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Distinct effects of p38alpha deletion in myeloid lineage and gut epithelia in mouse models of inflammatory bowel disease.

ABSTRACT: p38Alpha is a mitogen-activated protein kinase that mediates inflammatory responses, but its role in inflammatory bowel disease is unclear. The effects of p38alpha inhibitors have been inconsistent in animal models and clinical studies of inflammatory bowel disease, possibly arising from the different functions of p38alpha in different tissues or cell types. We investigated the effects of p38alpha inhibition in myeloid versus colonic epithelium.We studied mice with myeloid cell-specific and intestinal epithelial cell-specific disruption of p38alpha (LtrLys(Cre)-p38alpha(Delta/Delta) mice and Villin(Cre)-p38alpha(Delta/Delta) mice), as well as p38beta, gamma, and delta knockout. Colitis was induced using dextran sodium sulfate or trinitrobenzene sulfonic acid (TNBS).Mice with myeloid cell-specific deletion of p38alpha had less inflammation and an improved disease condition compared with wild-type mice, whereas mice with intestinal epithelial cell-specific deletion of p38alpha had increased progression of colitis that resulted from disrupted intestinal epithelial homeostasis. The distinct effects of p38alpha disruption in different tissue types might underlie the unsuccessful therapeutic application of p38 inhibitors to colitis. We found that a gamma-secretase inhibitor, which functions opposite that of a p38 inhibitor in the regulation of intestinal epithelial homeostasis, can significantly improve the effects of a p38 inhibitor in reducing colitis.p38Alpha has distinct functions in mouse myeloid cells versus colonic epithelium; these differences should be taken into consideration in defining the role of p38alpha in inflammation and developing p38 inhibitors as therapeutics.

SUBMITTER: Otsuka M

PROVIDER: S-EPMC2846963 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Distinct effects of p38alpha deletion in myeloid lineage and gut epithelia in mouse models of inflammatory bowel disease.

Otsuka Motoyuki M Kang Young Jun YJ Ren Jianlin J Jiang Huiping H Wang Yinbin Y Omata Masao M Han Jiahuai J

Gastroenterology 20100118 4

<h4>Background & aims</h4>p38Alpha is a mitogen-activated protein kinase that mediates inflammatory responses, but its role in inflammatory bowel disease is unclear. The effects of p38alpha inhibitors have been inconsistent in animal models and clinical studies of inflammatory bowel disease, possibly arising from the different functions of p38alpha in different tissues or cell types. We investigated the effects of p38alpha inhibition in myeloid versus colonic epithelium.<h4>Methods</h4>We studie ...[more]

PMID: 20080092

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Project description:BackgroundThe human gut microbiome performs important functions in human health and disease. A classic example for host-gut microbial co-metabolism is host biosynthesis of primary bile acids and their subsequent deconjugation and transformation by the gut microbiome. To understand these system-level host-microbe interactions, a mechanistic, multi-scale computational systems biology approach that integrates the different types of omic data is needed. Here, we use a systematic workflow to computationally model bile acid metabolism in gut microbes and microbial communities.ResultsTherefore, we first performed a comparative genomic analysis of bile acid deconjugation and biotransformation pathways in 693 human gut microbial genomes and expanded 232 curated genome-scale microbial metabolic reconstructions with the corresponding reactions (available at https://vmh.life ). We then predicted the bile acid biotransformation potential of each microbe and in combination with other microbes. We found that each microbe could produce maximally six of the 13 secondary bile acids in silico, while microbial pairs could produce up to 12 bile acids, suggesting bile acid biotransformation being a microbial community task. To investigate the metabolic potential of a given microbiome, publicly available metagenomics data from healthy Western individuals, as well as inflammatory bowel disease patients and healthy controls, were mapped onto the genomes of the reconstructed strains. We constructed for each individual a large-scale personalized microbial community model that takes into account strain-level abundances. Using flux balance analysis, we found considerable variation in the potential to deconjugate and transform primary bile acids between the gut microbiomes of healthy individuals. Moreover, the microbiomes of pediatric inflammatory bowel disease patients were significantly depleted in their bile acid production potential compared with that of controls. The contributions of each strain to overall bile acid production potential across individuals were found to be distinct between inflammatory bowel disease patients and controls. Finally, bottlenecks limiting secondary bile acid production potential were identified in each microbiome model.ConclusionsThis large-scale modeling approach provides a novel way of analyzing metagenomics data to accelerate our understanding of the metabolic interactions between the host and gut microbiomes in health and diseases states. Our models and tools are freely available to the scientific community.

Project description:Inflammatory bowel disease (IBD) is a group of chronic diseases of the digestive tract that affects millions of people worldwide. Genetic, environmental and microbial factors have been implicated in the onset and exacerbation of IBD. However, the mechanisms associating gut microbial dysbioses and aberrant immune responses remain largely unknown. The integrative Human Microbiome Project seeks to close these gaps by examining the dynamics of microbiome functionality in disease by profiling the gut microbiomes of >100 individuals sampled over a 1-year period. Here, we present the first results based on 78 paired faecal metagenomes and metatranscriptomes, and 222 additional metagenomes from 59 patients with Crohn's disease, 34 with ulcerative colitis and 24 non-IBD control patients. We demonstrate several cases in which measures of microbial gene expression in the inflamed gut can be informative relative to metagenomic profiles of functional potential. First, although many microbial organisms exhibited concordant DNA and RNA abundances, we also detected species-specific biases in transcriptional activity, revealing predominant transcription of pathways by individual microorganisms per host (for example, by Faecalibacterium prausnitzii). Thus, a loss of these organisms in disease may have more far-reaching consequences than suggested by their genomic abundances. Furthermore, we identified organisms that were metagenomically abundant but inactive or dormant in the gut with little or no expression (for example, Dialister invisus). Last, certain disease-specific microbial characteristics were more pronounced or only detectable at the transcript level, such as pathways that were predominantly expressed by different organisms in patients with IBD (for example, Bacteroides vulgatus and Alistipes putredinis). This provides potential insights into gut microbial pathway transcription that can vary over time, inducing phenotypical changes that are complementary to those linked to metagenomic abundances. The study's results highlight the strength of analysing both the activity and the presence of gut microorganisms to provide insight into the role of the microbiome in IBD.

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Distinct effects of p38alpha deletion in myeloid lineage and gut epithelia in mouse models of inflammatory bowel disease.

Publications

Distinct effects of p38alpha deletion in myeloid lineage and gut epithelia in mouse models of inflammatory bowel disease.

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