Scientists find candidate genes that could drive inflammation

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A recent study reveals the genetic factors that might make individuals more prone to inflammatory bowel disease (IBD) when they consume a high-fat diet.

The researchers leveraged genetically diverse but well-characterized mice populations to pinpoint genes influenced by diet, thereby offering potential treatment targets for IBD in both mice and humans.

Diving into Genetic Interactions

While it’s known that a high-fat diet can heighten the risk of IBD, the degree to which diet impacts individuals differs, hinting at a complex interplay with genetic factors.

Over 200 risk genes for IBD have been identified so far, but finding an effective treatment remains elusive, emphasizing the need to understand the gene-by-environment interactions that underlie inflammation and potentially evolve into IBD.

“Differences in the clinical presentation of IBD among patients, as well as diversity in diet and lifestyle, render human genetic studies challenging,” says lead author Xiaoxu Li, a Doctoral Research Assistant at the Institute of Bioengineering, École Polytechnique Fédérale 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.”

Key Findings: Pro-Inflammatory and Anti-Inflammatory Cytokines

The study’s authors used mouse genetic reference populations (GRPs) to map genetic factors crucial in IBD induced by a high-fat diet.

In examining the colons of 52 mice fed with either a chow or a high-fat diet, they discovered a subset of mice that were particularly susceptible to high-fat-diet-induced intestinal inflammation.

Interestingly, they observed an increase in the levels of a pro-inflammatory cytokine called interleukin-15 in mice more prone to developing IBD, while the levels of the anti-inflammatory cytokine, Interleukin-10, were decreased.

This finding suggests that changes in the levels of genes linked to IBD reflect the overall inflammatory status of mice.

Identifying Genetic Clusters Linked to IBD

By categorizing different mouse strains based on their likelihood of developing IBD-like genetic signatures, the researchers delved deeper using gene co-expression network analysis.

They identified two distinct modules (clusters) of genes related to known genetic signatures of human IBD.

Most genes within these IBD-associated modules were immune response-related genes, some of which are known to play a part in Crohn’s disease.

The researchers were able to identify potential regulators of these genes’ expression.

Finding the Culprits: EPHA6 and MUC4

To discover the candidate genes that influence gut inflammation specifically following a high-fat diet, the team performed QTL (quantitative trait loci) analysis. This revealed a QTL related to chronic intestinal inflammation in mice.

By cross-checking their findings with risk genes for IBD using genome-wide association study data from UK Biobank, the team pinpointed two probable gene candidates, EPHA6 and MUC4.

Their analysis suggests that increased expression of the MUC4 gene in a part of the colon might raise the risk of IBD in humans.

Senior author Johan Auwerx, a Professor at the Institute of Bioengineering, EPFL, highlights,

“Our systems genetics approach using GRP mice enables the prioritization of candidate genes in a complex disease which, when combined with human genome-wide association studies from UK Biobank, are generalizable to human patients and may have clinical value.”

The authors caution that their results are observational and correlative, necessitating further investigation to establish a causative link between the candidate genes andIBD.

While this study has significantly advanced our understanding of how diet and genetics interact to influence the risk of developing IBD, it has also highlighted the potential for more personalized dietary recommendations and treatments based on an individual’s unique genetic makeup.

Future research will need to verify these findings in human populations and assess the potential of these genes as therapeutic targets.

If you care about inflammation, please read studies about vitamin D deficiency linked to chronic inflammation, and tart cherry could help reduce inflammation.

For more information about health, please see recent studies about vitamin B6 linked to lower death risk in heart disease, and results showing anti-inflammatory diet could help prevent fatty liver disease.

The study was published in eLife. Follow us on Twitter for more articles about this topic.

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