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Crohns Disease Research Group

Crohn's Disease Research Group

Crohn's Disease Research Group

Head of Group
Professor John Hermon-Taylor

Senior Scientist
Dr. Tim Bull

Post Doctoral Research Scientists
Dr. Karim Sidi Boumedine
Dr. Liz Mcminn

Clinical Research Fellow
Miss Angela Skull

The Crohn's Research Group has been researching the involvement of Mycobacterium avium subspecies paratuberculosis (MAP) in the causation of disease in animals and transmission of these pathogens to humans in retail pasteurised milk. Genomic research has identified additional DNA present in MAP but not in Mycobacterium avium subspecies avium (MAA). This 'extra' DNA includes 14-18 copies of an insertion sequence 'IS900', the 6496bp cassette of low % G+C DNA designated GS, and about 11Kb of additional DNA in the region of IS900 Locus 6. This extra DNA influences the expression of genes in MAP and provides the genetic machinery for coating the surface of MAP with derivitized fucose. This may assist the organism in its ability to adopt a protease-resistant ZN-negative non-bacillary form present in animals with paucimicrobial Johne's Disease and humans with Crohn's Disease.
The 11 Kb of extra DNA around IS900 Locus 6 is found in virulent MAP strains from animals and humans with Crohn's Disease and is absent from some vaccine strains of MAP. This region includes three tetR transcriptional regulators and genes encoding polyketide synthase and an apparently MAP specific catalase.

New methods exploiting the extraordinary physical robustness of MAP have been exploited by the group to develop much improved procedures for detecting low abundance MAP in humans, both in endoscopic ileocolonic mucosal biopsies and in full thickness surgical gut samples. These studies are still in progress but already confirm the presence of MAP in a minority proportion of normal people consistent with widespread exposure, and show unequivocally that MAP is present in over 90% of people with Crohn's Disease.
Studies are also in progress using state-of-the-art DNA vaccine technologies to develop a therapeutic DNA vaccine for treating Crohn's Disease sufferers by assisting in immune-mediated microbial clearance. Such therapy is expected to complement the use of new combinations of anti-MAP drugs currently under development for the treatment of active Crohn's Disease.

The group is working with Government agencies in the UK to assist in a co-ordinated program relevant to animal health and food safety, designed to reduce exposure of the human population to MAP. The group has active collaborations with science laboratories involved in parallel research throughout the world, including Prof. Roger Pickup (CEH, Lake Windermere, UK) in environmental studies, Prof. Marcel Behr (Div. Infectious Diseases, McGill University, Canada) Microarray analysis of MAP transcriptomes, Prof. Raul Barletta (University of Nebraska-Lincoln, USA) generation and study of specific MAP gene knockouts by transposon mutagenesis, Prof. Saleh Naser/ Dr Ira Shafran (University of Central Florida, USA) studies of MAP from humans in the US, Prof. Ivo Pavlik (Central Veterinary Research Institute, Brno, Czech Republic) MAP typing and as well as clinical gastroenterologists from the Dept. Medicine University Tampere Finland and Dept. Medicine University Umea, Sweden. Our major study of MAP in surgical resection samples is being carried out in collaboration with large acute hospitals in Carmarthen, Llanelli, Swansea and Llandough in South Wales, UK which has a high incidence of Crohn's Disease.
The work is supported by 5-year Group and Component research grants from UK Medical Research Council and National Environment Research Council, medical research charities Action Medical Research and The UK Ileostomy Association, as well as other charities and private donors.

What Is In Your Glass Of Milk ?

What Does Your Glass of Milk Contain ?

MAP - Mycobacterium Avium sub species Paratuberculosis ?
2 x Bovine Sugars ?
Mucus ?
Faeces ?
Antibiotic ?
Steroids ?
Growth / Yield Hormone ?

Please Boil Your Milk Before You Consume.

Please Do Not ReInfest Your Body With MAP.

Unraveling The Mystery Of Crohns Disease

Prof.John Hermon-Taylor.

Saturday Evening Post - USA.

Unraveling the mystery of Crohn's disease: could bacteria found in dairy products play a key role in Crohn's disease?

Saturday Evening Post, March-April, 2004 by Patrick Perry

In November 2000, German veterinarian Dr. Heinrich Dahmen began to suffer the unrelenting symptoms of severe pain, cramping, diarrhea, weight loss, and blood loss. After meeting with a gastroenterologist, Dahmen was diagnosed with Crohn's disease and started on conventional treatments for the disease, including immunosuppressive agents and the steroid prednisone.

After brief relief, Dahmen's condition worsened, and he faced invasive surgery to remove part of his inflamed digestive tract. Before undergoing the procedure, he followed up on a tip about the promising work of London investigators who were working on a new radical approach to the disorder. In July 2001, he traveled to London, where the research team found that Dahmen harbored an infectious agent believed to be involved in Crohn's disease. They began treating Dahmen with an antibiotic regimen that proved effective against the pathogen, and his condition slowly improved. Today, Dr. Dahmen is back in his busy veterinary practice, free of symptoms and feeling "cured" of the disease. Follow-up endoscopy and other tests confirm that Dahmen is in remission--his life has returned to normal.

