Ulcerative Colitis caused by Bacteria?
Introduction
Ulcerative colitis is a complex chronic inflammatory disease that affects the large intestine and the rectum. UC causes inflammation or sores in the lining of the colon and rectum. These ulcers form where inflammation has killed the cells that usually line the colon.Ulcerative colitis can take many forms and depends on the area affected. The four major forms are ulcerative proctitis, proctosigmoiditis,left-sided colitis, and pancolitis. Ulcerative proctitis is the least severe IBD and is defined by inflammation that affects the rectum and does not cover more than six inches. Left-sided colitis is when inflammation of the colon only occurs on the left side. Pancolitis is when there is inflammation throughout the colon. While the term Ulcerative Colitis will be used pancolitis will be the form that is focused on because this is the most serious form of the disease.
Symptoms of ulcerative colitis include, but are not limited to abdominal cramps, diarrhea, anemia, weight loss, fatigue, rectal bleeding, loss of appetite, loss of bodily fluids and nutrients, joint pain, as well as others. These symptoms are also common symptoms of other Inflammatory Bowel Diseases (IBD) which makes diagnosis complicated. Also multiple IBD's can occur at the same time and one can progress into the other further complicating diagnosis.
Ulcerative Colitis is closely related to another IBD, Crohn's disease. Crohn's disease differs from UC in that it affects deeper into the small intestines. Other than that difference the two diseases are very similar. The exact pathogenesis of Ulcerative colitis in unknown and remains an important topic of research. Ulcerative colitis most commonly starts in late adolesence to early adulthood, but can occur in young children and elderly people. Ulcerative colitis is found all over the world, but is most common in England, North America, and Northern Europe. Up to 20% of people with UC have a primary relative with the disease or another IBD which suggests that there may be a genetic component to the disease.
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Pathogenesis
The exact pathogenesis of Ulcerative Colitis is unknown. Patients with UC show abnormalities in the response of their immune system. The immune system is chronically activated producing inflammation even in the absence of microbes. Doctors are unsure whether the immune response causes the disease or is in response to the disease. It is likely that no one pathogen or factor is the sole cause f UC. Ulcerative colitis is not caused by specific foods or stress, but these factors may worsen symptoms associated with UC. One common theme researchers find is that patients with UC show elevated levels of microbes in their body. This has been shown in both animal models as well as clinical trials. Mice with targeted deletion of the interlukin-2 gene spontaneously develop Ulcerative colitis in normal conditions, but fail to exhibit the disease in germ free environments(Sellon).
Colonic mucus samples taken from a 12-year-old girl suffering from UC were isolated and studied using cloning and sequencing of the 16S rRNA genes. The sequences were studied using BLAST and the bacteria were assigned to one of the four major phyla:Firmucutes
Bacteroidetes,Actinobacteria,and Proteobacteria. There was a significant difference in the dominant bacteria group of colonic microbiota between the patient with UC and healthy individuals. Several studies show the colonic microbiota of healthy individuals are dominated by Bacteroidetes and Clostridium. The most dominant groups in the study were Proteobacteria and Clostridium. There was also high incidents of Enterobacteriacea and Bacteroidetes fragilis in the UC patient. Also, there was a substantial presence of Pseudomonas aeruginosa in the patient diagnosed with Ulcerative Colitis. The presence of P. aeruginosa in the feces of a healthy individual has never been reported before. The findings of this study support the hypothesis that bacteria play a role in Ulcerative Colitis.(Wang Paper)
Another study also supports bacterial involvement in UC. Bacteria from inflamed mucosa were isolated and identified. Twenty bacterial species were isolated from both healthy and diseased individuals. Bacteroides distasonis. B. vulgatus, and Fuscobacterium varium were detected in half the patients with UC. The levels of F. varium were significantly different than healthy individuals. F. varium invades the inflamed mucus and lives in the crypts. The results from this study suggest F. varium is associated with Ulcerative Colitis.(Ohkusa paper)
Both studies showed that there is a difference in the level as well as the makeup of the intestinal microbiota between Ulcerative Colitis patients and healthy individuals. While both studies suggest that bacteria play a role in Ulcerative Colitis they do not claim that the bacteria are the cause. However, the presence of the bacteria most likely enhance the symptoms of the disease.
Diagnosis
First a complete examination and review of symptoms and medical history of the patient is conducted. If the symptoms suggest an IBD doctors run a series of tests to rule out some IBD's and to see if there is a specific IBD causing the symptoms.
Stool samples are collected to rule out parasites or infection that cause colitis which mimics Ulcerative Colitis. Blood tests are also run to see if there is anemia, high white blood cell count, or sedimentation. Elevated white blood cell count and sedimentation are indicative of ongoing inflammation in the colon. Stool samples and blood tests can be used to suggest inflammation in the colon, but confirmation of Ulcerative Colitis requires visualization of the colon.
Colonoscopies allow direct visualizatin of the colon and can confirm Ulcerative Colitis. Biopsies of the colonic tissue can be taken during the colonscopy to determine the severity of the disease.
Another way to confirm the diagnosis of UC is a barium enema X-ray. A chalky substance is inserted in the rectum and injected in the colon. The barium outlines the colon on the x-ray so the colon can be visualized. A Barium enema X-ray is useful, but is less accurate than direct visualization.
