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   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Scientists link genes to diet in inflammatory bowel disease    
    A study in mice identifies candidate genes associated with bowel   
   inflammation caused by a high-fat diet    
      
     Date:   
         July 5, 2023   
     Source:   
         eLife   
     Summary:   
         A study of the genetic variation that makes mice more susceptible   
         to bowel inflammation after a high-fat diet has identified candidate   
         genes which may drive inflammatory bowel disease (IBD) in humans.   
      
      
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   A study of the genetic variation that makes mice more susceptible to   
   bowel inflammation after a high-fat diet has identified candidate genes   
   which may drive inflammatory bowel disease (IBD) in humans. The findings   
   are published as a Reviewed Preprint in eLife.   
      
   Described by the editors as a fundamental study, the work provides a   
   framework for using systems genetics approaches to dissect the complex   
   mechanisms of gut physiology. The authors show how it is possible to use   
   genetically diverse but well-characterised mice to interrogate intestinal   
   inflammation and pinpoint genes influenced by the environment - in this   
   case, a high-fat diet - and identify potential treatment targets for IBD   
   in mice and humans. The editors describe the strength of the analyses   
   as compelling and add that, as a resource, it will be useful for linking   
   genetic variations and diet to gut- related disorders.   
      
   It is well established that a high-fat diet can increase the risk of IBD.   
      
   However, the impact of diet varies between individual people, suggesting   
   an interplay with genetic factors. More than 200 risk genes have been   
   identified for IBD, but there is still no effective treatment, and it is   
   therefore important to understand the gene-by-environment interactions   
   underpinning the inflammation that eventually evolves into IBD.   
      
   "Differences in the clinical presentation of IBD among patients, as   
   well as diversity in diet and lifestyle, render human genetic studies   
   challenging," explains lead author Xiaoxu Li, a Doctoral Research   
   Assistant at the Institute of Bioengineering, E'cole Polytechnique   
   Fe'de'rale de Lausanne (EPFL), Switzerland. "Genetically diverse   
   populations of mice allow us to mirror the differences in human   
   populations, while controlling several environmental factors, such as   
   temperature and diet, when exploring the genetic modulators of IBD in the   
   laboratory."  Li and colleagues used mouse genetic reference populations   
   (GRPs) to map the genetic factors that are important in IBD induced by a   
   high-fat diet. They measured the levels of gene expression in the colons   
   of 52 mice fed with either a chow or a high-fat diet and identified a   
   subset of mice that were more susceptible to high-fat-diet-induced   
   intestinal inflammation. Moreover, they found that levels of a   
   pro-inflammatory cytokine called interleukin-15 were increased in the   
   mice more likely to develop IBD, while levels of the anti- inflammatory   
   cytokine, Interleukin-10, were decreased. This indicates that changes in   
   the levels of genes associated with IBD reflect the general inflammatory   
   status of mice.   
      
   After classifying different mouse strains based on their likelihood of   
   developing IBD-like genetic signatures, the team explored this further   
   using gene co-expression network analysis. This identified two distinct   
   modules (clusters) of genes that are related to known genetic signatures   
   of human IBD.   
      
   Next, they looked at the function of these genes and how they are   
   controlled.   
      
   Both IBD-associated modules largely consisted of immune response-related   
   genes, including those known to be involved in Crohn's disease, and   
   the team identified the likely regulators of the expression of these   
   genes. But the genetic drivers behind the different susceptibility in   
   the mice were still elusive.   
      
   To find the candidate genes that influence gut inflammation specifically   
   following a high-fat diet, they performed QTL analysis to identify   
   quantitative trait loci (QTL) - regions of genes that interact with the   
   environment to impact the observable trait data. This revealed a QTL   
   that is related to chronic intestinal inflammation in mice.   
      
   To see whether genes under this QTL could play a role in human IBD,   
   the team then cross-checked their findings with risk genes for IBD by   
   conducting an analysis using genome-wide association study data from UK   
   Biobank*. They identified two plausible gene candidates, called EPHA6   
   and MUC4. In addition, using publicly available genetic variation data   
   for IBD, Crohn's disease and ulcerative colitis, they found evidence to   
   suggest that increased expression of the MUC4 gene in part of the colon   
   may increase the risk of IBD in humans.   
      
   A limitation of this analysis is that there were no mechanistic   
   investigations or studies that directly provide a causative link between   
   the candidate genes and IBD. The results are primarily observational   
   and correlative, but they provide a dataset that generates hypotheses   
   that can be studied further.   
      
   "Our results point to important potential roles of two gene candidates   
   in gut chronic inflammation that may lead to inflammatory disorders,"   
   says senior author Johan Auwerx, a Professor at the Institute of   
   Bioengineering, EPFL. "Our systems genetics approach using GRP mice where   
   the genetic backgrounds are known and the environment can be controlled   
   enables the prioritisation of candidate genes in a complex disease which,   
   when combined with human genome- wide association studies from UK Biobank,   
   are generalisable to human patients and may have clinical value."   
       * RELATED_TOPICS   
             o Health_&_Medicine   
                   # Gastrointestinal_Problems # Genes # Obesity #   
                   Cholesterol # Diet_and_Weight_Loss # Colitis #   
                   Crohn's_Disease # Nutrition   
       * RELATED_TERMS   
             o Irritable_bowel_syndrome o Coeliac_disease o Constipation   
             o Genetics o Heritability o Personalized_medicine o   
             Gastroenteritis o South_Beach_diet   
      
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   Journal Reference:   
      1. Xiaoxu Li et al. Genetic and dietary modulators of the inflammatory   
         response in the gastro-intestinal tract of the BXD mouse genetic   
         reference population. eLife, 2023 DOI: 10.7554/eLife.87569.2   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/07/230705115125.htm   
      
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