"From that time I felt better and better," Dr. Dahmen told the Post. "I think I'm totally cured now after a two-year therapy."

In the United States, a Florida woman after years of unsuccessful treatments is also experiencing a rebirth after undergoing antibiotic therapy two years ago, which has since eliminated the unpredictable, yet ever-present pain of Crohn's disease,

On the Trail of Crohn's Disease.

For decades, researchers have debated the link between an infectious agent and Crohn's, a disease that affects millions of people around the world often in the prime of life. Crohn's numbers among a group of mysterious ailments known as autoimmune disorders, where for as yet unknown reasons the body begins to attack itself, wreaking havoc on normal bodily functions. While scientists are working hard to unravel the cause, of great concern is the fact that the rates of autoimmune disorders, like Crohn's and multiple sclerosis, have more than doubled in the last four decades.

Current treatments focus on the symptoms, but do little to address the root cause of Crohn's, including the potential role of bacteria. Whether infection plays a role remains a hotly contested area among experts. The theory, however, is gaining ground as evidence mounts supporting the connection.

Infection has emerged as a causative agent in other diseases, but not without resistance. Con sider Australian researcher Dr. Barry Marshall, who faced an uphill battle when challenging the medical doctrine by suggesting that a bacterium causes most ulcers--a discovery that has changed the course of treatment and quality of life for millions, At that time, the then-radical notion and its proponents were widely ridiculed. Dr. Marshall believes that infectious agents may play a role in other diseases, including Crohn's.

"My hunch is that they are infectious diseases, and we haven't found the germ yet," Dr. Marshall said in a Post interview several years ago for the book The Saturday Evening Post Investigates Digestive Diseases.

But if a microorganism causes Crohn's, what is it and how is it transmitted?

Researchers point to a persuasive body of evidence linking the bacterium, called Mycobacterium avium subspecies paratuberculosis (MAP), to the disease and underscore the route of transmission into the human population through one of our most popular drinks--milk.

MAP infection causes a debilitating disorder called Johne's disease that commonly occurs in cattle throughout the world, including the United States. Cows with Johne's share similar symptoms to people with Crohn's. infected cows secrete the mycobacterium in their milk. Individuals with a genetic susceptibility to Crohn's may thus pick up the disease. Supporters of the theory note that Crohn's is most frequently found in developed countries where milk consumption is high, except in countries where milk is boiled prior to consumption--an extra measure of precaution that some suggest would be prudent today.

The dairy industry, however, vigorously maintains that current pasteurization techniques are adequate to eliminate the bacteria, while critics highlight studies of the milk supply where MAP survived conventional pasteurization processes. Several European countries, such as Britain, have called for more stringent pasteurization procedures to ensure eradication of the microorganisms from the milk supply.

In 2003, British scientists at St. George's Hospital Medical School in London offered more support for the link between Crohn's and the milk-borne bug. Their study reports that over 90 percent of patients with Crohn's had MAP.

"The rate of detection of MAP in individuals with Crohn's disease is highly significant," said the researchers, writing in the Journal of Clinical Microbiology. "The discovery that the MAP bug is present in the vast majority of Crohn's sufferers means it is almost certainly causing the intestinal inflammation."

Lead researcher of the study, Dr. John Hermon-Taylor, has been studying the MAP and Crohn's connection for many years and successfully treated Crohn's patients with an antibiotic regimen that is restoring health and quality of life in his patients.

The Post spoke with Dr. Hermon-Taylor, chairman, department of surgery, St. George's Hospital Medical School in London, to learn more about his research into the milk and Crohn's connection, as well as how antibiotics are bringing new hope to individuals suffering from the devastating disorder.

Post : When did Mycobacterium avium subspecies paratuberculosis (MAP) emerge as a potential causative agent of Crohn's disease?

Hermon-Taylor : The idea was first suggested by Thomas Kennedy Dalziel in a paper published in the British Medical Journal in 1913. The reason that it has taken so long for the issue to become clarified is because the Mycobacterium avium subspecies paratuberculosis, or MAP, doesn't grow consistently in culture, much like the leprosy bacillus which belongs to the same family of organisms. The methods normally used for identifying a bacterium--namely, seeing it through a microscope, growing its culture, or doing a blood test for it--do not work with MAP.

Post : Endoscopy and other techniques would not detect its presence?

Hermon-Taylor : Endoscopy as done in the past wouldn't detect it, but the paper that we published in the U.S. in the July 2003 Journal of Clinical Microbiology shows that if you take endoscopic mucosal biopsies fresh from the endoscopy suite into the lab--and test them by the methods that our science has very carefully optimized and perfected--you can detect MAP with great accuracy.

Using the polymerase chain reaction (PCR) technique, you can show that virtually everyone with chronic inflammation of the Crohn's disease type is infected with the MAP bug. MAP is an organism that is a specific cause of chronic inflammation of the intestine in many different species of animals, including primates.

