Effects of Dietary Selenium Supplementation on Intestinal Barrier and

Nov 26, 2018 - ... while the influences of the Se-intake-related microbiota on gut health were not thoroughly studied. This study compared the effects...
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Effects of Dietary Selenium Supplementation on Intestinal Barrier and Immune Responses Associated with Its Modulation of Gut Microbiota Qixiao Zhai,†,‡,∥,⊥,¶ Shi Cen,†,‡,¶ Peng Li,†,‡ Fengwei Tian,†,‡ Jianxin Zhao,†,‡ Hao Zhang,†,‡,§ and Wei Chen*,†,‡,§,# †

State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China § National Engineering Research Centre for Functional Food, Wuxi, Jiangsu 214122, China ∥ International Joint Research Laboratory for Probiotics at Jiangnan University, Wuxi, Jiangsu 214122, China ⊥ U.K.-China Joint Centre on Probiotic Bacteria, Norwich NR4 7UA, United Kingdom # Beijing Innovation Centre of Food Nutrition and Human Health, Beijing Technology and Business University (BTBU), Beijing 100048, China

Environ. Sci. Technol. Lett. Downloaded from pubs.acs.org by UNIV OF GOTHENBURG on 11/29/18. For personal use only.

‡

S Supporting Information *

ABSTRACT: Variations in selenium (Se) intake have been reported to affect the barrier function and immune responses in the gut. Previous studies mainly focused on the role of Se itself or its metabolites, while the influences of the Se-intake-related microbiota on gut health were not thoroughly studied. This study compared the effects of different dietary Se supplementation (Sedeficient, Se-adequate, and Se-supranutritional) on the gut microbiota of mice. Fecal microbiota transplantation (FMT) was further conducted to bypass the effect of Se itself and provided direct evidence that the effects of dietary Se supplementation on the intestinal barrier and immune responses are associated with its modulation of the gut microbiota. Deficient Se supplementation can result in a phenotype of gut microbiota that is more susceptible to dextran sulfate sodium (DSS)-induced colitis and Salmonella typhimurium infection. Sufficient or supranutritional Se intake can optimize the gut microbiota for protection against these intestinal dysfunctions.

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diseases and colorectal cancer,9,10 and dietary Se supplementation could be protective against these intestinal dysfunctions.11,12 Previous reports have showed that the beneficial functions of Se for the gut can largely be attributed to selenoproteins and Se metabolites (such as the monomethylated forms of Se), which play roles in redox homeostasis, intracellular signaling regulation, and induction of apoptosis in transformed cells.13,14 Besides these analyses, we draw attention to two previous studies showing that dietary Se supplementation can affect the composition of the gut microbiota, while the gut microbiota also influences Se bioavailability and selenoprotein expression in mice.15,16 Growing evidence has demonstrated the critical role of the gut microbiota in the physiologic and pathologic status of the host. On the basis of the potential interactions between Se

INTRODUCTION Selenium (Se) is an essential micronutrient for humans and other mammalian species. Due to the varied environmental distributions of Se resources, daily dietary Se intake in adults shows huge variations on a global scale.1 The most significant contrasts have been reported in China, with populations from Se-deficient regions being suboptimally supplied with Se (daily intake of 3−22 μg), but endemic selenosis being reported in seleniferous areas (daily intake of 240−6690 μg). To date, no well-standardized recommended dietary intake of Se has been established worldwide. Variations in Se intake have been reported to affect the immune, cardiovascular, reproductive and endocrine systems.2,3 Epidemiological and clinical studies indicated that Se deficiency is a risk factor for a range of chronic diseases,4,5 while adequate supplementation of this element can provide benefits against oxidative stress, inflammation, and carcinogenesis.6−8 The effects of Se on the gut have received growing attention recently. Several large-scale human studies indicated that Se deficiency could increase the incidence of inflammatory bowel © XXXX American Chemical Society

Received: Revised: Accepted: Published: A

October 24, 2018 November 20, 2018 November 26, 2018 November 26, 2018 DOI: 10.1021/acs.estlett.8b00563 Environ. Sci. Technol. Lett. XXXX, XXX, XXX−XXX

Letter

Environmental Science & Technology Letters

Figure 1. Effects of different Se supplementation on the Se status and gut microbiota of mice. (A) Gpx levels in the liver of mice. (B) Se concentrations in the blood of mice. (C) Boxplots of Shannon index for the gut microbiota of mice. The upper and lower lines represent the 25% and 75% quantile values, respectively. (D) Principal component analysis (PCA) plot for the genera of gut microbiota of mice. The ellipse represents the confidence region for each group. (E) Heatmap of the microbiota composition of mice. Red indicates increased genera and green indicates decreased genera. Hierarchical cluster analysis was applied to all of the genera. (F) Selected genera (Turicibacter, Dorea, and Akkermansia) whose relative abundance values were significantly altered by different Se treatments. Values are mean ± SD values of eight mice per group for Se status evaluation and six mice per group for gut microbiota analysis. *, **, and **** indicate significant differences (P < 0.05, P < 0.01 and P < 0.0001, respectively) between groups. n.s. indicates no significant differences (P > 0.05) between groups.

