Many patients with Crohn’s disease develop resistance to treatments.
Researchers have looked at how Chron’s disease-related bacteria can form drug resistance.
They found that bacteria associated with Crohn’s disease rely on multiple stress responses to survive, multiply, and develop – tolerating antibiotics within white blood cells called macrophages (large white blood cells).
Crohn’s disease is a lifelong illness which causes inflammation and ulceration of the digestive system. Symptoms of Crohn’s disease include urgent diarrhoea, abdominal pain, profound fatigue and weight loss.
There are approximately 160,000 patients with Crohn’s disease in the UK and this number is growing – it is a hidden health crisis.
The findings were published in the journal PLOS Pathogens by Olivier Espéli of the College de France and PSL Research University in Paris, and colleagues.
Chron’s disease and drug resistance
Chron’s disease is characterised by an imbalance in the intestinal microbiome. In particular, adherent-invasive Escherichia coli (AIEC) strains have been implicated in the disease. AIEC colonise intestinal cells and survive and replicate within macrophages.
In the new study, the researchers demonstrated that the AIEC LF82 strain can switch between replicating and non-growing states within macrophages. This switch can result from a stress response called the ‘stringent response’ immediately after uptake by macrophages, or at later stages, from DNA damage and a stress response called ‘SOS’ during replication within macrophages.
First, a stress response called the stringent response halts the replicative cell cycle of AIEC LF82 for a few hours, during which a large number of AIEC LF82 acquire the ability to tolerate antibiotic treatments.
Later, when AIEC multiplication restarts, it requires DNA repair, suggesting that AIEC have accumulated DNA damage during the first hours after infection. In this second phase, non-growing bacteria appeared frequently from the population of growing AIEC LF82, raising the proportion of antibiotic resistant AIEC LF82 by up to 10% of the population.
The results suggest that a reservoir of antibiotic resistant, non-growing bacteria could be responsible for long-term survival in the host as well as relapsing infections.
Espéli said: “Within their macrophage’s niche, Crohn’s disease associated bacteria become tolerant to antibiotics.”
A further study, conducted earlier this year, was the largest study ever to look at why patients with Crohn’s disease develop drug resistance to a commonly used group of medicines.
The study identified a genetic marker which could individualise drug treatment.
A UK wide collaboration led by the University of Exeter, Royal Devon & Exeter NHS Foundation Trust and the Wellcome Sanger Institute, has demonstrated that a genetic variant carried by 40% of the population explains why some patients develop antibodies against the anti-TNF drugs, infliximab and adalimumab and lose response.
Anti-tumour necrosis factor (TNF) drugs, infliximab and adalimumab, are used to treat patients with moderate to severe Crohn’s disease and ulcerative colitis when other treatments have not worked. Also known as biological medicines, these drugs work by blocking TNF, a protein which drives persistent gut inflammation.
One of the major reasons patients lose response is the development of an immune response to the drug (immunogenicity).
Anti-TNF drugs are large, complex molecules, made inside living cells.
Repeated administration causes the immune system to recognise the drug as a potential threat rather than a medicine, leading to the production of antibodies against the drug.
These antibodies increase the rate at which the drugs are removed from the body. As well as reducing the effectiveness of treatment, antibodies may also cause adverse drug reactions at the time of injection or infusion.
This research identified a genetic marker HLA-DQA1*05, carried by 40% of the European population that increases risk of development of antibodies against infliximab and adalimumab two-fold.
The authors conclude that a further trial is required to confirm that genetic testing prior to treatment will reduce the rate of treatment failure by facilitating the most effective choice of therapy for individual patients.