Curr Opin Gastroenterol. 2009;25(4):329-333. © 2009
Abstract and Introduction
Abstract
Purpose of review To summarize recent evidence on the role of intestinal bacteria in inflammatory bowel diseases, and of antibiotics and probiotics in their treatment. The implications connected with the use of antibiotics are also examined.
Recent findings The hypothesis that Mycobacterium paratuberculosis could be a causative agent of Crohn's disease has not been confirmed by a large trial on symptomatic patients treated by a combination of antibiotics active against this bacterium. An increased number of adherent-invasive Escherichia coli have been found in the intestinal tissue of patients with Crohn's disease, but their role in the pathogenesis of this condition remains to be defined. The combination of metronidazole and azathioprine, associating the effects of a reduced bacterial load with immunosuppression, appears to be a therapeutic option to decrease the recurrence of postoperative Crohn's disease in high-risk patients. However, concerns are raised by the possibility that antibiotics may induce disease relapse due to Clostridium difficile infection.
Summary Recent literature provides increasing support for the use of antibiotics in Crohn's disease, although the side effects limit their long-term use. The efficacy of antibiotics in ulcerative colitis is not confirmed by the available literature, except in severe colitis. More trials are needed to support the use of probiotics as therapy in inflammatory bowel disease.
Introduction
The most widely accepted hypothesis on the cause of inflammatory bowel disease (IBD) is that it is caused by an excessively aggressive immune response to antigens in the gut of genetically susceptible individuals.[1] Intestinal bacteria are dominant antigens present in the gut and their role in IBD is supported by many experimental and clinical data. Nevertheless, whereas antibiotics are widely used in clinical practice for treating IBD's septic complications,[2] only few clinicians consider these drugs useful in the active noncomplicated stages of IBD to reduce a possible antigenic overload.[3] A number of randomized studies on antibiotic therapy have been carried out with varied results, mainly in Crohn's disease, but also in ulcerative colitis and pouchitis. The antibiotics used were those with antimycobacterial activity, metronidazole (Metro) active against anaerobic bacteria, ciprofloxacine (Cipro) active against Escherichia coli and, most recently, the nonabsorbable rifaximin.
Antimycobacterial Therapy and Crohn's Disease
The pathological aspects of IBD lesions are similar to those of an infectious disease, and many studies have been directed towards the identification of a specific causative agent.
During the 1980s and 1990s some investigators reported the presence of atypical Mycobacteria in Crohn's disease intestine, with limited supporting immunological evidence.[4,5] With the hope of curing Crohn's disease, antibiotics active against atypical Mycobacteria have been tested with conflicting outcomes.[6] The most important study, published at the end of 2007, employed the antibiotic clofazimine together with clarithromycin and rifabutin, against placebo, for up to 2 years, in addition to a 16-week tapering course of prednisolone.[7] This antibiotic combination was chosen because of its activity against Mycobacterium paratuberculosis (MAP), the agent of Johne's disease in animals, considered a potential cause of Crohn's disease. Two hundred and thirteen Australian patients were enrolled and randomized. The only significant benefit was observed at 16 weeks, when antibiotics were combined with steroid. A modest nonsignificant advantage of antibiotics over placebo in reducing Crohn's disease relapse was registered at every observation time point during the 2-year period. In conclusion (and in line with a previous meta-analysis), this trial has shown that antimycobacterial treatment is not effective in inducing remission without a course of corticosteroids, and that the advantage of adding antimycobacterials to steroids is minimal.