Therefore, this study compared the effects of different dietary Se supplementation on the gut microbiota of mice. Fecal microbiota transplantation (FMT) was further con-

intake and gut microbiota, we hypothesized that the benefits of Se supplementation on gut health may be associated with its effects on the gut microbiota. B

DOI: 10.1021/acs.estlett.8b00563 Environ. Sci. Technol. Lett. XXXX, XXX, XXX−XXX

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Environmental Science & Technology Letters

Figure 2. Effects of FMT on the intestinal barrier and immune responses in normal mice. (A) mRNA expression levels of TJ proteins including ZO-1 and claudin-1 in the colon of mice. Data are expressed as fold change versus 0.15-Se-FMT group (set to 1). (B) SCFA levels in the colonic contents of mice. (C) Levels of sIgA in the colon of mice. (D) Levels of IL-1β in the colon of mice. (E) DX-4000-FITC levels in the serum of mice. Values are mean ± SD values of six mice per group. *, **, ***, and **** indicate significant differences (P < 0.05, P < 0.01, P < 0.001, and P < 0.0001, respectively) between groups. n.s. indicates no significant differences (P > 0.05) between groups.

Animal Experiment II. Eight-week-old mice were randomly assigned to five groups with six mice per group. They were pretreated with a cocktail of antibiotics as previously described in drinking water for 3 days.18 Twentyfour hours after antibiotic treatment, mice were given the corresponding fecal transplant materials (200 μL) prepared from animal experiment I via gavage. The FMT was conducted three times during the following 7 days after antibiotic treatment. The mice were sacrificed 7 days after the final FMT. Animal Experiment III. Eight-week-old mice were randomly assigned to five groups (10 mice per group) and received FMT as mentioned in animal experiment II. After the final FMT, mice received dextran sulfate sodium (DSS) (3% w/v, at a molecular weight of 36 000−50 000, MP Biomedicals) via distilled drinking water ad libitum for 7 days.19 The weight and motility of mice were recorded daily. The mice were sacrificed at the end of the treatment or at the time point when the weight loss reached 20% of the original weights. Animal Experiment IV. Eight-week-old mice were randomly assigned to five groups (six mice per group) and received FMT as mentioned in animal experiment II. After the final FMT, mice were infected with Salmonella typhimurium (SL1344, obtained from the Culture Collections of Food Microbiology of Jiangnan University) at a dose of 5 × 107 CFU in 50 μL of phosphate buffer solution (PBS) via gavage as previously described.20 Mice were sacrificed 48 h after infection. Analysis of Biological and Pathological Alterations in Mice. The methods are described in the Supporting Information. Statistical Analysis. The data were expressed as the mean ± standard deviation (SD). Differences between the means of the test were analyzed using one-way analysis of variance,

ducted to analyze how Se-intake-related changes in gut microbiota affect gut health.

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MATERIALS AND METHODS Animals and Experimental Diets. Male C57BL/6 mice purchased from the Shanghai Laboratory Animal Center (Shanghai, China) were used in all of the experiments. The mice were kept in specific pathogen-free (SPF) conditions in the animal experiment center in Jiangnan University. All of the protocols for this study were approved by the Ethics Committee of Jiangnan University, China (JN No.201509101219[64], JN No.20160818-20161016[59], and JN No. 20170323-20170615[33]). The procedures of this study were carried out in accordance with the European Community guidelines (directive 2010/63/EU) for the care and use of experimental animals. The experimental diets with different Se levels were obtained from Trophic Animal Feed High-tech Co. (Suzhou, China). The Se-deficient diet (Se-D) contained Se at a level 0.05) between groups.

