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Comparative Study
. 2010 May;24(4):631-40.
doi: 10.1016/j.bbi.2010.01.015. Epub 2010 Feb 6.

Sickness behavior induced by endotoxin can be mitigated by the dietary soluble fiber, pectin, through up-regulation of IL-4 and Th2 polarization

Christina L Sherry  1 , Stephanie S Kim, Ryan N Dilger, Laura L Bauer, Morgan L Moon, Richard I Tapping, George C Fahey Jr, Kelly A Tappenden, Gregory G Freund
Affiliations
Comparative Study

Sickness behavior induced by endotoxin can be mitigated by the dietary soluble fiber, pectin, through up-regulation of IL-4 and Th2 polarization

Christina L Sherry et al. Brain Behav Immun. 2010 May.

Abstract

Peripheral activation of the immune system by infectious agents triggers the brain-cytokine system causing sickness behaviors which profoundly impact well-being. Dietary fiber is a beneficial foodstuff that, from a gastrointestinal tract perspective, exists in both insoluble and soluble forms. We show that a diet rich in soluble fiber protects mice from endotoxin-induced sickness behavior by polarizing mice Th2 when compared to a diet containing only insoluble fiber. Mice fed soluble fiber became less sick and recovered faster from endotoxin-induced sickness behaviors than mice fed insoluble fiber. In response to intraperitoneal endotoxin, mice fed soluble fiber had up-regulated IL-1RA and reduced IL-1beta and TNF-alpha in the brain as compared to mice fed insoluble fiber. Importantly, mice fed soluble fiber had a basal increase in IL-4 in the ileum and spleen which was absent in MyD88 knockout mice. Con-A stimulated splenocytes from mice fed soluble fiber showed increased IL-4 and IL-5 and decreased IL-2, IL-12 and IFN-gamma when compared to mice fed insoluble fiber. Likewise, endotoxin-stimulated macrophages from mice fed soluble fiber demonstrated decreased IL-1beta, TNF-alpha, IFN-gamma, IL-12 and nitrate and increased IL-1RA, arginase 1 and Ym1 when compared to mice fed insoluble fiber. Finally, the behavioral protection afforded by feeding mice soluble fiber was reduced in IL-4 knockout mice, as was the impact of soluble fiber on Con-A stimulated splenocytes and endotoxin activated macrophages. These data show that a diet rich in soluble fiber protects against endotoxin-induced sickness behavior by polarizing mice Th2 and promoting alternative activation of macrophages.

