Restoring Retinoic Acid Attenuates Intestinal Inflammation and Tumorigenesis in APCMin/+ Mice

Penny, Hweixian Leong; Prestwood, Tyler R.; Bhattacharya, Nupur; Sun, Fionna; Kenkel, Justin A.; Davidson, Matthew G.; Shen, Lei; Zúñiga, Luis A.; Seeley, E. Scott; Pai, Reetesh K.; Choi, Okmi; Tolentino, Lorna; Wang, Jinshan; Napoli, Joseph L.; Engleman, Edgar G.

doi:10.1158/2326-6066.cir-15-0038

Cited by 44 publications

(36 citation statements)

References 49 publications

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“…APC min1/2 mice placed on a vitamin A-deficient diet had increased GI inflammation and tumorigenesis that could be reversed by vitamin A repletion. 31 Taken together, these data suggest that vitamin A and retinoic acid regulate T-cell function to limit inflammation following chemical and infectious injury in the gut. These data are in agreement with our findings in human allogeneic transplant, in which higher free vitamin A levels were associated with reduced GVHD and improved survival.…”

Section: Cumulative Incidence Of Mbi-lcbimentioning

confidence: 90%

Lower levels of vitamin A are associated with increased gastrointestinal graft-versus-host disease in children

Lounder

Khandelwal

Dandoy

et al. 2017

Blood

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• Vitamin A levels below the median at day 30 posttransplant are associated with increased cumulative incidence of GI GVHD in children.• Potential mechanisms include increased intestinal permeability and increased lymphocyte homing to the intestine.Vitamin A promotes development of mucosal tolerance and enhances differentiation of regulatory T cells. Vitamin A deficiency impairs epithelial integrity, increasing intestinal permeability. We hypothesized that higher vitamin A levels would reduce the risk of graftversus-host disease (GVHD) through reduced gastrointestinal (GI) permeability, reduced mucosal injury, and reduced lymphocyte homing to the gut. We tested this hypothesis in a cohort study of 114 consecutive patients undergoing allogeneic stem cell transplant. Free vitamin A levels were measured in plasma at day 30 posttransplant. GI GVHD was increased in patients with vitamin A levels below the median (38% vs 12.4% at 100 days, P 5 .0008), as was treatment-related mortality (17.7% vs 7.4% at 1 year, P 5 .03). Bloodstream infections were increased in patients with vitamin A levels below the median (24% vs 8% at 1 year, P 5 .03), supporting our hypothesis of increased intestinal permeability. The GI mucosal intestinal fatty acid-binding protein was decreased after transplant, confirming mucosal injury, but was not correlated with vitamin A levels, indicating that vitamin A did not protect against mucosal injury. Expression of the gut homing receptor CCR9 on T-effector memory cells 30 days after transplant was increased in children with vitamin A levels below the median (r 5 20.34, P 5 .03). Taken together, these data support our hypothesis that low levels of vitamin A actively promote GI GVHD and are not simply a marker of poor nutritional status or a sicker patient. Vitamin A supplementation might improve transplant outcomes. (Blood. 2017;129(20):2801-2807

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Section: Cumulative Incidence Of Mbi-lcbimentioning

confidence: 90%

Lower levels of vitamin A are associated with increased gastrointestinal graft-versus-host disease in children

Lounder

Khandelwal

Dandoy

et al. 2017

Blood

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“…Cytochrome P450 26 B1 (CYP26B1) participates in the degradation of RA, and homozygous carriers of the CYP26B1 polymorphism rs2241057 have been associated as risk factor of CD development, linking an elevated catabolic function of RA to IBD ( 215 ). Supplementation of VitA/RA seems to attenuate intestinal inflammation in experimental models and even induces a shift in Th17/Tregs in UC biopsies ( 216 – 218 ). VitA appears to influence the microbiota, as its deficiency seems to favor a non-symptomatic reservoir of E. coli -like enteric infections ( 219 , 220 ).…”