Significant increases in the levels of Turicibacter and Akkermansia and decreases in the level of Mucispirillum were detected in mice supplied with supranutritional Se (0.40-Se diet) when compared with results for mice receiving Sesufficient (0.15-Se) diet (Figures 1F and S1). Turicibacter has been reported to display potential anti-inflammatory activities in the gut, and high levels of these bacteria were also observed in mutant mice that were resistant to colitis.25,26 The increase in intestinal Akkermansia abundance after supranutritional Se supplementation was in line with a previous report.15 A number of recent studies have provided evidence that Akkermansia plays an important role in the gut barrier protection, immune modulation, and metabolic regulation of the host.27 The abundance of this genus inversely correlates with the onset of various physiological dysfunctions including inflammatory bowel disease, obesity, and diabetes.28,29 Mucispirillum is believed to be sensitive to the mucin production of the host and marked increases of these bacteria have been associated with helminth infection.30 Animal Experiment II: Transplantation of Fecal Microbiota from Different Se-Supplied Donors Showed Varied Effects on the Intestinal Barrier and Immune Responses in Normal Mice. Se-D-FMT induced a lower

followed by Tukey’s post hoc test. A P value of 0.05, Figure 1C). However, different Se intakes induced significant changes in the compositions of the gut microbiota (Figure 1D,E). At the genus level, the Se-D diet induced marked increases in the level of Dorea (P < 0.05, Figure 1F) when compared with the Se-sufficient diet (0.15-Se). Dorea sp. is one of the populous species of the gut microbiota and produces both hydrogen and carbon dioxide in the intestines.21 The abundance of Dorea was previously found to be increased in patients diagnosed with irritable bowel syndrome,22 multiple sclerosis,23 and nonalcoholic fatty liver,24 indicating potential adverse health effects of the overgrowth of this genus. D

DOI: 10.1021/acs.estlett.8b00563 Environ. Sci. Technol. Lett. XXXX, XXX, XXX−XXX

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Environmental Science & Technology Letters

Figure 4. Effects of FMT on the intestinal barrier and immune responses in ST-treated mice. (A) ST load in the mLNs, liver, and spleen of mice. (B) mRNA expression levels of TJ proteins including ZO-1 and claudin-1 in the colon of mice. Data are expressed as fold change versus 0.15-SeFMT group (set to 1). (C) DX-4000-FITC levels in the serum of mice. (D) Levels of endotoxin in the serum of mice. (E)−(G) Biomarkers related to immune responses including IL-1β (E), IL-6 (F), and TNF-α (G) in the colon of mice. Values are mean ± SD values of six mice per group. *, **, ***, and **** indicate significant differences (P < 0.05, P < 0.01, P < 0.001, and P < 0.0001, respectively) between groups. n.s. indicates no significant differences (P > 0.05) between groups.

the effect of Se itself and provide direct evidence that the effects of dietary Se supplementation on intestinal barrier and immune responses are associated with its modulation of the gut microbiota. Variations in the gut microbiota, along with its metabolites (such as SCFAs), have been reported to affect the function of TJ proteins, the responses of intestinal immune system and the metabolism of epithelial cells, which further influenced the gut permeability and systemic circulation.32,33 This may explain the findings of the present trial that mice treated with different FMTs showed varied gut barrier status and immune response. Animal Experiment III: Mice Colonized with Gut Microbiota from Different Se-Supplied Donors Showed Varied Resistance to DSS-Induced Colitis. The survival rates of DSS-treated mice in Se-D-FMT, 0.15-Se-FMT, and 0.40-Se-FMT groups were 60%, 80%, and 100%, respectively (Figure 3A). Mice colonized with the gut microbiota from deficient Se-supplied donors showed more severe symptoms of colitis when compared with mice in 0.15-Se-FMT and 0.40-SeFMT groups, as indicated by the disease activity index (DAI) and colitis damage scores (Figure 3B,C). Compared with the other two groups, Se-D-FMT significantly increased the gut

level of mRNA expression of ZO-1 and claudin-1, two TJ proteins playing a role in the gut barrier function,31 in the colon of mice when compared with results of the 0.15-Se-FMT and 0.40-Se-FMT treatments (Figure 2A), while other tight junctions (TJs) were not differentially affected by these three FMTs (Figure S2A). Similar alterations in the levels of shortchain fatty acids (SCFAs) were also observed in the colonic contents of mice colonized with different gut microbiota (Figure 2B). Among these SCFAs, butanoic acid and isobutyric acid were most significantly affected (P < 0.05, Table S1). The levels of sIgA and IL-1β were markedly altered by different FMTs (Figure 2C,D), while the other detected biomarkers related to immune responses in colon remained unchanged (Figure S2C−F). No significant differences in the levels of serum DX-4000-FITC (Figure 2E) and endotoxin (Figure S2B) were observed among the three groups. The effects of dietary Se supplementation against inflammation and cancer in the gut have been well documented.9,19 These studies mainly focused on the role of Se itself or the in vivo Se-metabolites, while the influences of the Se-intakerelated microbiota on gut health were not thoroughly studied. In the present study, FMT treatments were applied to bypass E

DOI: 10.1021/acs.estlett.8b00563 Environ. Sci. Technol. Lett. XXXX, XXX, XXX−XXX

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Environmental Science & Technology Letters

