ABSTRACT
Exclusive enteral nutrition (EEN) with fiber-free diets is an effective steroid-sparing treatment to induce clinical remission in children with Crohn's disease (CD). However, the mechanism underlying the beneficial effects of EEN remains obscure. Using a model of microbiota-dependent colitis with the hallmarks of CD, we find that the administration of a fiber-free diet prevents the development of colitis and inhibits intestinal inflammation in colitic animals. Remarkably, fiber-free diet alters the intestinal localization of Mucispirillum schaedleri, a mucus-dwelling pathobiont, which is required for triggering disease. Mechanistically, the absence of dietary fiber reduces nutrient availability and impairs the dissimilatory nitrate reduction to ammonia (DNRA) metabolic pathway of Mucispirillum, leading to its exclusion from the mucus layer and disease remission. Thus, appropriate localization of the specific pathobiont in the mucus layer is critical for disease development, which is disrupted by fiber exclusion. These results suggest strategies to treat CD by targeting the intestinal niche and metabolism of disease-causing microbes.
Subject(s)
Colitis , Crohn Disease , Microbiota , Humans , Child , Animals , Crohn Disease/therapy , Diet , Colitis/therapy , Treatment OutcomeABSTRACT
The events in the immune response to hepatitis B virus (HBV) remain unclear. We analyzed the direct influence of HBV on gene expression in human hepatocytes under immunodeficient conditions using a human hepatocyte chimeric mouse model. HBV-infected or non-infected chimeric mouse livers were collected, and gene expression profiles were compared. Since IL-8 was the most significantly up-regulated gene at 8 weeks after HBV infection, we focused on IL-8 and found that HBx and the large HBs (L-HBs) protein induce transcription of IL-8 via endoplasmic reticulum stress. This stress induces IL-8 transcription via NFAT activation and contributes to suppression of interferon responsiveness in HBV-infected human hepatocytes. In the present study, we identified a novel regulatory mechanism in which the L-HBs protein activates IL-8 via endoplasmic reticulum stress, suggesting a key role for IL-8 in the immune response to HBV and a potential new target for antiviral treatments of HBV infection.
Subject(s)
Endoplasmic Reticulum/metabolism , Hepatitis B virus/physiology , Hepatitis B, Chronic/metabolism , Hepatocytes/virology , Interleukin-8/metabolism , Animals , Cells, Cultured , Hepatitis B, Chronic/immunology , Hepatocytes/metabolism , Humans , Liver/metabolism , Mice , Stress, Physiological , Up-RegulationABSTRACT
A water-soluble PEG derivative having both amino and carboxylic acid side chains (PEG-AC) was synthesized and explored for its transcription- and transfection-enhancing activity. PEG-AC could be deposited onto the surface of DNA/polycation complexes to form a ternary complex with slightly negative surface potential. PEG-AC-coating on the plasmid/PEI complexes obviously enhanced their transcriptional activity, and 31-fold higher consumption of UTP was observed. Amphoteric PEG-AC would loosen the tightly compacted DNA/PEI complex and facilitate the approach of transcriptional factors. PEG-AC also evidently improved the transgene expression level on the cultured CHO cells.