Section: Nutrients and Their Impact On Microbiota And Immune Responsementioning

confidence: 99%

The Impact of Western Diet and Nutrients on the Microbiota and Immune Response at Mucosal Interfaces

et al. 2017

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Recent findings point toward diet having a major impact on human health. Diets can either affect the gut microbiota resulting in alterations in the host’s physiological responses or by directly targeting the host response. The microbial community in the mammalian gut is a complex and dynamic system crucial for the development and maturation of both systemic and mucosal immune responses. Therefore, the complex interaction between available nutrients, the microbiota, and the immune system are central regulators in maintaining homeostasis and fighting against invading pathogens at mucosal sites. Westernized diet, defined as high dietary intake of saturated fats and sucrose and low intake of fiber, represent a growing health risk contributing to the increased occurrence of metabolic diseases, e.g., diabetes and obesity in countries adapting a westernized lifestyle. Inflammatory bowel diseases (IBD) and asthma are chronic mucosal inflammatory conditions of unknown etiology with increasing prevalence worldwide. These conditions have a multifactorial etiology including genetic factors, environmental factors, and dysregulated immune responses. Their increased prevalence cannot solely be attributed to genetic considerations implying that other factors such as diet can be a major contributor. Recent reports indicate that the gut microbiota and modifications thereof, due to a consumption of a diet high in saturated fats and low in fibers, can trigger factors regulating the development and/or progression of both conditions. While asthma is a disease of the airways, increasing evidence indicates a link between the gut and airways in disease development. Herein, we provide a comprehensive review on the impact of westernized diet and associated nutrients on immune cell responses and the microbiota and how these can influence the pathology of IBD and asthma.

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“…17,18 Palovarotene, a potent RAR-g agonist, is particularly effective in preventing chondrogenesis and HO in both a genetic model of fibrodysplasia ossificans progressiva (FOP) as well as in an animal model of combat-related HO. [19][20][21] In addition to its effects on chondrogenesis, RA is also a potent inhibitor of inflammatory cytokine expression [22][23][24] ; this anti-inflammatory effect may provide another mechanism of HO inhibition.…”

mentioning

confidence: 99%

Palovarotene inhibits connective tissue progenitor cell proliferation in a rat model of combat‐related heterotopic ossification

Wheatley

Cilwa

Dey

et al. 2017

Journal Orthopaedic Research

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Heterotopic ossification (HO) develops in the extremities of wounded service members and is common in the setting of high-energy penetrating injuries and blast-related amputations. No safe and effective prophylaxis modality has been identified for this patient population. Palovarotene has been shown to reduce bone formation in traumatic and genetic models of HO. The purpose of this study was to determine the effects of Palovarotene on inflammation, progenitor cell proliferation, and gene expression following a blast-related amputation in a rodent model (n = 72 animals), as well as the ability of Raman spectroscopy to detect early HO before radiographic changes are present. Treatment with Palovarotene was found to dampen the systemic inflammatory response including the cytokines IL-6 (p = 0.01), TNF-α (p = 0.001), and IFN-γ (p = 0.03) as well as the local inflammatory response via a 76% reduction in the cellular infiltration at post-operative day (POD)-7 (p = 0.03). Palovarotene decreased osteogenic connective tissue progenitor (CTP-O) colonies by as much as 98% both in vitro (p = 0.04) and in vivo (p = 0.01). Palovarotene treated animals exhibited significantly decreased expression of osteo- and chondrogenic genes by POD-7, including BMP4 (p = 0.02). Finally, Raman spectroscopy was able to detect differences between the two groups by POD-1 (p < 0.001). These results indicate that Palovarotene inhibits traumatic HO formation through multiple inter-related mechanisms including anti-inflammatory, anti-proliferative, and gene expression modulation. Further, that Raman spectroscopy is able to detect markers of early HO formation before it becomes radiographically evident, which could facilitate earlier diagnosis and treatment. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1135-1144, 2018.

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Restoring Retinoic Acid Attenuates Intestinal Inflammation and Tumorigenesis in APCMin/+ Mice

Cited by 44 publications

References 49 publications

Lower levels of vitamin A are associated with increased gastrointestinal graft-versus-host disease in children

Lower levels of vitamin A are associated with increased gastrointestinal graft-versus-host disease in children

The Impact of Western Diet and Nutrients on the Microbiota and Immune Response at Mucosal Interfaces

Palovarotene inhibits connective tissue progenitor cell proliferation in a rat model of combat‐related heterotopic ossification

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