Se intake can optimize the gut microbiota for protection against intestinal dysfunctions.

permeability of DSS-treated mice, as indicated by the higher levels of serum DX-4000-FITC and endotoxin and lower levels of colonic TJ mRNA expression (Figure 3D−F). The levels of biomarkers related to immune responses (IL-1β, IL-6, IL-8, and TNF-α, Figure 3G−J) and oxidative stress (MDA and GPx, Table S2) in the colon were also markedly altered by different FMT treatments. The levels of ZO-2 mRNA expression, IL-10, and sIgA in the colon were not differentially affected by the three FMT treatments (Figure S3). Gut microbiota is a key determinant of the onset and severity of DSS-induced colitis34 and the transplantation of fecal microbiota from healthy donors can effectively alleviate this colitis in mice.35 Compared with the Se-deficient diet, supranutritional Se supplementation significantly decreased the abundance of Dorea and increased the levels of microbes with potential protective effects against colitis and gut barrier dysfunction such as Turicibacter and Akkermansia (Figure 1F). This may explain the findings that 0.40-Se-FMT was the most protective against DSS-induced colitis and Se-D-FMT treatment was the least effective. Animal Experiment IV: Mice Colonized with Gut Microbiota from Different Se-Supplied Donors Showed Varied Resistance to Salmonella typhimurium (ST) Infection. Colonization and invasion by pathogens including ST have been reported to be related with the microbiota, immune system, and barrier function of the gut.36 Compared with the Se-D-FMT group, transplantation of microbiota from the sufficient and supranutritional Se-supplied donors significantly decreased ST loads in the tissues of mice (Figure 4A). Mice in the Se-D-FMT group showed poorer gut barrier function (Figure 4B−D) and more severe intestinal inflammation (Figure 4E−G) after ST infection than those in the other two groups. These results were in line with those from DSS-challenged animal trial. The mRNA expression of ZO-2 and occludin levels of IL-8, IL-10, and sIgA in colon were not differentially affected by the three FMT treatments (Figure S4). FMT induced more significant effects on mice treated with DSS or ST than on normal mice. This may demonstrate that, relative to the typical gut microbiota, altered microbiota induced by different Se supplementations may especially play a role in the onset of intestinal disorders. Compared with mice from the other two groups, mice in Se-D-FMT group showed more severe gut barrier dysfunction, intestinal inflammation, and histological injury, indicating that the gut microbiota from Se-deficient donors was more sensitive to xenobiotics. A high Se intake may be advisible for the prevention and alleviation of intestinal dysfunctions, as 0.40-Se-FMT provided more significant protection than 0.15-Se-FMT. The gender-specific effects and other immune-response related biomarkers such as the ratio of foxp3+/CD4+ will in evaluated in the following study to further understand the effects of Se-associated gut microbiota on intestinal immune status.37,38 In conclusion, this study provided evidence that alterations to the gut microbiota induced by dietary Se supplementation could affect the gut barrier and immune responses of the host. Our results were comparable to previous studies using identical strains and genders of mice,15,39 showing that the mechanism is at least partly due to the effects of the altered gut microbiota, independent of the direct effects of Se on the gut, as evidenced by FMT. Deficient Se supplementation may result in a phenotype of gut microbiota that is more susceptible to DSSinduced colitis and ST-infection. Sufficient or supranutritional

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.estlett.8b00563.

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Detailed methods for the process of four animal trials and the determination of parameters related to the biological and pathological alterations in mice; some genera of gut microbiota that were significantly altered by different Se treatments (Figure S1); biomarkers that were not significantly altered in normal (Figure S2), DSS-treated (Figure S3), and ST-infected (Figure S4) mice receiving different FMT treatments; concentrations of SCFAs in the colonic contents of mice (Table S1); effects of FMT on colonic oxidative stress status in DSStreated mice (Table S2) (PDF)

AUTHOR INFORMATION

Corresponding Author

*Wei Chen. E-mail: [email protected]. Phone: (86) 510-85912155. Fax: (86)510-85912155. ORCID

Qixiao Zhai: 0000-0003-1415-7247 Jianxin Zhao: 0000-0002-7414-9030 Wei Chen: 0000-0003-3348-4710 Author Contributions ¶

These authors contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of Jiangsu Province (BK20160175), National Natural Science Foundation of China Program (No. 31871773, 31530056, and 31820103010), National FirstClass Discipline Program of Food Science and Technology (JUFSTR20180102), Collaborative innovation center of food safety and quality control in Jiangsu Province, and BBSRC Newton Fund Joint Centre Award (BB/J004529/1).

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DOI: 10.1021/acs.estlett.8b00563 Environ. Sci. Technol. Lett. XXXX, XXX, XXX−XXX