Post : Could you tell us about your research used to discover the bug in infected individuals?

Hermon-Taylor: We used the PCR test between 1989 and 1992 and found that about two-thirds of people with Crohn's disease were infected with the MAP bug. We published the findings in 1992 in Gut.

In 2000 I at last received a large grant from the U.K. Medical Research Council--our equivalent of the NIH in the United States. This five-year award has enabled us to go back to the beginning and really look at the methods to see why there have been so many conflicting results in the field. Apart from some people actually just not doing the procedures properly, the main problem is that the MAP bug is present in Crohn's disease in a very tough "Teflon-coated" invisible form. Standard laboratory reagents that would break open ordinary bugs, even tuberculosis bacilli, and release their DNA don't work for MAP. We found that you had to include a special mechanical disruption step in processing the tissue sample to access MAP DNA reliably.

When we did this, we found that virtually everyone with Crohn's disease is infected with MAP. We verified this absolutely by sequencing the DNA amplification products. Furthermore, using improved liquid cultures developed by Becton, Dickinson and Company in the U.S. and applying our DNA test to the cultures, we were able to show that 60 percent of the Crohn's disease-derived cultures incubated for more than 38 weeks contained MAP growing very, very slowly.

Post : Where do the MAP bacteria originate?

Hermon-Taylor: The MAP bug belongs to the group of organisms called mycobacteria. The most notorious mycobacteria are those causing tuberculosis and leprosy. But there is another "basket" of mycobacteria called Mycobacterium avium, so called because they were first found in birds.

MAP is, however, a clandestine bug, and it can live in animals and humans for years without necessarily causing disease. But in animals who become susceptible or inherit a susceptibility, or in humans who become susceptible or inherit a susceptibility, MAP infection can slowly lead to the emergence of chronic inflammation of the intestine. MAP demonstrates what scientists call "tissue tropism"; that is to say, if it is inhaled or ingested, it homes in on the gut and ends up causing chronic inflammation of the intestine.

Post : Does this eventually lead to Crohn's disease?

Hermon-Taylor: Our evidence and that of others suggests that the MAP bug causes most Crohn's disease. Expressed in a different way, if there were no MAP bugs in the world, there would hardly be any Crohn's disease at all.

Post : What led to the spread of the organisms?

Hermon-Taylor: The MAP bug was first identified in 1895, causing chronic inflammation of the intestine, in a cow in Germany. What MAP has done almost certainly is to take ad vantage over the last 150 years or so of the opportunities created by the rapidly expanding human populations of Western Europe and North America. This has been accompanied by increasing populations of domestic animals. They are, after all, our food animals. Instead of each sparsely distributed family having one cow, sheep and goat, we congregate in cities, and one family owns 300 cows and 300 sheep. Crowded farm environments, particularly in temperate regions with the animals housed in winter, create biological opportunities for amplification of the MAP organisms. When circumstances provide an ecological opportunity for bacteria in this way, they undergo what is called an adaptive radiation, and they change. This has happened with the cholera bacillus, salmonella bacillus, meningitis bacillus, Helicobacter pylori bacillus, and so on. The MAP which have emerged over the last 100 years have diverged into strains that prefer to infect cows, although they can infect sheep, and strains which prefer to infect sheep but can infect cows. We have evidence of the emergence of a humanized strain of these organisms.

Post : How do MAP bugs spread into humans?

Hermon-Taylor: The herd prevalence of MAP infection--that is to say, the percentage of herds which have two or more animals infected with the MAP bug--in Western Europe and North America runs between about two and 70 percent of herds. The infection is often subclinical, so you don't know the herd is infected. There is a huge regional variation, but herd prevalence in the range of 25 to 55 percent is common. Individual animal infection rates range between about one and eight percent. What all this says is, the domestic livestock of Western Europe and North America are extensively infected with the MAP bug.

And there are wildlife reservoirs. Research in Scotland, for example, has shown that rabbits on farms with infected domestic animals get infected with MAP. The organism is amplified and shed in the rabbit pellets. Grazing cattle will not eat grass contaminated with fox or dog feces, but they eat rabbit droppings. A short-range cycle of reinfection develops. This gives the organism a further opportunity to change. In addition, MAP goes up the rabbit predator chain to the foxes, carrion birds and so on.

Infected animals secrete the organism in their milk. We showed from 1990 to 1994 that there was a very high risk in Britain, that the MAP bug was being transmitted to the human population in retail pasteurized cow's milk supplies. This has since been confirmed by research carried out for the U.K. government's Food Standards Agency. The results of the work done by Dr. Irene Grant were published in 2002 in Applied and Environmental Microbiology. Using the DNA test and our optimized methods, she found that 11.8 percent of hundreds of bottles and cartons of milk from all over Britain tested positive for the MAP bug. She actually cultured live MAP from two percent of milk samples. She DNA-fingerprinted the MAP isolates, and they were not common laboratory strains.

But because MAP is so reluctant to grow in culture, the true proportion of retail cartons and bottles of pasteurized cow's milk in Britain contaminated with live MAP is much more likely to be closer to 10 percent than two percent.

