF rats. HF feeding led to an ∼15% decrease in ileal villus height compared with LF rats (P < 0.05), which was restored by blueberry supplementation. Ileal gene expression of Muc2 was ∼150% higher in HF_BB rats compared with HF rats (P < 0.05), with expression in the LF group not being different from that in either the HF or HF_BB groups. Tumor necrosis factor α (Tnfa) and interleukin 1β (Il1b) gene expression in visceral fat was increased by HF feeding when compared with the LF group (by 300% and 500%, respectively; P < 0.05) and normalized by blueberry supplementation. Finally, blueberry improved markers of insulin sensitivity. Hepatic insulin receptor substrate 1 (IRS1) phosphorylation at serine 307:IRS1 ratio was ∼35% higher in HF rats compared with LF rats (P < 0.05) and HF_BB rats.

Conclusion: In HF-diet-fed male rats, blueberry supplementation led to compositional changes in the gut microbiota associated with improvements in systemic inflammation and insulin signaling.

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Figures

FIGURE 1
FIGURE 1
Body weight (A), adiposity index (B), blood glucose (C), and serum insulin (D) during an oral-glucose-tolerance test (2 mg/kg) in rats fed an LF, HF, or HF_BB diet for 8 wk. Values are means ± SEMs, n = 8/group. Labeled means at a time without a common letter differ, P < 0.05. HF, high fat; HF_BB, high fat with 10% blueberry; LF, low fat.
FIGURE 2
FIGURE 2
Microbial composition of rats fed an LF, HF, or HF_BB diet for 8 wk. The bacterial relative abundances at the phylum (A), class (B), order (C), family (D), and genus (E) levels and principal components analysis on all taxonomic levels (F) are shown. n = 8. *,**,***Differences between the HF_BB group and the LF and HF groups: *P < 0.05, **P < 0.01, ***P < 0.001. ##Differences between the LF and HF groups, P < 0.01. Bacteria in any shade of green belong to the Firmicutes phylum, shades of red indicate Bacteriodetes, yellow indicates Proteobacteria, purple indicates Verrucomicrobia, and blue indicates Fusobacteria. The phylogenic tree (phylum, class, order, and family in order) is indicated by the letters preceding the taxa. Phylum: F, Firmicutes; B, Bacteriodetes; Fu, Fusobacteria; D, Deferribacteres; V, Verrucomicrobia; P, Proteobacteria. Class: C, Clostridia; B, Bacilli; N, Negativictes; E, Erysipelotrichia; B, Bacteriodetes; F, Flavobacteria; γ, Gammaproteobacteria. Order: C, Clostridiales; L, Lactobacillales; S, Selenomonadales; E, Erysipelotrichiales; B, Bacteriales; F, Flavobacteriales; F, Fusobacteriales; D, Deferribacteriales; V, Verrucomicrobiales; P, Pasteurellales. Family: C, Clostridiaceae; R, Ruminococcaceae; S, Streptococcaceae; V, Veillonellaceae; P, Prevetollaceae; F, Flavobacteriaceae; V, Verrucomicrobiaceae; P, Pasteurellaceae. HF, high fat; HF_BB, high fat with 10% blueberry; LF, low fat; PC, principal component.
FIGURE 3
FIGURE 3
Serum SCFAs (A) and gene expression of Gpr43 and Glp1 in the ileum (B) of rats fed an LF, HF, or HF_BB diet for 8 wk. Values are means ± SEMs, n = 8. Labeled means without a common letter differ, P < 0.05. Glp1, glucagon-like peptide 1; Gpr43, G-protein-coupled receptor 43; HF, high fat; HF_BB, high fat with 10% blueberry; LF, low fat.
FIGURE 4
FIGURE 4
Villus length (A), goblet cells/crypt (B), Defb2 and Muc2 gene expression (C), and gene expression of inflammatory markers (D) in the ileum of rats fed an LF, HF, or HF_BB diet for 8 wk. Values are means ± SEMs, n = 8. Labeled means without a common letter differ, P < 0.05. Cd11d, cluster of differentiation 11d; Cd68, cluster of differentiation 68; Defb2, β-defensin 2; HF, high fat; HF_BB, high fat with 10% blueberry; Il1b, interleukin 1β; Il6, interleukin 6; LF, low fat; Muc2, mucin 2; Tnfa, tumor necrosis factor α.
FIGURE 5
FIGURE 5
Circulating LPS (A), NF-κB p65 phosphorylation (B), gene expression of inflammatory markers (C), and gene expression of Ppara and Ppard (D) in adipose tissue of rats fed an LF, HF, or HF_BB diet for 8 wk. Values are means ± SEMs; n = 8, except for (B), n = 4–6. Labeled means without a common letter differ, P < 0.05. Cd11d, cluster of differentiation 11d; Cd68, cluster of differentiation 68; HF, high fat; HF_BB, high fat with 10% blueberry; Il1b, interleukin 1β; Il6, interleukin 6; LBP, LPS-binding protein; LF, low fat; Ppara, peroxisome proliferator-activated receptor α; Ppard, peroxisome proliferator-activated receptor δ; Tnfa, tumor necrosis factor α.
FIGURE 6
FIGURE 6
Histology (A, B), IRS1 phosphorylation (C, D), and MDA (E) in the liver and urinary F2-isoprostanes (F) of rats fed an LF, HF, or HF_BB diet for 8 wk. Values are means ± SEMs, n = 8; except for (A, B), n = 6–8. Labeled means without a common letter differ, P < 0.05. HF, high fat; HF_BB, high fat with 10% blueberry; IRS1, insulin receptor substrate 1; LF, low fat; MDA, malondialdehyde; p-IRS1(Ser307), insulin receptor substrate1 phosphorylation at serine 307.
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