Bacteria activated by the plant sugar xylan produce drugs inside the gut to treat bowel disease
Modified gut bacteria that produce therapeutic agents in response to specific dietary sugars could be employed as novel treatments for bowel disorders. In a new study, US and UK researchers show that intestinal inflammation in mice can be reduced by live, genetically engineered bacteria that sit in the gut.
The researchers introduced a gene for a human protein called keratinocyte growth factor-2 (KGF-2), which helps keep the cells that line the gut healthy, into the bacterium Bacteroides ovatus. They hijacked the bug’s own sugar-degrading mechanisms to gain control over production of the protein - the gene was precisely positioned in an area of the genome only activated in the presence of the plant sugar xylan.
’The real novelty of our approach is that you can regulate the [protein] production,’ says lead researcher Simon Carding of the University of East Anglia and Institute of Food Research in the UK. ’The protein is regulated in the same manner as the xylan-degrading enzymes, which are collected together on a specific region of the bacterial chromosome.’
When mice with severe gut inflammation were fed the genetically engineered bacteria and then xylan in their drinking water, they fared significantly better than mice given unmodified bacteria, or modified bacteria but without the sugar. According to Carding’s team, oral administration could be preferable to straight injections of KGF-2, which require high doses to produce therapeutic benefits.
Crucially, KGF-2 release could be controlled by dietary supplements. Xylan is a complex polysaccharide found in plant cell walls, but because it is most highly concentrated in parts of plants that are removed during food processing - such as tree bark and rice husks - most people only consume very small amounts.
The findings by Carding’s group certainly drew our attention,’ says Mark Vaeck, CEO of ActoGeniX, a Belgium company developing treatments for inflammatory bowel disease. ’This further illustrates the possibilities of oral administration of therapeutic proteins by a bacterial delivery system, which is the general basis of ActoGeniX’s therapeutic delivery platform. Provided that his prototype is able to pass the necessary regulatory and environmental evaluations to obtain approval for initiation of clinical trials, it may become a valuable candidate to be tested in patients with certain disease conditions.’
According to Carding, plans for scale-up are well underway and formulations suitable for human consumption could reach Phase I clinical trials within the next eighteen months. He says a neat biosafety feature of the system should help allay any environmental concerns. ’The only way this bacterium will work is if it’s inside the large intestine, which is essentially an oxygen deficient environment. In the air, it dies rapidly and this essentially contains it and prevents its spread within the environment.’
et alGUT, 2009