Post : Would the same hold true in the United States?

Hermon-Taylor: Research carried out by the Institute for Food Safety and Hygiene, Faculty of Veterinary Medicine at the University of Zurich in Switzerland, using the methods we provided them, found that 19.7 percent of 1,384 bulk tanks of milk from all over Switzerland tested positive for the MAP bug. Work from the Veterinary Research Institute in Brno in the Czech Republic has reproduced the U.K. work of Dr. Irene Grant and cultured live MAP from two percent of samples of retail pasteurized milk in the Czech Republic.

Given what has been found in other countries, there is likely to be a similar risk that the MAP bug is also conveyed to people in the U.S. in milk supplies.

Post : Is milk then the primary mode of transmission of Crohn's?

Hermon-Taylor: It would be a major route of transmission. Another potential route is from the environment. Unlike the tuberculosis bacillus, tough MAP bugs can survive for months or years in the environment. Organisms that survive in the environment, which are already known to cause disease in animals and humans, include organisms like Cryptosporidium and Legionella, for example. Infected animals shed millions of the MAP bugs onto pastures. We have been doing research over the past 2 1/2 years which shows, as you would predict, that MAP bugs are flushed into surface waters like rivers. Where a river heavily contaminated with MAP runs through a population center, there is a risk that the organisms--which will aerosol off the water--may reach the human population by inhalation.

Post : Would boiling the milk to a certain temperature kill the bacterium?

Hermon-Taylor: Yes, it would almost certainly kill it. However, we do not know exactly if there is a commercially acceptable time-temperature combination that will ensure the destruction of all live MAP. Finding out what will kill MAP is particularly difficult because the only established method we have at present for telling whether MAP bugs are alive or dead is to try to culture them. And as we have already seen, even when MAP has not been heat-shocked, it is very reluctant to grow in culture.

But the probability is that if you took a kitchen thermometer and heated milk to 80 to 85 degrees Centigrade (177 to 185 degrees Fahrenheit) and set it aside to let it cool, it would substantially reduce or remove the risk of consuming live MAP bugs.

Post : In this way, are we doing everything possible to kill the organisms in milk?

Hermon-Taylor: That's right. I have been living with this knowledge for a long time. I knew MAP bugs were in milk in Britain in 1991. It's necessary to get the problem in perspective.

In the first half of the 20th century, most of the population of Western Europe and North America drank live, virulent tuberculosis bacilli before pasteurization of milk was generally implemented. Only a very small percentage of the people exposed to the bacilli came down with TB. The same thing is happening with the MAP bug. You have either to inherit or acquire a susceptibility to be at risk of developing disease. Alternatively you might get a huge dose of MAP just after having had the flu, or you may be exposed to a particularly nasty strain of the MAP bug. We know that even in human isolates, there are differences in the genomes and behavior of different human isolates of MAP.

Post : But susceptibility and milk must be present at the same time?

Hermon-Taylor: The key factor is the MAP bug. Susceptibility is an enabling co-factor. There has been some very good genetic research identifying the CARD 15/NOD2 gene abnormality, affecting about 15 percent of people with Crohn's disease. These people are mostly of Caucasian or Western European origin, living in North America and Western Europe and elsewhere. We should note, however, that 85 percent of people living in North America and Western Europe who have Crohn's disease don't have a defective CARD 15/NOD2 gene. Furthermore, the CARD 15/NOD2 abnormality doesn't work for people in China, Japan, or Korea who have Crohn's disease. In these countries the incidence of Crohn's disease is rising steeply, as also is the consumption of cow's milk.

Post : Are conventional therapies used to treat Crohn's today rendered useless if the cause is MAP? And if so, what is the treatment strategy?

Hermon-Taylor: In 1992, I came up with the following cascade of reasoning in the search for anti-MAP treatments for people with Crohn's disease whom I knew to be infected with the MAP bug. First is the knowledge, widely available in the chemotherapeutic literature, that clinical infections with any M. avium complex organisms like the MAP bug are poorly responsive to standard unmodified Streptomyces antibiotics. Drugs like streptomycin and rifamycin, which have worked wonderfully for TB and leprosy, don't work well with M. avium complex and MAP bugs.

Next, we also knew that the MAP bug divided very slowly, so that drugs like ciprofloxacin, which work by inhibiting DNA replication, would also not be much use.

The next group of drugs used in the standard treatment of TB--like isoniazid, ethambutol, and pyrazinamide--mostly acts by blocking the synthesis of lipid molecules in the cell walls of classical bacillary-form mycobacteria. These lipid molecules are responsible for the pink-staining ZN reaction. But I knew that the MAP bugs in Crohn's disease are not in their ZN-positive pink-staining form, so treatment with these drugs wasn't going to work, either.