CT enterography MR enterography are new imaging methods for visualizing the digestive system. CT etnerography combines a CT scan with contrast to image the small bowel. CT enterography is used specifically for daignosing Crohn's disease, but is also useful in diagnosing UC. MR enterography shows images of the bowel without using radiation. The tests and procedures that are used to diagnose Ulcerative Colitis may differ depending on the physician's preference and the equipment and diasgnostic center availability.
Treatment
There are several different treatment option for patients with
Ulcerative Colitis. The disease is managed from patient to patient and what works for one patient may not work for another patient. Based on the severity of the inflammation a doctor will reccommend the treatment or option that is believed to work the best. More of often than not there is not just one treatment that a patient will receive. The treatments are adaptive and change with the severity of the inflammation as well as how the inflammation responds to the treatment. The treatment plans are unique to each individual patient and that patients needs. Sometimes very mild forms of UC can be controlled with lifestyle and diet changes. However, most UC patients require some form of medication. There are several different medications that are prescribed
Mesalamine and Balsalazide are usually prescribed as the first line medications. Both medications work to reduce the inflammation in the colon. The exact mechanism of how the inflammation is reduced is unknown.
Corticosteroids are prescribed to reduce inflammation in the colon, but are not intended for long term use. Corticosteroids are used when there is an intense flare-up of inflammation to reduce the inflammation to a more managable level.
Azathiprine and 6-Mercaptopurine suppress the immune system slightly and reduce bowel inflammation. Patients who take these medications have to be monitorred carefully because with a suppressed immune system they are more susceptible to infections.
Inflixmab is precribed to patients with moderate to severe Ulcerative Colitis that has not responded to other treatments. This medicine can reduce the need for surgery by almost 50%.
Surgery is used as treatment when UC has not responded to other treatments or precancerous changes develop on the colon. Approximately 25-30% of patients with UC end up needing surgery. Ileoanal anastomosis is the most common surgery for UC. All of the colon and the diseased lining of the rectum are removed. The primary advantage of Ileaonal anastomosis is that waste can still be eliminated normally afterward and the surgery can be done laproscopically. Proctocolectomy with ileostomy is also another common surgery for UC patients which also involves removing the colon and the rectum. However, a stoma (opening) is created on the outside of the body and waste is elimanted through the stoma into a bag. Complications of this surgery include infections and complications with the stoma.(Mayo clinic.org)
Prognosis
Ulcerative colitis is a chronic disease consisting of multiple flare-ups followed by periods of remission. The goal of most treatment options is to reduce the flare-ups and prolong the periods of remission. Rapid initial inflammation may result in more severe complications. Very rarely does total remission occur after only one flare-up. If this occurs the inflammation was more likely due to an infection in the colon and not UC. People with ulcerative proctitis have the best prognosis. Individuals with ulcerative colitis that affects the entire colon with more severe inflammation have the worst prognosis. As stated before 25-30% of patients require surgery at some point in their life. The main advantage to surgery is that the surgery results in curing of the disease. Complications of ulcerative colitis include, but are not limited to severe bleeding, perforated colon, severe dehydration, liver disease, osteoporosis, inflammation of skin, an incrased risk of colon cancer, and toxic megacolon(Mayo). Toxic megacolon is rapid widening of the large intestine in one hour to a few days. Most often toxic megacolon results in surgery and removal of the colon. Approximately 5% of patients with ulcerative colitis develop colon cancer. The risk of cancer increases with duration of the disease as well as how severe the damage to the colon is. The risk of cancer in patients with the entre colon affected is up to thirty two times more than healthy individuals(digestive.niddk). Precancerous changes called dysplasia can occur in the cells lining the colon and colonoscopies every one to two years are suggested for patients with IBD in order to screen for dysplasia.
Genetic component
There seems to be a genetic component that contributes to ulcerative colitis. Twenty percent of patients with ulcerative colitis have a family member of relative with either ulcerative colitis or Crohn's disease. Recently multiple studies have used genome wide association scans to investigate genetic susceptibility to ulcerative colitis. Approximately thirty genes have been identified that may increase suscpetibility to UC. These genes include immunoglbin receptor gene FCGR2A, 5p15, 2p16, ORMDL3, ECM1, as well as regions on chromosomes 1p36, 12q15, 7q22, 22q13, and IL23R (medicine net) At this point it is unclear whether the identification of these genes will help in treatment with the disease, but may help with determining the pathogenesis.
One study that looked at the genetic component of ulcerative colitis used mice as a model organism. In mice oral administration of dextran sulfate sodium(DSS) results in both acute and chronic ulcerative colitis in mice. Using this model differential susceptibility to DSS was tested in mice. Various inbred strains of mice were used to test susceptibility. After twenty one days of being exposed to DSS the mice were euthanized and samples from the cecum and colon were evaluated. A pathologist examined the samples and scored them for lesions based on severity, ulceration, hyperplasia, and area affected. The study concluded that there were significant differences in susceptibility to DSS among different strains. The strain differences will be useful for design in the genetic mapping to identify genes that determine suscpetibility to DSS-induced colitis. The identification of th genes may predict pathways for for intervention in humans. This study further supports the notion that there is a genetic component of ulcerative colitis.
<br< Further research is needed to determine the mechanism in which the identified genes result in greater susceptibility to ulcerative colitis. The mechanism may provide a future target for medicine.
Research
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Conclusion
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References
Edited by student of Joan Slonczewski for BIOL 238 Microbiology, 2009, Kenyon College.
