Diet-induced obesity exacerbates imiquimod-mediated psoriasiform dermatitis in anti-PD-1 antibody-treated mice: Implications for patients being treated with checkpoint inhibitors for cancer

Yu, Sebastian; Wu, Xuesong; Shi, Zhengang; Huynh, Mindy; Jena, Prasant Kumar; Sheng, Lili; Zhou, Yan; Han, Dan; Wan, Yu; Hwang, Samuel T

doi:10.1016/j.jdermsci.2020.01.011

Cited by 37 publications

(31 citation statements)

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“…IL-17A is implicated in the development of chronic inflammatory diseases in the brain, skin, and liver as well as liver cancer [ 31 – 34 ]. FPC diet-fed mice had increased mRNA level of Rorγt , a transcriptional factor for Il-17 expression, accompanied by elevated hepatic protein levels of IL-17A and TNFα as well as mRNA levels of Il6 , Il1β, and Tgfβ , which generate Th17 cells; inulin supplementation prevented these changes (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Increased IL-17A is also found in mouse models of Alzheimer’s diseases and hepatic fibrosis [ 43 , 44 ]. Moreover, our recent publication shows that short-term feeding of another WD leads to T helper type 1−/T helper type 17-biased skin inflammation before significant body weight gain is noted [ 31 ]. WD intake for 4 weeks promotes mild dermatitis and accumulation of IL-17A-producing γδ T cells in the skin.…”

Section: Discussionmentioning

confidence: 99%

“…WD intake for 4 weeks promotes mild dermatitis and accumulation of IL-17A-producing γδ T cells in the skin. Furthermore, supplementation with cholestyramine, a BA sequestrant, can prevent skin inflammation along with a reduction in the infiltration of γδ T cells and the expression of proinflammatory mediators [ 31 ]. The differentiation of Th17 cells relies on a variety of cytokines, and transcriptional factors such as RORγt and TGFβ in synergy with IL6 are critical for generating Th17 cells [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

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Dysregulated bile acid receptor-mediated signaling and IL-17A induction are implicated in diet-associated hepatic health and cognitive function

et al. 2020

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Background Chronic consumption of high sugar and high fat diet associated with liver inflammation and cognitive decline. This paper tests a hypothesis that the development and resolution of diet-induced nonalcoholic fatty liver disease (NAFLD) has an impact on neuroplasticity and cognition. Methods C57BL/6 wild-type mice were fed with either a healthy control diet (CD) or a fructose, palmitate, and cholesterol (FPC)-enriched diet since weaning. When mice were 3-months old, FPC diet-fed mice were randomly assigned to receive either FPC-enriched diet with or without 6% inulin supplementation. At 8 months of age, all three groups of mice were euthanized followed by analysis of inflammatory signaling in the liver and brain, gut microbiota, and cecal metabolites. Results Our data showed that FPC diet intake induced hepatic steatosis and inflammation in the liver and brain along with elevated RORγ and IL-17A signaling. Accompanied by microglia activation and reduced hippocampal long-term potentiation, FPC diet intake also reduced postsynaptic density-95 and brain derived neurotrophic factor, whereas inulin supplementation prevented diet-reduced neuroplasticity and the development of NAFLD. In the gut, FPC diet increased Coriobacteriaceae and Erysipelotrichaceae, which are implicated in cholesterol metabolism, and the genus Allobaculum, and inulin supplementation reduced them. Furthermore, FPC diet reduced FXR and TGR5 signaling, and inulin supplementation reversed these changes. Untargeted cecal metabolomics profiling uncovered 273 metabolites, and 104 had significant changes due to FPC diet intake or inulin supplementation. Among the top 10 most affected metabolites, FPC-fed mice had marked increase of zymosterol, a cholesterol biosynthesis metabolite, and reduced 2,8-dihydroxyquinoline, which has known benefits in reducing glucose intolerance; these changes were reversible by inulin supplementation. Additionally, the abundance of Barnesiella, Coprobacter, Clostridium XIVa, and Butyrivibrio were negatively correlated with FPC diet intake and the concentration of cecal zymosterol but positively associated with inulin supplementation, suggesting their benefits. Conclusion Taken together, the presented data suggest that diet alters the gut microbiota and their metabolites, including bile acids. This will subsequently affect IL-17A signaling, resulting in systemic impacts on both hepatic metabolism and cognitive function.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Dysregulated bile acid receptor-mediated signaling and IL-17A induction are implicated in diet-associated hepatic health and cognitive function

et al. 2020

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“…Inulin prevents FPC diet-induced in ammatory signaling IL-17A is implicated in the development of chronic in ammatory diseases in the brain, skin, and liver as well as liver cancer [30][31][32][33]. FPC diet-fed mice had increased mRNA level of Rorγt, a transcriptional factor for Il-17 expression, accompanied by elevated hepatic protein levels of IL-17A and TNFα as well as mRNA levels of Il6, Il1β, and Tgfβ, which generate Th17 cells; inulin supplementation prevented these changes (Fig.…”

Section: Resultsmentioning

confidence: 99%

Dysregulated Bile Acid Receptor-mediated Signaling and IL-17A Induction are Implicated in Diet-associated Hepatic Health and Cognitive Function