In the early 1990s, new drugs were becoming available. One of those was rifabutin, a chemical modification of rifamycin. Another was clarithromycin from Abbott in Chicago. Clarithromycin is a native erythromycin molecule produced by Streptomyces, with a small chemical modification. These two drugs are much more active both in the lab, and in animals, against organisms of the M. avium complex. Also, they concentrated inside the cells where MAP was predicted to be. They had to be used together. If you use single agent therapy to treat MAP infections, you will get drug resistance within weeks or months. I began treating people with rifabutinclarithromycin combinations in 1992. Sometimes I also used another potentiating drug called clofazimine. We published the results in 1997.

There are now four open-label clinical studies carried out independently--one more in the U.K.; one by Tom Borody, M.D., in Sydney, Australia; and one by Ira Shafran, M.D., at the University of Central Florida--which essentially all say the same thing. That is, that somewhere between 50 to 75 percent of people with active Crohn's disease who can take rifabutin and clarithromycin treatment will get better and heal--sometimes like magic. The people who do not respond are infected with MAP bugs that are already resistant. Still, a majority of people--in my hands about 70 percent can take this treatment--get better. MAP infections are very difficult to eradicate.

Post : How many gastroenterologists are using this therapy to treat Crohn's patients?

Hermon-Taylor: Very few--less than one percent.

Post : If effective, why is the therapy not being used to treat such a severe disease?

Hermon-Taylor: There are several reasons. First, gastroenterologists don't believe MAP causes Crohn's disease, although most of them don't know the scientific evidence out there. Second, these drugs are not approved for use in Crohn's disease, although they are approved for the treatment of infections caused by nontuberculous mycobacteria. Third, these are only open studies and not the results of randomized, placebo-controlled clinical trials. From 1997 to 1999, I helped set up a randomized, controlled trial in several centers throughout Australia. It began in September 1999 and finished in September 2003. Four years later and at a cost of millions of dollars, the trial now has to run another year before the code is broken and the results analyzed.

Post : Any preliminary data that you can share?

Hermon-Taylor : Not publicly available, but it is highly likely that the randomized controlled trial will confirm the consistent results of the open label studies. This is, that a substantial proportion of people sick with Crohn's disease will heal when treated with these agents.

I have a cohort of people, some of them quite young, who had end-stage colonic Crohn's and were facing irreversible surgery and a lifetime of living with an abdominal stoma. Today they are walking around living normal lives because of these anti-MAP drugs.

MAP in March 2006.

INT 11/03/06.
31 MARCH 2006.

SECOND PROGRESS REPORT ON STRATEGY FOR THE CONTROL OF MYCOBACTERIUM AVIUM SUBSPECIES PARATUBERCULOSIS (MAP) IN COWS' MILK

Executive Summary

1. In May 2002, the Agency�s strategy for the precautionary control of MAP in cows' milk, developed in consultation with Defra, the industry and other stakeholders, was presented to the Board.

2. Board members were informed of progress to implement the strategy in May 2003 (paper note 03/05/01). This information paper provides an update on developments since then. No action is required.

Primary Production Division

Contact: Geraldine Hoad Tel: 020 7276 8968 (GTN 276 8968), Email: geraldine.hoad@foodstandards.gsi.gov.uk
Tim Foster Tel: 020 7276 8302 (GTN 276 8302),
Email: tim.foster@foodstandards.asi.gov.uk

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INT 11/03/06.
31 MARCH 2006.

SECOND PROGRESS REPORT ON STRATEGY FOR THE CONTROL OF MYCOBACTERIUM AVIUM SUBSPECIES PARATUBERCULOSIS (MAP) IN COWS' MILK

Issue

1. To provide an update on developments to implement the strategy for the control of MAP in cows' milk.

Backqround

2. MAP is a bacterium that occurs naturally in the environment throughout the world. It has been known for many years to be the cause of Johne�s disease (a chronic gastrointestinal infection) in cattle, sheep, goats and other ruminants. Crohn�s disease is a chronic inflammatory bowel disease of humans that can be severe, prolonged and debilitating. The cause of the disease is unknown, although one suggestion which has received a lot of attention is a link with MAP. In 2000, the Advisory Committee on the Microbiological Safety of Food (ACMSF) considered evidence that MAP was present in pasteurised milk.

The Committee noted that the then current balance of scientific opinion neither proved nor disproved the link between MAP and Crohn�s disease and advised that there was no need at that time for anyone to change their dietary habits. However given the different views on possible links to human illness, which were not likely to be resolved in the near future, the Committee recommended that the Agency should convene a group of stakeholders to consider all aspects of control of this organism.

3. The Agency used the output from the following stakeholder workshop in May 2001 to draw up a strategy with the aim of reducing the likelihood of consumers being exposed to MAP when consuming milk. In setting this objective, the Agency put to one side the question of whether or not MAP is the cause of Crohn�s disease. It was thought that it would take some years for this question to be resolved, but the Agency believed that precautionary action to reduce human exposure to MAP should be put in place sooner rather than later, and should not wait for the link to be proved or disproved. The draft strategy was presented to the Board in December 2001 and then submitted for public

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consultation. In the light of comments received, a revised strategy was presented to Members for information in May 20021 (Paper 02/05/02). The strategy proposed control measures at 3 key stages in milk production and processing: (i) in cattle;

(ii) during milking; and (iii) after milking, including pasteurisation.
4.