Some comments supported the conclusions of this trial, whereas others disputed it, affirming that the causality of MAP in Crohn's disease cannot still be completely refuted.[8,9–12] The main objections were: the well known antibiotic resistance of MAP, the relatively low doses of antimycobacterials employed, and the use in the placebo arm of mesalamine and/or azathioprine which have a potential anti-MAP effect. Such arguments, however, are unconvincing in view of the fact that current antitumour necrosis factor (TNF) treatments induce remission of active Crohn's disease and heal colonic and ileal lesions. TNF plays a key role in the host reaction against mycobacteria, namely granuloma formation and control of inflammatory disease. Over 70 cases of tuberculosis in close temporal association with the initiation of treatment with anti-TNF agents have been reported in Crohn's disease. However, anti-TNF therapy has never been associated with disseminated MAP in Crohn's disease, a strong argument against the role of MAP as infectious agent of Crohn's disease.
Consequently, it would seem that the small clinical advantage observed with antimycobacterials, as shown in some studies, is ascribable to a generic effect directed towards those commensal enteric bacteria which may have a pathogenic potential without being typical infectious agents.[13]
Antibiotics and Crohn's Disease
In the last years several groups have reported the presence of E. coli in Crohn's disease ileal and colonic tissue.[14,15] E. coli with adherent-invasive properties (AIEC) found in these specimens is able to colonize the intestinal mucosa and to invade and replicate within macrophages, inducing the secretion of a large quantity of TNF.[16] Clarithromycin, a macrolide wide-spectrum antibiotic, can penetrate into macrophages and can be effective in eradicating the bacteria.
The only trial performed last year in active Crohn's disease has compared clarithromycin 1g against placebo, administered for 3 months to 41 patients with Crohn's disease with CDAI over 200 points and high concentration of C-reactive protein (CRP).[17•] There was no difference in the remission or response rate at 3 months between the antibiotic and placebo and the study was stopped. It is possible that clarithromycin, given its mediocre activity against E. coli, is not the best antibiotic to treat Crohn's disease flares, assuming that AIEC is really implicated.
Maintenance of Crohn's disease remission induced by surgery or by drugs is a key goal for a gastroenterologist. His/her job is to increase the time until reappearance of lesions and to reduce their severity without inducing significant side effects. A patient's compliance with the prescribed drug is crucial. It is well established that surgery in Crohn's disease is followed by a high 1-year endoscopic recurrence and that bacteria are strongly suspected to be implicated in the recurrence of the lesions. Antianaerobic bacterial drugs, such as metro and ornidazole, have been shown to reduce the severity of endoscopic recurrence after Crohn's disease surgery, but their long-term use is burdened by a low compliance because of an elevated number of side effects. A randomized, placebo-controlled study employed a 3-month course of metro in combination with a 1-year of azathioprine to reduce the 1-year endoscopic recurrence in 81 operated patients with high risk of recurrence.[18••] This strategy reduces the period of metro use utilizing it as bridge therapy, given the slow action of azathioprine. Four patients were withdrawn because of side effects; in three of them side effects probably due to metro occurred in the first 3 months. The difference in recurrence rates between metro and azathioprine and metro and placebo was statistically significant, 55 vs. 78%, respectively, thus offering the prospect of a biologically plausible therapy with limited side effects. This strategy combines the approach of reducing the anaerobic bacteria with the down-regulation of immune response. In fact, a recent study on Crohn's disease paediatric patients reported that a subset of such patients with antibodies against microbial antigens was more susceptible to complications.[19•]
The most significant reason for antibiotic treatment failure is the emergence of side effects, particularly important in long-term treatment. The interest of clinicians has been recently moved towards the nonabsorbable antibiotic rifaximin which, due to its high safety profile, is suitable for long-term treatment. Rifaximin, active against anaerobic bacteria and E. coli, has been approved for the treatment of traveller's diarrhoea. In 2008 two case reports described the response to rifaximin in six patients with Crohn's disease.[20,21] In one of these articles the clinical remission obtained in three newly diagnosed ileal Crohn's disease patients was confirmed also by a capsule endoscopy mucosal improvement.[20] The doses employed varied from 600 to 800 mg daily for a period of 3 weeks to over 6 months. A previous rifaximin-controlled trial had shown that 800 mg given twice daily for 3 months in patients with elevated CRP provided the best result.[22]
Abstract and Introduction
Abstract
Purpose of review To summarize recent evidence on the role of intestinal bacteria in inflammatory bowel diseases, and of antibiotics and probiotics in their treatment. The implications connected with the use of antibiotics are also examined.
