Intestinal alkaline phosphatase promotes gut bacterial growth by reducing the concentration of luminal nucleotide triphosphates

Malo, Madhu S.; Moaven, Omeed; Muhammad, Nur; Biswas, Brishti; Alam, Sayeda Nasrin; Economopoulos, Konstantinos P.; Gul, Sarah; Hamarneh, Sulaiman R.; Malo, Nondita S.; Teshager, Abeba; Mahgoub, Mohamed; Tao, Qingsong; Narisawa, Sonoko; Millán, José Luis; Hohmann, Elizabeth L.; Warren, H. Shaw; Robson, Simon C.; Hodin, Richard A.

doi:10.1152/ajpgi.00357.2013

Cited by 84 publications

(101 citation statements)

References 65 publications

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“…The resident gut microbiome is one of the most abundant sources of LPS in humans and animals. Dysbiosis of gut microbiota has been linked to intestinal inflammation (Malo et al, 2014). There are much difficulties associated with studying gene expression in human tissues, especially in the intestinal tract.…”

Section: Introductionmentioning

confidence: 99%

Intestinal alkaline phosphatase and sodium butyrate may be beneficial in attenuating LPS-induced intestinal inflammation

et al. 2016

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ABSTRACT. In this study, we evaluated the effect of intestinal alkaline phosphatase (IAP) and sodium butyrate (NaBu) on lipopolysaccharide (LPS)-induced intestinal inflammation. Intestinal alkaline phosphatase and RelA/p65 (NF-κB) gene expressions in porcine jejunum explants were evaluated following exposure to sodium butyrate (NaBu) and essential oil from Brazilian red pepper (EO), alone or in combination with NaBu, as well as exogenous IAP with or without LPS challenge. Five piglets weighing approximately 20 kg each were sacrificed, and their jejunum were extracted. The tissues were segmented into 10 parts, which were exposed to 10 treatments. Gene expressions of IAP and RelA/p65 (NF-κB) in jejunal explants were evaluated via RT-PCR. We found that EO, NaBu, and exogenous IAP were able to up-regulate endogenous IAP and enhance RelA/p65 (NF-κB) gene expression. However, only NaBu and exogenous IAP down-regulated LPSinduced inflammatory response via RelA/p65 (NF-κB). In conclusion, we demonstrated that exogenous IAP and NaBu may be beneficial in attenuating LPS-induced intestinal inflammation.

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Section: Introductionmentioning

confidence: 99%

Intestinal alkaline phosphatase and sodium butyrate may be beneficial in attenuating LPS-induced intestinal inflammation

et al. 2016

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“…The intestinal ALP (ALPI) is abundantly present in the apical microvilli of the brush border of enterocytes (21) and actively secreted into the intestinal lumen (22,23). Recent studies have shown that ALPI regulates neutral pH in the intestine (24), protects gut barrier function (18,(25)(26)(27), and preserves gut microbial homeostasis (28,29). Our studies using zebrafish larvae have demonstrated an integral role of ALPI in establishing a balanced host immune response to the microbiota during gut colonization (16,30).…”

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confidence: 88%

“…Consequently, Akp3 Ϫ/Ϫ mice displayed higher hepatic expression of major histocompatibility complex class II molecules (20) and signs of metabolic endotoxemia (27). Akp3 Ϫ/Ϫ mice were found to contain dramatically fewer and also different types of aerobic and anaerobic microbes in stools compared to wild-type mice (28,29). Together, these observations from routinely maintained animals indicate that Akp3 plays a role in maintaining gut barrier function and microbial homeostasis.…”

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confidence: 91%

Intestinal Alkaline Phosphatase Deficiency Leads to Lipopolysaccharide Desensitization and Faster Weight Gain