The actions aim to:
1. reduce or eliminate the carriage and shedding of MAP by dairy cattle;

2. reduce contamination of milk with MAP during the milking process;

3. make sure that pasteurisation is carried out effectively;

4. identify more effective ways of treating milk in order to eliminate MAP.

5. Implementation of the strategy is shared by Defra and the Agency. Defra is responsible for measures to reduce prevalence of MAP in dairy herds (aim 1), while the Agency leads on aims 2, 3 and 4 which relate to consumer health protection.

6. The strategy includes an action plan, with target dates for completing short term (by May 2003), medium term (by May 2008) and long term (after May 2008) actions. The Board was informed of progress against the action plan in May 20032 (paper 03/05/01). Progress since then against each of the points is
summarised in the Annex. Progress to date.

7. Work has been carried out on all four strands of the strategy. The issues are complex, and a single measure that could be quickly applied to control MAP in milk has not been identified. It is therefore envisaged that a combination of measures is needed to achieve control. While research has identified some milking hygiene and milk processing measures that could help, indications are that reduction of MAP in dairy herds is likely to have the greatest impact on MAP contamination of milk. With this in mind the Agency continues to work together with all interests, and with Defra in particular, to identify effective control measures.

1 http://www.food.gov.uk/multimedia/pdfs/papernote02-05-02.pdf

2 http://www.food.gov.uk/multimedia/pdfs/map_strategy.pdf

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MAP and Crohn�s disease � latest developments

8. Published research into a possible link between MAP and Crohn�s disease remains inconclusive. However, a number of research projects have recently been completed.

9. A clinical trial aimed at determining whether antimycobacterial therapy has a long-term benefit for patients with Crohn's disease was carried out in Australia. The results have yet to be published, although they were reported to a meeting of the British Gastroenterology Society in March 2005. The results showed that treatment with antimycobacterial drugs provided evidence of short-term benefits but there was no evidence of a cure. The researchers claimed that the study provided evidence against the �continuing� role of MAP infection in Crohn's disease.

10. In 2003, the Health Protection Agency (HPA) completed a Defra funded study to investigate whether MAP can survive within water distribution. MAP was not isolated from any of the sites tested in this study.

11. An ecological study was carried out in cattle to compare the incidence of Johne�s disease with admission rates for patients newly diagnosed with Crohn's disease. This unpublished study found no correlation between Johne�s disease incidence in cattle during 1992 to 1993 and from 2000 to 2002 with patients admitted due to severe Crohn's disease in 2000 to 2002. The researchers concluded that the findings do not support a causal role for MAP in the aetiology of Crohn's disease.

12. The report of a case control study commissioned by Defra and the Drinking Water Inspectorate (DWI) on the possible role of MAP in the aetiology of Crohn�s disease was published in July 2005. The study examined whether the consumption of drinking water, pasteurised milk and dairy products is associated with a risk of developing Crohn�s disease. The results do not provide any evidence of an increased risk of Crohn�s disease from the consumption of drinking water, including bottled water, pasteurised milk or dairy products. However, a statistical association3 was recorded between eating meat and developing the disease in the response to one of a variety of supplementary questions asked. The authors suggest a possible link with animal protein consumption - a finding that has been noted in other, earlier work. They have 3 Statistical associations by themselves do not necessarily imply cause and effect.

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stressed that the finding should be treated with caution and could be a statistical anomaly because the primary aim of the study was not to investigate meat consumption and Crohn�s disease.

13. The ACMSF considered the DWI report in September 2005 and considered the study had been been well designed and conducted and that the data analysis was thorough. The results did not point to a causal role for MAP in Crohn�s disease and Members concluded that the findings of the report did not suggest a need to change current FSA advice on consumption of meat4. However, the Committee requested that the FSA consider further the survival of MAP in solid foods and possible options for research in this area are being assessed. The ACMSF was not in a position to comment on a possible association between total animal protein and Crohn�s disease. The Committee requested that the FSA seek an opinion on this matter from the Scientific Advisory Committee on Nutrition (SACN) and this is under consideration by the Secretariat.

14. In February 2006, the results of a study on Crohn�s disease carried out by University College London were published in The Lancet. The study aimed to test the hypothesis that Crohn�s disease is a form of immunodeficiency caused by impaired innate immunity. Tests were carried out on people with Crohn�s disease and a control group of people without Crohn�s disease. In the Crohn�s patients it was demonstrated that the immune response was poor. White blood cells, called neutrophils, produced by the body to heal damage in the bowel were produced in far fewer numbers in Crohn�s patients compared to controls. In addition, when bacteria were injected under the skin the inflammatory response, in terms of an increased blood flow to the site, was abnormally low compared to controls. The researchers concluded that in Crohn�s disease, a constitutionally weak immune response leads to delayed or incomplete removal of bacteria and other bowel contents. These can then breach the mucosal barrier of the bowel wall resulting in chronic inflammation. Current treatments aimed at controlling Crohn�s disease are immunosuppressive and may accentuate the underlying immunodeficiency. The researchers hope to investigate whether drugs which increase blood flow would be effective in aiding the healing or prevention of lesions in Crohn�s disease.