Recent findings The hypothesis that Mycobacterium paratuberculosis could be a causative agent of Crohn's disease has not been confirmed by a large trial on symptomatic patients treated by a combination of antibiotics active against this bacterium. An increased number of adherent-invasive Escherichia coli have been found in the intestinal tissue of patients with Crohn's disease, but their role in the pathogenesis of this condition remains to be defined. The combination of metronidazole and azathioprine, associating the effects of a reduced bacterial load with immunosuppression, appears to be a therapeutic option to decrease the recurrence of postoperative Crohn's disease in high-risk patients. However, concerns are raised by the possibility that antibiotics may induce disease relapse due to Clostridium difficile infection.
Summary Recent literature provides increasing support for the use of antibiotics in Crohn's disease, although the side effects limit their long-term use. The efficacy of antibiotics in ulcerative colitis is not confirmed by the available literature, except in severe colitis. More trials are needed to support the use of probiotics as therapy in inflammatory bowel disease.
Introduction
The most widely accepted hypothesis on the cause of inflammatory bowel disease (IBD) is that it is caused by an excessively aggressive immune response to antigens in the gut of genetically susceptible individuals.[1] Intestinal bacteria are dominant antigens present in the gut and their role in IBD is supported by many experimental and clinical data. Nevertheless, whereas antibiotics are widely used in clinical practice for treating IBD's septic complications,[2] only few clinicians consider these drugs useful in the active noncomplicated stages of IBD to reduce a possible antigenic overload.[3] A number of randomized studies on antibiotic therapy have been carried out with varied results, mainly in Crohn's disease, but also in ulcerative colitis and pouchitis. The antibiotics used were those with antimycobacterial activity, metronidazole (Metro) active against anaerobic bacteria, ciprofloxacine (Cipro) active against Escherichia coli and, most recently, the nonabsorbable rifaximin.
Antimycobacterial Therapy and Crohn's Disease
The pathological aspects of IBD lesions are similar to those of an infectious disease, and many studies have been directed towards the identification of a specific causative agent.
During the 1980s and 1990s some investigators reported the presence of atypical Mycobacteria in Crohn's disease intestine, with limited supporting immunological evidence.[4,5] With the hope of curing Crohn's disease, antibiotics active against atypical Mycobacteria have been tested with conflicting outcomes.[6] The most important study, published at the end of 2007, employed the antibiotic clofazimine together with clarithromycin and rifabutin, against placebo, for up to 2 years, in addition to a 16-week tapering course of prednisolone.[7] This antibiotic combination was chosen because of its activity against Mycobacterium paratuberculosis (MAP), the agent of Johne's disease in animals, considered a potential cause of Crohn's disease. Two hundred and thirteen Australian patients were enrolled and randomized. The only significant benefit was observed at 16 weeks, when antibiotics were combined with steroid. A modest nonsignificant advantage of antibiotics over placebo in reducing Crohn's disease relapse was registered at every observation time point during the 2-year period. In conclusion (and in line with a previous meta-analysis), this trial has shown that antimycobacterial treatment is not effective in inducing remission without a course of corticosteroids, and that the advantage of adding antimycobacterials to steroids is minimal.
Some comments supported the conclusions of this trial, whereas others disputed it, affirming that the causality of MAP in Crohn's disease cannot still be completely refuted.[8,9–12] The main objections were: the well known antibiotic resistance of MAP, the relatively low doses of antimycobacterials employed, and the use in the placebo arm of mesalamine and/or azathioprine which have a potential anti-MAP effect. Such arguments, however, are unconvincing in view of the fact that current antitumour necrosis factor (TNF) treatments induce remission of active Crohn's disease and heal colonic and ileal lesions. TNF plays a key role in the host reaction against mycobacteria, namely granuloma formation and control of inflammatory disease. Over 70 cases of tuberculosis in close temporal association with the initiation of treatment with anti-TNF agents have been reported in Crohn's disease. However, anti-TNF therapy has never been associated with disseminated MAP in Crohn's disease, a strong argument against the role of MAP as infectious agent of Crohn's disease.
