Project: The use of polyamines to treat inflammatory bowel disease (includes Crohn’s Disease)
Year: 2014 – IN PROGRESS
Researcher: University of Bristol
Polyamines are critical for the maintenance of normal gut function and play important roles in regulating inflammation and promoting healing. They are a group of amino acid derivatives which are naturally produced by cells of the intestine and bacteria resident within the gut. Changes in the bacterial population in the gut can result in an alteration in polyamine levels since not all bacteria produce polyamines and those that do produce them in varying quantities. Patients with active inflammatory bowel disease have an altered intestinal bacterial population. Levels of polyamines, particularly those thought to have anti-inflammatory properties, are known to be decreased in inflammatory bowel disease patients. Supplementing this deficiency is a possible mechanism by which inflammation could be reduced.
This project will:
1) Determine the effects of individual polyamines on intestinal cells using laboratory models.
2) Determine the mechanism by which polyamines exert their effects.
3) Identify intestinal bacteria and probiotics capable of producing individual polyamines and quantify production.
This work will identify a novel, rational treatment mechanism which would supplement the polyamine deficiency in inflammatory bowel disease and reduce inflammation. It will identify potential routes of targeted treatment which could increase the intestinal concentration of polyamines, such as dietary supplementation or modulation of the intestinal bacterial population by introduction of a probiotic, use of antibiotics or faecal transplant. Since inflammatory bowel disease treatments are mainly based on suppression of symptoms by anti-inflammatory drugs, polyamines would provide an alternative to the current treatments and their side effects, and another mechanism for control of symptoms where conventional treatment fails.
Interim Results – March 2016
In the work carried out so far, a laboratory model of intestinal epithelial cells has been used to determine the role of individual polyamines in the processes required to maintain a robust epithelial barrier: cell growth, maintenance of tight cell junctions, and death.
Following challenge with bacteria, tight cell junctions between epithelial cells are broken down and an increased number of cells die, leading to a breakdown of barrier function. It has been found that while spermidine (one type of polyamine), promoted maintenance of tight cell junctions, they slowed growth of epithelial cells following bacterial challenge. Spermine, (another type of polyamine) had no effect on either of these parameters. Therefore, it is suggested that the high level of spermidine present in the IBD gut blocks renewal of the epithelium during chronic inflammation. Additionally, it has been found that spermine reduced levels of cell death in response to bacterial challenge. Since IBD patients have a spermine deficiency in the gut, it is suggested that levels of epithelial cell death will be increased.
It is proposed that the effect of dysregulated polyamines in IBD patients is twofold:
- Overexpression of spermidine prevents growth of cells to renew the epithelial barrier following damage due to inflammation
- A lack of spermine increases cell death, further exacerbating the loss of epithelial cells
An increased loss of epithelial cells, coupled with an inability to grow new cells, leads to an insufficient number of cells to maintain a competent barrier. This will allow gut contents to enter intestinal tissue and enhance inflammation.
This work is continuing to further investigate the role of spermidine in epithelial cell growth and determine where the block to cell production and subsequent epithelial barrier repair is. Alongside this, intestinal bacteria capable of producing polyamines and quantity of production will be investigated. In particular, the major bacterial species present in the IBD gut for their ability to produce spermidine and spermine will be examined. Once this is completed predictions about whether modulation of the levels of these bacteria could redress the imbalance between spermidine and spermine and allow healing of the epithelial barrier will be made.