et al. 2015

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Animals develop in the presence of complex microbial communities, and early host responses to these microbes can influence key aspects of development, such as maturation of the immune system, in ways that impact adult physiology. We previously showed that the zebrafish intestinal alkaline phosphatase (ALPI) gene alpi.1 was induced by Gram-negative bacterium-derived lipopolysaccharide (LPS), a process dependent on myeloid differentiation primary response gene 88 (MYD88), and functioned to detoxify LPS and prevent excessive host inflammatory responses to commensal microbiota in the newly colonized intestine. In the present study, we examined whether the regulation and function of ALPI were conserved in mammals. We found that among the mouse ALPI genes, Akp3 was specifically upregulated by the microbiota, but through a mechanism independent of LPS or MYD88. We showed that disruption of Akp3 did not significantly affect intestinal inflammatory responses to commensal microbiota or animal susceptibility to Yersinia pseudotuberculosis infection. However, we found that Akp3 ؊/؊ mice acquired LPS tolerance during postweaning development, suggesting that Akp3 plays an important role in immune education. Finally, we demonstrated that inhibiting LPS sensing with a mutation in CD14 abrogated the accelerated weight gain in Akp3 ؊/؊ mice receiving a high-fat diet, suggesting that the weight gain is caused by excessive LPS in Akp3 ؊/؊ mice. Mammals coexist with a consortium of microorganisms, their microbiota. The most populous microbial community is present in the gastrointestinal tract. A mutually beneficial relationship has been forged between the host and its associated gut microbiota. While the host intestine provides a nutrient-rich environment for the microbes, the gut microbiota modulate host metabolism (1), promote immune maturation (2), preserve gut epithelial barrier function (3), and prevent growth of pathogens (4). Despite these benefits, the intestinal microbiota are a continuous source of antigens and toxins, which can provoke host inflammatory responses. Regulatory mechanisms therefore must exist to prevent unlimited immune activation by microbial products.Alkaline phosphatases (ALPs) are a superfamily of metalloenzymes that are widely found in organisms ranging from bacteria to humans (5) and catalyze the hydrolytic removal of phosphate from a variety of molecules (6). Importantly, ALPs have been shown to remove the lipid A phosphates of the endotoxin lipopolysaccharide (LPS) (7-10). LPS is a constituent of the outer membrane of Gram-negative bacteria (11) which compose a substantial proportion of the mammalian gut microbiota (12). In mammals, LPS is transferred by LPS binding protein to CD14, which then presents the molecule to the TLR4 (Toll-like receptor 4)/MD-2 receptor complex, resulting in the activation of innate immune signaling. The two phosphate groups of the LPS lipid A moiety support stable binding to the receptor complex, and dephosphorylation of lipid A greatly reduces the inflammatory activity of...

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“…IAP mRNA levels are reduced in patients with UC [55]. IAP also promotes growth of intestinal commensal bacteria, preserving homeostasis of the gut microbiota [53,56]. As a naturally occurring enzyme, IAP has a low risk profile [57,58].…”

Section: New Therapeutic Approachesmentioning

confidence: 99%

Impact of Modern Drug Therapy on Surgery: Ulcerative Colitis

Kuehn

Hodin

2018

Visc Med

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Background: The primary treatment of ulcerative colitis (UC) is conservative, and substantial therapeutic progress has been made in the past few decades. Meanwhile, biologicals have become a mainstay in the treatment for steroid-refractory UC. Despite further development of drug therapy and an increased time span to operation, a significant proportion of patients with UC require surgical intervention. Surgical intervention needs to be carried out in medically refractory cases, imminent or malignant transformation, or complications. This article discusses the impact of modern drug therapy on surgery for UC. Methods: A selective literature search of PubMed was conducted, taking into account current studies, reviews, meta-analyses, and guidelines. Selected articles were then reviewed in detail and recommendations were drafted based on data and conclusions of the articles. Results: In recent years, modern drug therapy has changed the timing, approach, and outcomes of surgery for UC. Most of the studies showed a decrease in surgery rates over time while the rate of emergency colectomies remains unchanged. So far, no convincing surgery-sparing effect of newer medications has been established, and it remains debatable if surgery rates have decreased because of improved management for UC in general or due to the introduction of biologicals. The intensified conservative therapy with increasing use of biologics has been accompanied by a trend towards performing a three-step procedure in the last decade. There is a subset of patients with complex refractory disease who most likely benefit from elective surgery as an alternative to prolonged conservative therapies after failure of first-line treatment. The majority of patients after ileal pouch-anal anastomosis can avoid hospitalizations and colitis-related medications with their associated potential adverse effects. In addition, the procedure substantially reduces UC-related symptoms and the risk for dysplasia or cancer. There is a long-term pouch success rate of >90% after 10 and 20 years of follow-up. Conclusion: Conservative medical therapy in the treatment of UC will continue to develop and the number of approved therapeutics will grow. Surgery should not be considered as the negative endpoint of treatment modalities but as a good alternative to a prolonged conservative therapy for some patients. In conclusion, a close cooperation between the various disciplines in the pre- and postoperative management is essential in order to optimize the timing and outcome of patients with UC.

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Intestinal alkaline phosphatase promotes gut bacterial growth by reducing the concentration of luminal nucleotide triphosphates

Cited by 84 publications

References 65 publications

Intestinal alkaline phosphatase and sodium butyrate may be beneficial in attenuating LPS-induced intestinal inflammation

Intestinal alkaline phosphatase and sodium butyrate may be beneficial in attenuating LPS-induced intestinal inflammation

Intestinal Alkaline Phosphatase Deficiency Leads to Lipopolysaccharide Desensitization and Faster Weight Gain

Impact of Modern Drug Therapy on Surgery: Ulcerative Colitis

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