Consequently, it would seem that the small clinical advantage observed with antimycobacterials, as shown in some studies, is ascribable to a generic effect directed towards those commensal enteric bacteria which may have a pathogenic potential without being typical infectious agents.[13]
Antibiotics and Crohn's Disease
In the last years several groups have reported the presence of E. coli in Crohn's disease ileal and colonic tissue.[14,15] E. coli with adherent-invasive properties (AIEC) found in these specimens is able to colonize the intestinal mucosa and to invade and replicate within macrophages, inducing the secretion of a large quantity of TNF.[16] Clarithromycin, a macrolide wide-spectrum antibiotic, can penetrate into macrophages and can be effective in eradicating the bacteria.
The only trial performed last year in active Crohn's disease has compared clarithromycin 1g against placebo, administered for 3 months to 41 patients with Crohn's disease with CDAI over 200 points and high concentration of C-reactive protein (CRP).[17•] There was no difference in the remission or response rate at 3 months between the antibiotic and placebo and the study was stopped. It is possible that clarithromycin, given its mediocre activity against E. coli, is not the best antibiotic to treat Crohn's disease flares, assuming that AIEC is really implicated.
Maintenance of Crohn's disease remission induced by surgery or by drugs is a key goal for a gastroenterologist. His/her job is to increase the time until reappearance of lesions and to reduce their severity without inducing significant side effects. A patient's compliance with the prescribed drug is crucial. It is well established that surgery in Crohn's disease is followed by a high 1-year endoscopic recurrence and that bacteria are strongly suspected to be implicated in the recurrence of the lesions. Antianaerobic bacterial drugs, such as metro and ornidazole, have been shown to reduce the severity of endoscopic recurrence after Crohn's disease surgery, but their long-term use is burdened by a low compliance because of an elevated number of side effects. A randomized, placebo-controlled study employed a 3-month course of metro in combination with a 1-year of azathioprine to reduce the 1-year endoscopic recurrence in 81 operated patients with high risk of recurrence.[18••] This strategy reduces the period of metro use utilizing it as bridge therapy, given the slow action of azathioprine. Four patients were withdrawn because of side effects; in three of them side effects probably due to metro occurred in the first 3 months. The difference in recurrence rates between metro and azathioprine and metro and placebo was statistically significant, 55 vs. 78%, respectively, thus offering the prospect of a biologically plausible therapy with limited side effects. This strategy combines the approach of reducing the anaerobic bacteria with the down-regulation of immune response. In fact, a recent study on Crohn's disease paediatric patients reported that a subset of such patients with antibodies against microbial antigens was more susceptible to complications.[19•]
The most significant reason for antibiotic treatment failure is the emergence of side effects, particularly important in long-term treatment. The interest of clinicians has been recently moved towards the nonabsorbable antibiotic rifaximin which, due to its high safety profile, is suitable for long-term treatment. Rifaximin, active against anaerobic bacteria and E. coli, has been approved for the treatment of traveller's diarrhoea. In 2008 two case reports described the response to rifaximin in six patients with Crohn's disease.[20,21] In one of these articles the clinical remission obtained in three newly diagnosed ileal Crohn's disease patients was confirmed also by a capsule endoscopy mucosal improvement.[20] The doses employed varied from 600 to 800 mg daily for a period of 3 weeks to over 6 months. A previous rifaximin-controlled trial had shown that 800 mg given twice daily for 3 months in patients with elevated CRP provided the best result.[22]