ABSTRACT
BACKGROUND AND AIMS: Bacterially derived factors from the gut play a major role in the activation of inflammatory pathways in the liver and in the pathogenesis of alcoholic liver disease. The intestinal brush-border enzyme intestinal alkaline phosphatase (IAP) detoxifies a variety of bacterial pro-inflammatory factors and also functions to preserve gut barrier function. The aim of this study was to investigate whether oral IAP supplementation could protect against alcohol-induced liver disease. METHODS: Mice underwent acute binge or chronic ethanol exposure to induce alcoholic liver injury and steatosis ± IAP supplementation. Liver tissue was assessed for biochemical, inflammatory, and histopathological changes. An ex vivo co-culture system was used to examine the effects of alcohol and IAP treatment in regard to the activation of hepatic stellate cells and their role in the development of alcoholic liver disease. RESULTS: Pretreatment with IAP resulted in significantly lower serum alanine aminotransferase compared to the ethanol alone group in the acute binge model. IAP treatment attenuated the development of alcohol-induced fatty liver, lowered hepatic pro-inflammatory cytokine and serum LPS levels, and prevented alcohol-induced gut barrier dysfunction. Finally, IAP ameliorated the activation of hepatic stellate cells and prevented their lipogenic effect on hepatocytes. CONCLUSIONS: IAP treatment protected mice from alcohol-induced hepatotoxicity and steatosis. Oral IAP supplementation could represent a novel therapy to prevent alcoholic-related liver disease in humans.
Subject(s)
Alkaline Phosphatase/administration & dosage , Dietary Supplements , Fatty Liver, Alcoholic/prevention & control , Alanine Transaminase/blood , Animals , Coculture Techniques , Cytokines/analysis , Cytokines/blood , Ethanol , Fatty Liver, Alcoholic/blood , Fatty Liver, Alcoholic/enzymology , Female , Hepatic Stellate Cells/enzymology , Hepatocytes/enzymology , Intestines/enzymology , Lipogenesis , Lipopolysaccharides/blood , Liver/chemistry , Mice , Mice, Inbred C57BL , Permeability , Tissue Plasminogen Activator , Triglycerides/analysisABSTRACT
BACKGROUND: The Agency for Healthcare Research and Quality patient safety indicators (PSIs) and Centers for Medicare and Medicaid Services hospital-acquired conditions (HACs) are publicly reported metrics that illustrate the overall quality of care provided at an institution. The national incidences of PSIs and HACs in traumatic brain injury (TBI) patients were estimated using the Nationwide Inpatient Sample database. OBJECTIVE: To establish baseline incidences of PSIs and HACs among surgical TBI patients treated at nonfederal hospitals in the United States, and to identify patient factors contributing to these adverse events. METHODS: The Nationwide Inpatient Sample database was queried for patients admitted with International Classification of Diseases, Ninth Revision diagnosis codes consistent with TBI between 2002 and 2011. The incidences of PSIs and HACs were estimated for TBI patients and evaluated for correlation with multiple factors, including comorbidity score, teaching hospital status, and insurance status. RESULTS: There were 15403 total PSIs among 24012 TBI patients. There were only 165 HACs among 24012 TBI patients. Only sepsis, deep vein thrombosis, and pressure ulcers occurred in more than 1% of patients. Patient age, sex, comorbidity score, and teaching hospital status were all found to significantly impact PSI incidence. Comorbidity score was found to significantly impact HAC incidence. Compared with private insurance, Medicaid patients developed significantly more HACs. CONCLUSION: These data may be used as reference values for hospitals reporting their own rates and seeking to improve the quality of care they provide for TBI patients.
Subject(s)
Brain Injuries/surgery , Iatrogenic Disease/epidemiology , Patient Safety/standards , Adult , Aged , Female , Hospitals, Teaching , Humans , Incidence , Male , Middle Aged , Patient Safety/statistics & numerical data , United StatesABSTRACT
The intestinal microbiota plays a pivotal role in maintaining human health and well-being. Previously, we have shown that mice deficient in the brush-border enzyme intestinal alkaline phosphatase (IAP) suffer from dysbiosis and that oral IAP supplementation normalizes the gut flora. Here we aimed to decipher the molecular mechanism by which IAP promotes bacterial growth. We used an isolated mouse intestinal loop model to directly examine the effect of exogenous IAP on the growth of specific intestinal bacterial species. We studied the effects of various IAP targets on the growth of stool aerobic and anaerobic bacteria as well as on a few specific gut organisms. We determined the effects of ATP and other nucleotides on bacterial growth. Furthermore, we examined the effects of IAP on reversing the inhibitory effects of nucleotides on bacterial growth. We have confirmed that local IAP bioactivity creates a luminal environment that promotes the growth of a wide range of commensal organisms. IAP promotes the growth of stool aerobic and anaerobic bacteria and appears to exert its growth promoting effects by inactivating (dephosphorylating) luminal ATP and other luminal nucleotide triphosphates. We observed that compared with wild-type mice, IAP-knockout mice have more ATP in their luminal contents, and exogenous IAP can reverse the ATP-mediated inhibition of bacterial growth in the isolated intestinal loop. In conclusion, IAP appears to promote the growth of intestinal commensal bacteria by inhibiting the concentration of luminal nucleotide triphosphates.