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Figures

Fig. 1
Fig. 1. Soluble fiber protects against endotoxemia
A, Chow and 5% cellulose (cellulose) fed mice were administered carrier (PBS) or LPS IP and social withdrawal measured prior to LPS (0 h) and at 2, 4, 8 and 12 h post LPS. Results are expressed as percentage change from the 0 h measurement, means ± SEM; n = 8; *p<0.05, main effect of diet, #p<0.05, treatment effect of LPS. B, 10% pectin (pectin) and cellulose fed mice were administered LPS IP and social withdrawal measured prior to LPS (0 h) and at 2, 4, 8 and 12 h post LPS. Results are expressed as percentage change from the 0 h measurement, means ± SEM; n = 8; *p<0.05, main effect of diet, #p<0.05, treatment effect of LPS. C, Pectin and cellulose fed mice were administered LPS IP (0 h) and temperature measured. Results are expressed as a change from pre-LPS (0 h) measurement, means ± SEM; n = 4; arrowp<0.05, main effect of time. D, Pectin and cellulose fed mice were administered LPS IP and food intake and body weight measured 24 h post LPS. Results are expressed as percentage change from the pre-LPS measurement, means ± SEM; n = 4; *p<0.05, main effect of diet. E, Pectin and 10% cellulose fed mice were administered LPS IP and social withdrawal measured prior to LPS (0 h) and at 2, 4, 8 and 12 h post LPS. Results are expressed as percentage change from the 0 h measurement, means ± SEM; n = 8; *p<0.05, main effect of diet, #p<0.05, treatment effect of LPS
Fig. 1
Fig. 1. Soluble fiber protects against endotoxemia
A, Chow and 5% cellulose (cellulose) fed mice were administered carrier (PBS) or LPS IP and social withdrawal measured prior to LPS (0 h) and at 2, 4, 8 and 12 h post LPS. Results are expressed as percentage change from the 0 h measurement, means ± SEM; n = 8; *p<0.05, main effect of diet, #p<0.05, treatment effect of LPS. B, 10% pectin (pectin) and cellulose fed mice were administered LPS IP and social withdrawal measured prior to LPS (0 h) and at 2, 4, 8 and 12 h post LPS. Results are expressed as percentage change from the 0 h measurement, means ± SEM; n = 8; *p<0.05, main effect of diet, #p<0.05, treatment effect of LPS. C, Pectin and cellulose fed mice were administered LPS IP (0 h) and temperature measured. Results are expressed as a change from pre-LPS (0 h) measurement, means ± SEM; n = 4; arrowp<0.05, main effect of time. D, Pectin and cellulose fed mice were administered LPS IP and food intake and body weight measured 24 h post LPS. Results are expressed as percentage change from the pre-LPS measurement, means ± SEM; n = 4; *p<0.05, main effect of diet. E, Pectin and 10% cellulose fed mice were administered LPS IP and social withdrawal measured prior to LPS (0 h) and at 2, 4, 8 and 12 h post LPS. Results are expressed as percentage change from the 0 h measurement, means ± SEM; n = 8; *p<0.05, main effect of diet, #p<0.05, treatment effect of LPS
Fig. 1
Fig. 1. Soluble fiber protects against endotoxemia
A, Chow and 5% cellulose (cellulose) fed mice were administered carrier (PBS) or LPS IP and social withdrawal measured prior to LPS (0 h) and at 2, 4, 8 and 12 h post LPS. Results are expressed as percentage change from the 0 h measurement, means ± SEM; n = 8; *p<0.05, main effect of diet, #p<0.05, treatment effect of LPS. B, 10% pectin (pectin) and cellulose fed mice were administered LPS IP and social withdrawal measured prior to LPS (0 h) and at 2, 4, 8 and 12 h post LPS. Results are expressed as percentage change from the 0 h measurement, means ± SEM; n = 8; *p<0.05, main effect of diet, #p<0.05, treatment effect of LPS. C, Pectin and cellulose fed mice were administered LPS IP (0 h) and temperature measured. Results are expressed as a change from pre-LPS (0 h) measurement, means ± SEM; n = 4; arrowp<0.05, main effect of time. D, Pectin and cellulose fed mice were administered LPS IP and food intake and body weight measured 24 h post LPS. Results are expressed as percentage change from the pre-LPS measurement, means ± SEM; n = 4; *p<0.05, main effect of diet. E, Pectin and 10% cellulose fed mice were administered LPS IP and social withdrawal measured prior to LPS (0 h) and at 2, 4, 8 and 12 h post LPS. Results are expressed as percentage change from the 0 h measurement, means ± SEM; n = 8; *p<0.05, main effect of diet, #p<0.05, treatment effect of LPS