15. The Department of Health (DH) set up an ad-hoc working group to consider the research needed to establish whether or not there is a causative link between 4 Meat may be eaten as part of a balanced and varied diet and is a good source of iron, zinc, B vitamis and protein. However due to its high saturated fat content, it should be eaten in moderation. Further information about eating and cooking meat can be found at www.eatwell.gov.uk

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MAP and Crohn�s disease. The working group reported its findings to the National Expert Panel on New and Emerging Infections in June 2005. The Panel concluded that given the many factors in addition to MAP that would be needed to be taken into account when undertaking any research into the causes of Crohn�s disease, this should be a matter for the Medical Research Council to take forward. This was discussed by the Advisory Committee on Dangerous Pathogens in January 2006 and it was agreed to refer the issue to the Medical Research Council. The next steps in this process are being pursued with DH officials.

Conclusion

16. The Agency is not aware of any developments to suggest that its current advice on the drinking of milk needs updating at this time. The Agency and DH, together with their expert committees, continue to keep evidence on the possible link between MAP and Crohn�s disease under review.

17.Work to deliver the strategy will continue but may be subject to review in the light of new developments as the strategy is intended to be an evolving document. Board Action Required

18. The paper is for information only. No action is required.

5 Advice can be found on

http://www.eatwell.gov.uk/healthydiet/nutritionessentials/milkanddairy/

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ANNEX PROGRESS AGAINST THE ACTION PLAN

AIM 1: TO REDUCE OR ELIMINATE THE CARRIAGE AND SHEDDING OF MAP BY DAIRY CATTLE

� To assess and validate current methods for detecting MAP infection in cattle (short term).

� Conduct a survey of MAP infection in the UK dairy herd (medium term). Underway: In January 2006, a study commenced to develop an integrated strategy to determine both the current extent of MAP infection in the UK dairy herd and provide mechanisms for on-going surveillance to assess the effectiveness of any implemented control strategy. The study, being undertaken by Veterinary Laboratories Agency and funded by Defra, SEERAD and DARDNI, aims:

� to determine the herd-level prevalence of Johne�s disease in the UK dairy herd;

� to examine the effect of current management practices and herd localisation on variation in this prevalence;

� to assess direct sampling of bulked faeces as a method for on-going monitoring of Johne�s Disease;

� to establish the genetic diversity of MAP in the UK;

� and to validate a liquid culture system for pooled faeces as a rapid high throughput diagnostic tool for MAP. A sample size of 150 herds (leading to an anticipated minimum of 100 herds) will be used. Testing will be carried out on blood, faeces and milk and the study design has been modified slightly to take account of information presented at the recent international meeting on Johne�s disease in Copenhagen. The study is due to complete in late 2007.

� To produce guidance for farmers on the control of MAP infection, which could be included in farm assurance or herd health schemes (short term)

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Completed: Defra guidance for the dairy industry on Johne�s disease in dairy herds, produced with input from the Agency and DH as well as the devolved administrations and the dairy industry, was launched at the Dairy Event at the National Agricultural Centre (NAC) at Stoneleigh in September 2004. Copies of the leaflet on the guidance have been issued to dairy farmers throughout the UK. More detailed guidance notes were sent to local veterinary inspectors, animal health offices, regional veterinary laboratories, private veterinary practices and stakeholders throughout the UK as well as libraries at veterinary and agricultural universities. The guidance documents can be downloaded from:

www.defra.gov.uk/animalh/diseases/other/johnes.htm

TCCC.UK took part in this consultationin DEFRA 2002 / 2004.

In September 2005, a joint industry-Government initiative, supported by Defra, was launched aimed at raising the awareness of Johne�s disease in beef cattle and methods for its control. The initiative includes an explanatory leaflet for farmers, a comprehensive information pack for use by veterinary practices for use at client meetings and a poster campaign in auction markets and farmer meetings over the winter. This guidance is to be �hosted� on the British Cattle Veterinary Association website and a link to the Defra website will be available.

� Development of a better vaccine against MAP for use in cattle (long term) The Product License for the live vaccine produced by the Veterinary Laboratory Agency (VLA) expired on the 29th October 2005. A limited supply is available from existing stocks and once this has been used up an inactivated vaccine from Spain will be imported. Vaccination does not completely prevent infection but, if linked to management practices to reduce transmission, it may be expected to reduce the amount of disease occurring in infected herds and the level of contamination of the environment. However, the imported vaccine may interfere with the interpretation of the tuberculin test. Defra leads on this issue and continues to review developments in this area.