Jena

Sheng

Nguyen

et al. 2020

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Background: Chronic consumption of high sugar and high fat diet associated with liver inflammation and cognitive decline. This paper tests a hypothesis that the development and resolution of diet-induced nonalcoholic fatty liver disease (NAFLD) has an impact on neuroplasticity and cognition. Methods: C57BL/6 wild-type mice were fed with either a healthy control diet (CD) or a fructose, palmitate, and cholesterol (FPC)-enriched diet since weaning. When mice were 3-months old, FPC diet-fed mice were randomly assigned to receive either FPC-enriched diet with or without 6% inulin supplementation. At 8 months of age, all three groups of mice were euthanized followed by analysis of inflammatory signaling in the liver and brain, gut microbiota, and cecal metabolites. Results: Our data shows that FPC diet intake induced hepatic steatosis and inflammation in the liver and brain along with elevated RORγ and IL-17A signaling. Accompanied by microglia activation and reduced hippocampal long-term potentiation, FPC diet intake also reduced postsynaptic density-95 and brain derived neurotrophic factor, whereas inulin supplementation prevented diet-reduced neuroplasticity and the development of NAFLD. In the gut, FPC diet increased Coriobacteriaceae and Erysipelotrichaceae, which are implicated in cholesterol metabolism, and the genus Allobaculum, and inulin supplementation reduced them. Furthermore, FPC diet reduced FXR and TGR5 signalling, and inulin supplementation reversed these changes. Untargeted cecal metabolomics profiling uncovered 273 metabolites, and 104 had significant changes due to FPC diet intake or inulin supplementation. Among the top 10 most affected metabolites, FPC-fed mice had marked increase of zymosterol, a cholesterol biosynthesis metabolite, and reduced 2,8-dihydroxyquinoline, which has known benefits in reducing glucose intolerance; these changes were reversible by inulin supplementation. Additionally, the abundance of Barnesiella, Coprobacter, Clostridium XIVa, and Butyrivibrio were negatively correlated with FPC diet intake and the concentration of cecal zymosterol but positively associated with inulin supplementation. suggesting their benefits. Conclusion: Taken together, the presented data suggest that diet alters the gut microbiota and their metabolites, including bile acids. This will subsequently affect IL-17A signaling, resulting in systemic impacts on both hepatic metabolism and cognitive function.

show abstract

“…Inulin prevents FPC diet-induced in ammatory signaling IL-17A is implicated in the development of chronic in ammatory diseases in the brain, skin, and liver as well as liver cancer [31][32][33][34]. FPC diet-fed mice had increased mRNA level of Rorγt, a transcriptional factor for Il-17 expression, accompanied by elevated hepatic protein levels of IL-17A and TNFα as well as mRNA levels of Il6, Il1β, and Tgfβ, which generate Th17 cells; inulin supplementation prevented these changes ( Figure 3A, B).…”

Section: Resultsmentioning

confidence: 99%

Dysregulated Bile Acid Receptor-mediated Signaling and IL-17A Induction are Implicated in Diet-associated Hepatic Health and Cognitive Function

Jena

Sheng

Nguyen

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Chronic consumption of high sugar and high fat diet associated with liver inflammation and cognitive decline. This paper tests a hypothesis that the development and resolution of diet-induced nonalcoholic fatty liver disease (NAFLD) has an impact on neuroplasticity and cognition. Methods: C57BL/6 wild-type mice were fed with either a healthy control diet (CD) or a fructose, palmitate, and cholesterol (FPC)-enriched diet since weaning. When mice were 3-months old, FPC diet-fed mice were randomly assigned to receive either FPC-enriched diet with or without 6% inulin supplementation. At 8 months of age, all three groups of mice were euthanized followed by analysis of inflammatory signaling in the liver and brain, gut microbiota, and cecal metabolites. Results: Our data showed that FPC diet intake induced hepatic steatosis and inflammation in the liver and brain along with elevated RORγ and IL-17A signaling. Accompanied by microglia activation and reduced hippocampal long-term potentiation, FPC diet intake also reduced postsynaptic density-95 and brain derived neurotrophic factor, whereas inulin supplementation prevented diet-reduced neuroplasticity and the development of NAFLD. In the gut, FPC diet increased Coriobacteriaceae and Erysipelotrichaceae, which are implicated in cholesterol metabolism, and the genus Allobaculum, and inulin supplementation reduced them. Furthermore, FPC diet reduced FXR and TGR5 signaling, and inulin supplementation reversed these changes. Untargeted cecal metabolomics profiling uncovered 273 metabolites, and 104 had significant changes due to FPC diet intake or inulin supplementation. Among the top 10 most affected metabolites, FPC-fed mice had marked increase of zymosterol, a cholesterol biosynthesis metabolite, and reduced 2,8-dihydroxyquinoline, which has known benefits in reducing glucose intolerance; these changes were reversible by inulin supplementation. Additionally, the abundance of Barnesiella, Coprobacter, Clostridium XIVa, and Butyrivibrio were negatively correlated with FPC diet intake and the concentration of cecal zymosterol but positively associated with inulin supplementation, suggesting their benefits. Conclusion: Taken together, the presented data suggest that diet alters the gut microbiota and their metabolites, including bile acids. This will subsequently affect IL-17A signaling, resulting in systemic impacts on both hepatic metabolism and cognitive function.

show abstract

Diet-induced obesity exacerbates imiquimod-mediated psoriasiform dermatitis in anti-PD-1 antibody-treated mice: Implications for patients being treated with checkpoint inhibitors for cancer

Cited by 37 publications

References 37 publications

Dysregulated bile acid receptor-mediated signaling and IL-17A induction are implicated in diet-associated hepatic health and cognitive function

Dysregulated bile acid receptor-mediated signaling and IL-17A induction are implicated in diet-associated hepatic health and cognitive function

Dysregulated Bile Acid Receptor-mediated Signaling and IL-17A Induction are Implicated in Diet-associated Hepatic Health and Cognitive Function

Dysregulated Bile Acid Receptor-mediated Signaling and IL-17A Induction are Implicated in Diet-associated Hepatic Health and Cognitive Function

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