Intestinal alkaline phosphatase is protective to the preterm rat pup intestine

Heinzerling, Nathan P.; Liedel, Jennifer L.; Welak, Scott R.; Fredrich, Katherine; Biesterveld, Ben E.; Pritchard, Kirkwood A.; Gourlay, David M.

doi:10.1016/j.jpedsurg.2014.01.031

Cited by 23 publications

(16 citation statements)

References 40 publications

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“…Importantly, oral ALPI supplementation protected ALPI-deficient mice from increased susceptibility to DSS-induced colitis (Ramasamy et al, 2011) and from chronic colitis induced by recurrent non-lethal infections by S. typhimurium (Yang et al, 2017). This treatment also significantly reduced intestinal inflammation in several mouse models of colitis and prevented LPS translocation (Ramasamy et al, 2011;Martínez-Moya et al, 2012;Rentea et al, 2012;Heinzerling et al, 2014;Biesterveld et al, 2015). Moreover, a small trial in patients with ulcerative colitis showed that administration of exogenous ALPI was not only well tolerated but also associated with short-term improvement in clinical scores (Lukas et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis

et al. 2018

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Herein, we report the first identification of biallelic‐inherited mutations in ALPI as a Mendelian cause of inflammatory bowel disease in two unrelated patients. ALPI encodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll‐like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter‐subunit interactions, and heterologous expression in HEK293T cells demonstrated that all ALPI mutations were loss of function. ALPI mutations impaired either stability or catalytic activity of ALPI and rendered it unable to detoxify lipopolysaccharide‐dependent signalling. Furthermore, ALPI expression was reduced in patients’ biopsies, and ALPI activity was undetectable in ALPI‐deficient patient's stool. Our findings highlight the crucial role of ALPI in regulating host–microbiota interactions and restraining host inflammatory responses. These results indicate that ALPI mutations should be included in screening for monogenic causes of inflammatory bowel diseases and lay the groundwork for ALPI‐based treatments in intestinal inflammatory disorders.

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Section: Discussionmentioning

confidence: 99%

Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis

et al. 2018

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“…Rather, infants born at moderate-and late-preterm gestations represent 85% preterm population 23 and thus pose the greatest potential public health burden of adult morbidity consequent on preterm birth. 5,24 Compared to other paradigms of preterm birth in small animals, 17,22,25 we believe that our medical induction of labour confers significant theoretical and survival advantages. First, the combination of progesterone blockade followed by stimulation of uterine activity and vaginal delivery more closely emulates the normal parturition process.…”

Section: Discussionmentioning

confidence: 99%

Premature guinea pigs: a new paradigm to investigate the late-effects of preterm birth

Berry

Gray

Wright

et al. 2014

J Dev Orig Health Dis

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Preterm birth is common and the associated short-term morbidity well described. The adult-onset consequences of preterm birth are less clear, but cardiovascular and metabolic health may be adversely affected. Although large animal models of preterm birth addressing important short-term issues exist, long-term studies are hampered by significant logistical constraints. Current small animal models of prematurity require terminal caesarean section of the mother; both caesarean birth and early maternal care modify offspring adult cardio-metabolic function. We describe a novel method for inducing preterm labour in guinea pigs. With support comparable to that received by moderately preterm human infants, preterm pups are viable. Growth trajectories between preterm and term-born pups differ significantly; between term equivalent age and weaning ex-preterm animals demonstrate increased weight and ponderal index. We believe this novel paradigm will significantly improve our ability to investigate the cardio-metabolic sequelae of preterm birth throughout the life course and into the second generation.

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“…Intestinal ALP (iALP) is a brush-border-associated protein secreted by enterocytes and its activity is considered a valuable marker of crypt-villus differentiation (Sussman et al 1989;Fevr et al 2007). The exact function of iALP is not known, but recently it has been the focus of studies investigating a protective role against lipopolysaccharide-mediated enterocolitis (Heinzerling et al 2014;Goldberg et al 2008). We did not have sufficient serum sample volume to differentiate the various alkaline phosphatase isozymes.…”

Section: Discussionmentioning

confidence: 99%

Tankyrase Inhibition Causes Reversible Intestinal Toxicity in Mice with a Therapeutic Index < 1

Zhong¹,

Katavolos²,

Nguyen³

et al. 2015

Toxicol Pathol

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Activated Wnt/β-catenin signaling is frequently associated with colorectal cancer. Wnt inhibitors, including tankyrase inhibitors, are being explored as potential anticancer agents. Wnt signaling is also critical for intestinal tissue homeostasis, and Wnt inhibitors have been shown to cause intestinal toxicity in mice by affecting intestinal stem cells. This study sought to characterize the intestinal toxicity of tankyrase inhibitors, including reversibility, and to assess their therapeutic index. Novel tankyrase inhibitor G-631 caused dose-dependent intestinal toxicity with a therapeutic index < 1 after 14 days of dosing in mice. At a tolerated subtherapeutic dose level, the intestinal toxicity was composed of enteritis characterized by villus blunting, epithelial degeneration, and inflammation, which fully reversed after 14 days of recovery. Doubled exposure showed weak antitumor activity in a xenograft colorectal cancer model but also caused more severe intestinal toxicity characterized by multifocal-regionally extensive necrotizing and ulcerative enteritis leading to morbidity or moribundity in some animals. This toxicity was only partially reversed after 14 days of recovery, with evidence of crypt and villus regeneration, mildly blunted villi, and/or scarring in association with chronic inflammation of the submucosa. Therefore, the clinical utility of tankyrase inhibitors is likely limited by the on-target intestinal toxicity and a therapeutic index < 1 in mice.

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Intestinal alkaline phosphatase is protective to the preterm rat pup intestine

Cited by 23 publications

References 40 publications

Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis

Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis

Premature guinea pigs: a new paradigm to investigate the late-effects of preterm birth

Tankyrase Inhibition Causes Reversible Intestinal Toxicity in Mice with a Therapeutic Index < 1

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