AIM 2: TO REDUCE CONTAMINATION OF MILK WITH MAP DURING THE MILKING PROCESS

� To conduct research into teat cleaning practices and publish advice (short term)

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Completed: The Agency commissioned the University of Wolverhampton and Harper Adam University College to investigate the efficacy of common teat cleaning practices at dairy farms in England and Wales. This work found that some of the teat cleaning routines tested were more effective than others but that the effectiveness of any particular approach was influenced by how it was applied. The researchers presented the findings at the Dairy Event and at the British Mastitis conference in 2004. The research report has been placed in the Agency library and the results and conclusions were used to update guidance to be issued shortly by the Dairy Hygiene Inspectorate to all dairy farmers in England and Wales. The guidance highlights the importance of effective pre-milking teat cleaning of all cows, not just those which are visibly dirty, and describes the most effective methods.

� Review current advice on hygiene practices during milking with a view to issuing consolidated guidance (medium term)

� Review ways of disseminating advice on hygiene practices during milking so as to optimise future delivery (medium term) Completed: A guidance booklet for farmers on milk hygiene on the dairy farm was produced in collaboration with the Dairy Hygiene Inspectorate and was sent to all dairy farmers in England and Wales in 2004. In addition, guidance and advice on compliance with the hygiene legislation is provided during inspections. The booklet was also issued to DARD Inspectors in Northern Ireland. A revised guidance booklet reflecting the new EU hygiene legislation will shortly be sent to all dairy farmers in England and Wales. Similar guidance will also be distributed to dairy farmers in Scotland and Northern Ireland.

� Set up a consultative group to bring together those responsible for Defra�s Johne�s disease control strategy, the industry and other major stakeholders (short term) Actioned: A network has been set up by the Agency to update a wide range of stakeholders on developments relating to the implementation of the strategy and to provide a means for them to contribute to these activities. Since developing the strategy, there have been no particular issues on which it has been necessary to seek comments from the network. This progress report will be sent to them for information.

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AIM 3: MAKE SURE THAT PASTEURISATION IS CARRIED OUT EFFECTIVELY

� Recommend that dairies maintain their current pasteurisation procedures until the outcome of research on the pasteurisation conditions required to eliminate MAP is known (short term) Actioned: The appropriateness of this advice was reviewed in 2005 in the light of the findings from the LINK project highlighted under Aim 4 (see below). The Agency has considered the project results and considers that its current advice on the drinking of milk does not need updating.

� Produce pasteurisation guidance for dairies (to be aimed particularly at small dairies and on-farm pasteurisers) (medium term) Underway: The new EU food hygiene legislation (Regulation (EC) No 852/2004) provides for the development of national guides to good hygiene practice and the application of HACCP principles. Dairy UK6 have begun to develop a national
Industry Guide to Good Hygiene Practice for the dairy sector, including the primary production requirements of Regulation (EC) 853/2004 pertinent to raw milk and dairy products. The guide is expected to be completed by the end of 2006 and will be subsequently assessed and, if satisfactory, granted recognition by the FSA. Dairy UK will also shortly be publishing a revised version of their Code of Practice on High Temperature Short Time Pasteurisation. This will be expected to address the issue of controlling the pasteurisation process.

The Agency is giving consideration to whether the initiative developed to help specialist cheesemakers implement effective food safety management procedures could be adapted to deliver improved food safety management among on-farm pasteurisers.

� Implement measures to improve inspection and enforcement (particularly in relation to on-farm pasteurisers) (medium term) Ongoing: Initial work to review current arrangements has been undertaken as part of the Foodborne Disease Strategy. The need for further work on this will be considered in the light of future developments, such as the outcome of the post

6 Dairy UK represents dairy processors, farming representatives, co-ops and bottle milk buyers.

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Hampton review on reorganisation of regulatory inspections and enforcement, including establishment of the Animal Health Themed Agency of which the Dairy Hygiene Inspectorate is expected to become a part.

� Repeat 1999/2000 FSA survey of MAP in raw and pasteurised cows' milk (long term) The long term value of a repeat study will need to be reviewed in the light of developments since May 2002, when the Strategy was first presented (see para 16 of the main paper).

AIM 4: TO IDENTIFY MORE EFFECTIVE WAYS OF TREATING MILK IN ORDER TO ELIMINATE MAP

� To conduct research to find effective ways of treating milk to eliminate MAP Actioned: The LINK project to investigate the efficiency of various pasteurisation time/temperature conditions in combination with homogenisation processes on the inactivation of MAP in milk has been completed. Two scientific papers to disseminate the research findings were published in 2005. The first paper reported that in 96.7% of samples MAP was completely inactivated by HTST (high temperature/short time) pasteurisation, either alone or in combination with homogenisation.

Where MAP colony counts were found (ie in the remaining 3.3%) the estimated log10 reduction by heat treatment, with or without homogenisation was 4.0 � 5.6. HTST pasteurisation achieved a greater than 5 log10 reduction in MAP numbers in most processing runs.

The second paper reported that there is potential for removal of MAP from milk by centrifugation or microfiltration. In laboratory experiments, both were shown to be capable of removing 95-99% of MAP from milk. FSA is considering the results with
a view to possible further research.

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DEFRA Johnes Disease Link

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