Fig. 1
Fig. 1. Soluble fiber protects against endotoxemia
A, Chow and 5% cellulose (cellulose) fed mice were administered carrier (PBS) or LPS IP and social withdrawal measured prior to LPS (0 h) and at 2, 4, 8 and 12 h post LPS. Results are expressed as percentage change from the 0 h measurement, means ± SEM; n = 8; *p<0.05, main effect of diet, #p<0.05, treatment effect of LPS. B, 10% pectin (pectin) and cellulose fed mice were administered LPS IP and social withdrawal measured prior to LPS (0 h) and at 2, 4, 8 and 12 h post LPS. Results are expressed as percentage change from the 0 h measurement, means ± SEM; n = 8; *p<0.05, main effect of diet, #p<0.05, treatment effect of LPS. C, Pectin and cellulose fed mice were administered LPS IP (0 h) and temperature measured. Results are expressed as a change from pre-LPS (0 h) measurement, means ± SEM; n = 4; arrowp<0.05, main effect of time. D, Pectin and cellulose fed mice were administered LPS IP and food intake and body weight measured 24 h post LPS. Results are expressed as percentage change from the pre-LPS measurement, means ± SEM; n = 4; *p<0.05, main effect of diet. E, Pectin and 10% cellulose fed mice were administered LPS IP and social withdrawal measured prior to LPS (0 h) and at 2, 4, 8 and 12 h post LPS. Results are expressed as percentage change from the 0 h measurement, means ± SEM; n = 8; *p<0.05, main effect of diet, #p<0.05, treatment effect of LPS
Fig. 1
Fig. 1. Soluble fiber protects against endotoxemia
A, Chow and 5% cellulose (cellulose) fed mice were administered carrier (PBS) or LPS IP and social withdrawal measured prior to LPS (0 h) and at 2, 4, 8 and 12 h post LPS. Results are expressed as percentage change from the 0 h measurement, means ± SEM; n = 8; *p<0.05, main effect of diet, #p<0.05, treatment effect of LPS. B, 10% pectin (pectin) and cellulose fed mice were administered LPS IP and social withdrawal measured prior to LPS (0 h) and at 2, 4, 8 and 12 h post LPS. Results are expressed as percentage change from the 0 h measurement, means ± SEM; n = 8; *p<0.05, main effect of diet, #p<0.05, treatment effect of LPS. C, Pectin and cellulose fed mice were administered LPS IP (0 h) and temperature measured. Results are expressed as a change from pre-LPS (0 h) measurement, means ± SEM; n = 4; arrowp<0.05, main effect of time. D, Pectin and cellulose fed mice were administered LPS IP and food intake and body weight measured 24 h post LPS. Results are expressed as percentage change from the pre-LPS measurement, means ± SEM; n = 4; *p<0.05, main effect of diet. E, Pectin and 10% cellulose fed mice were administered LPS IP and social withdrawal measured prior to LPS (0 h) and at 2, 4, 8 and 12 h post LPS. Results are expressed as percentage change from the 0 h measurement, means ± SEM; n = 8; *p<0.05, main effect of diet, #p<0.05, treatment effect of LPS
Fig. 2
Fig. 2. Soluble fiber up-regulates IL-1RA
10% pectin (pectin) and 5% cellulose (cellulose) fed mice were administered carrier (PBS) or LPS IP. At 2 h post LPS, real-time RT-PCR was used to quantify IL-1RA (A), IL-1β(B), TNF-α(B) and IL-6 (B) mRNAs from brain. Results are expressed as relative change in mRNA expression ( mRNA), means ± SEM; n = 6-8; *p<0.05 main effect of diet, #p<0.05 treatment effect of LPS.
Fig. 2
Fig. 2. Soluble fiber up-regulates IL-1RA
10% pectin (pectin) and 5% cellulose (cellulose) fed mice were administered carrier (PBS) or LPS IP. At 2 h post LPS, real-time RT-PCR was used to quantify IL-1RA (A), IL-1β(B), TNF-α(B) and IL-6 (B) mRNAs from brain. Results are expressed as relative change in mRNA expression ( mRNA), means ± SEM; n = 6-8; *p<0.05 main effect of diet, #p<0.05 treatment effect of LPS.
Fig. 3
Fig. 3. IL-4 production is augmented by soluble fiber
