Control of intestinal homeostasis through crosstalk between natural killer T cells and the intestinal microbiota

Dowds, C. Marie; Blumberg, Richard S.; Zeißig, Sebastian

doi:10.1016/j.clim.2015.05.008

Cited by 47 publications

(33 citation statements)

References 44 publications

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“…However, we were unable to reproduce these findings, and our results showed that middle-aged and aged mice had slightly increased liver injury after α-Galcer injection with peak serum ALT levels of 500 IU/L compared to young mice. The reasons for this discrepancy are not clear, but it may be related to different environment and gut microbiota that are known to affect NKT cell development [34]. Moreover, the number and activation of hepatic NKT cells were comparable in ethanol-fed middle-aged and young mice.…”

Section: Discussionmentioning

confidence: 99%

Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression

Ramírez

Yin

et al. 2017

Journal of Hepatology

146

112

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Background and Aims Aging is known to exacerbate the progression of alcoholic liver disease (ALD), but the underlying mechanisms remain obscure. Methods C57BL/6 mice were subjected to short-term (10-days) ethanol-plus-one binge or long- term (8-weeks) ethanol-plus-multiple binges of ethanol. Liver injury and fibrosis were determined. Hepatic stellate cells (HSCs) were isolated and used in in vitro studies. Results Compared to young (8–12 weeks) mice, middle-aged (12–14 months) and old (>16 months) mice were more susceptible to liver injury, inflammation, and oxidative stress induced by short-term-plus-one binge or long-term-plus-multiple binges of ethanol feeding. Long-term-plus- multiple binges of ethanol feeding induced greater liver fibrosis in middle-aged mice than that in young mice. Hepatic expression of Sirtuin 1 (SIRT1) protein was downregulated in the middle-aged mice compared to young mice. Restoration of SIRT1 expression via the administration of adenovirus-SIRT1 vector ameliorated short-term-plus-binge ethanol-induced liver injury and fibrosis in middle-aged mice. HSCs isolated from middle-aged mice expressed lower levels of SIRT1 protein and were more susceptible to spontaneous activation in in vitro culture than those from young mice. Overexpression of SIRT1 reduced activation of HSCs from middle-aged mice in vitro with downregulation of PDGFR-α and c-Myc, while deletion of SIRT1 activated HSCs isolated from young mice in vitro. Finally, HSC-specific SIRT1 knockout mice were more susceptible to short-term-plus-binge ethanol-induced liver fibrosis with upregulation of PDGFR-α expression. Conclusions Aging exacerbates ALD in mice through the downregulation of SIRT1 in hepatocytes and HSCs. Activation of SIRT1 may serve as a novel target for the treatment of ALD.

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Section: Discussionmentioning

confidence: 99%

Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression

Ramírez

Yin

et al. 2017

Journal of Hepatology

146

112

View full text Add to dashboard Cite

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“…CD patients maintained in remission on 6-MP therapy had reduced numbers of colonic LP CD3 + CD56 + cells compared to individuals unexposed to 6-MP. Mucosal NKT cells are known to contribute to intestinal immune responses in health and disease although their precise role in inflammatory bowel disease is an ongoing area of research [48]. Stimulation of CD1d-restricted Type I NKT appeared to improve disease scores in murine model of DSS colitis [49].…”

Section: Discussionmentioning

confidence: 99%

NK cells are biologic and biochemical targets of 6-mercaptopurine in Crohn's disease patients

Yusung

McGovern

Lin

et al. 2017

Clinical Immunology

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NK cells, which contribute to immune defense against certain viral infections and neoplasia, are emerging as modifiers of chronic immunologic diseases including transplant rejection and autoimmune diseases. Immunobiology and genetic studies have implicated NK cells as a modifier of Crohn’s disease, a condition often treated with thiopurine agents such as 6-mercaptopurine (6-MP). Here, we demonstrate that thiopurines mediate NK cell apoptosis via a caspase 3 and 9 inclusive pathway, and that this process is triggered by thiopurine-mediated inhibition of Rac1. We also show that CD patients in clinical remission maintained on 6-MP have decreased NK cell Rac1 activity, and decreased NK cell numbers in their intestinal biopsies. These observations suggest that thiopurine targeting of NK cells may be a previously unappreciated therapeutic action of these agents in IBD.

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“…High epithelial expression of Cd1d1 in intestine in response to microbial lipid antigens activates NKT-cells. 21 Recent evidence suggests that NKT-cells modulates host and commensal microbiota interactions, regulating intestinal homeostasis and preventing inflammation, 22 helping to explain similarities between NL, T1 and T2.…”

Section: Resultsmentioning

confidence: 99%

Mice exposed to infant formula enriched with polyamines: impact on host transcriptome and microbiome

et al. 2017

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Previous studies using a BALB/cOlaHsd model have shown the impact that the supplementation of infant formula with polyamines has on the modulation of microbial colonization and immune system development. To contribute to deciphering and identifying new complex interactions underlying the host response to polyamines, a systems biology approach integrating data from microbiota along the gastrointestinal tract, lymphocyte populations and immune system gene expression analysis of a lactating mice model fed different diets was carried out. The study design included four different dietary regimens including the following: mice fed by normal lactation; early weaned mice given commercial infant formula; and early weaned mice fed with infant formula enriched with two different concentrations of polyamines. Cluster analysis by principal component analysis and heat map demonstrated that the bacterial communities and immune system status differed between groups. The assessment of the relationship between immune system development, microbiota succession and polyamine supplementation in a global manner proved that the supplementation of infant formula with polyamines promotes similar microbial communities along the whole gastrointestinal tract, and results in similar lymphocyte populations and expression of immune related-genes to those with the normal lactated milk and the results differ from those with the infant formula without polyamines. Further studies should be conducted in human subjects to verify the current results, as the supplementation of polyamines may resemble the effect of natural breastfeeding practices in the gastrointestinal microbiota and immune system development in a mouse model.

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Control of intestinal homeostasis through crosstalk between natural killer T cells and the intestinal microbiota

Cited by 47 publications

References 44 publications

Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression

Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression

NK cells are biologic and biochemical targets of 6-mercaptopurine in Crohn's disease patients

Mice exposed to infant formula enriched with polyamines: impact on host transcriptome and microbiome

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