Mice were fed 10% pectin (pectin) or 5% cellulose (cellulose) for 6 wks. A, Real-time RT-PCR was used to quantify IL-4 mRNAs from the indicated tissues. Results are expressed as relative change in mRNA expression (ΔmRNA), means ± SEM; n = 6-8; *p<0.05 main effect of diet. B, ELISA was used to quantify IL-4 from the indicated tissues. Results are expressed as means ± SEM; n = 5-7; *p<0.05 main effect of diet. C, Wild type (WT) and MyD88 KO mice were fed 10% pectin (pectin) or 5% cellulose (cellulose) for 6 wks. Real-time RT-PCR was used to quantify IL-4 mRNAs from the indicated tissues. Results are expressed as relative change in mRNA expression (ΔmRNA), means ± SEM; n = 3; *p<0.05 main effect of diet.
Fig. 3
Fig. 3. IL-4 production is augmented by soluble fiber
Mice were fed 10% pectin (pectin) or 5% cellulose (cellulose) for 6 wks. A, Real-time RT-PCR was used to quantify IL-4 mRNAs from the indicated tissues. Results are expressed as relative change in mRNA expression (ΔmRNA), means ± SEM; n = 6-8; *p<0.05 main effect of diet. B, ELISA was used to quantify IL-4 from the indicated tissues. Results are expressed as means ± SEM; n = 5-7; *p<0.05 main effect of diet. C, Wild type (WT) and MyD88 KO mice were fed 10% pectin (pectin) or 5% cellulose (cellulose) for 6 wks. Real-time RT-PCR was used to quantify IL-4 mRNAs from the indicated tissues. Results are expressed as relative change in mRNA expression (ΔmRNA), means ± SEM; n = 3; *p<0.05 main effect of diet.
Fig. 3
Fig. 3. IL-4 production is augmented by soluble fiber
Mice were fed 10% pectin (pectin) or 5% cellulose (cellulose) for 6 wks. A, Real-time RT-PCR was used to quantify IL-4 mRNAs from the indicated tissues. Results are expressed as relative change in mRNA expression (ΔmRNA), means ± SEM; n = 6-8; *p<0.05 main effect of diet. B, ELISA was used to quantify IL-4 from the indicated tissues. Results are expressed as means ± SEM; n = 5-7; *p<0.05 main effect of diet. C, Wild type (WT) and MyD88 KO mice were fed 10% pectin (pectin) or 5% cellulose (cellulose) for 6 wks. Real-time RT-PCR was used to quantify IL-4 mRNAs from the indicated tissues. Results are expressed as relative change in mRNA expression (ΔmRNA), means ± SEM; n = 3; *p<0.05 main effect of diet.
Fig. 4
Fig. 4. Arginase and Ym1 expression in peritoneal macrophages
Mice were fed 10% pectin (pectin) or 5% cellulose (cellulose) for 6 wks. Real-time RT-PCR was used to quantify arginase (Arg) and Ym1 mRNAs from peritoneal macrophages. Results are expressed as relative change in mRNA expression (ΔmRNA), means ± SEM; n = 6-8; *p
Fig. 5
Fig. 5. IL-4 knockout (KO) blunts the impact of soluble fiber on endotoxemia resistance
A, 10% pectin (pectin) and 5% cellulose (cellulose) fed wild type (WT) and IL-4 KO mice were administered carrier (PBS) or LPS IP and social withdrawal measured at 2 h post LPS. Results are expressed as percentage change from cellulose PBS WT mice, means ± SEM; n = 3-4; #p<0.05, treatment effect of LPS, *p<0.05 main effect of diet, $p<0.05 phenotype effect. B, IL-4 KO mice were fed 10% pectin (pectin) or 5% cellulose (cellulose) for 6 wks. Real-time RT-PCR was used to quantify arginase (Arg) and Ym1 mRNAs from peritoneal macrophages. Results are expressed as relative change in mRNA expression (ΔmRNA), means ± SEM; n = 3; *p<0.05 main effect of diet.
Fig. 5
Fig. 5. IL-4 knockout (KO) blunts the impact of soluble fiber on endotoxemia resistance
A, 10% pectin (pectin) and 5% cellulose (cellulose) fed wild type (WT) and IL-4 KO mice were administered carrier (PBS) or LPS IP and social withdrawal measured at 2 h post LPS. Results are expressed as percentage change from cellulose PBS WT mice, means ± SEM; n = 3-4; #p<0.05, treatment effect of LPS, *p<0.05 main effect of diet, $p<0.05 phenotype effect. B, IL-4 KO mice were fed 10% pectin (pectin) or 5% cellulose (cellulose) for 6 wks. Real-time RT-PCR was used to quantify arginase (Arg) and Ym1 mRNAs from peritoneal macrophages. Results are expressed as relative change in mRNA expression (ΔmRNA), means ± SEM; n = 3; *p<0.05 main effect of diet.
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