Probiotics for Crohn's disease: what have we learned?

Short abstract

Probiotics do not seem to be a therapeutic option for patients with Crohn's disease, either in the acute phase or for maintenance

A causative role of bacteria in Crohn's disease (CD) has been surmised for a long time. Only in recent years however has there been a large body of evidence from genetic and bacteriological studies indicating that the intestinal flora is the essential factor in driving the Crohn's inflammatory process in genetically susceptible individuals.¹,²,³,⁴,⁵

The therapeutic arsenal for treating CD assumes the correctness of the above hypothesis. Thus immunosuppressors are used to reduce the host response and antibiotics are used to suppress the bacterial flora, with a consequent decreased activation of the gut immune system.⁶ Between the two strategies it should theoretically be better to remove the harmful cause instead of reducing the host defences by inducing a form of immunodeficiency that is susceptible to opportunistic infections.

If the intervention on the gut flora works, substituting antibiotics (which are heavily burdened by side effects) with probiotics is an appealing alternative. Probiotics are defined as a living microbial food ingredient with a beneficial effect on human health⁷; however, the concept that probiotics are a type of long life elixir useful in many pathological conditions needs to be viewed with caution.

In a world medical scenario, where new science develops new drugs and the financial cost increases, natural remedies, relatively cheap and potentially free from side effects, catch the consumer's attention, thereby possibly biasing medical judgement.

To date, diverse probiotics, containing different strains and quantities of bacteria, are sold on the market.⁸ Their therapeutic effects may include a competitive action with commensal and pathogenic flora and an influence on the immune response through various mechanisms.⁹ Probiotics have been successfully employed in the treatment of antibiotic associated and Clostridium difficile diarrhoea,¹⁰,¹¹ traveller's diarrhoea,¹² and rotavirus infection.¹³ For inflammatory bowel diseases (IBD), some researchers have reported success with different strains of probiotics in the treatment of ulcerative colitis,¹⁴,¹⁵ CD,¹⁶,¹⁷,¹⁸ and in pouchitis treatment and prevention.¹⁹,²⁰E coli Nissle 1917, the yeast Saccharomyces boulardii, Lactobacillus rhamnosus strain GG (LGG), and VSL#3, a cocktail of eight different strains, are the various probiotics employed in these studies. Several significant flaws however limit the importance of many of the probiotic trials, such as inclusion of too few patients,¹⁶,¹⁷ too low a dose of the control drug,¹⁴ or the association of the probiotic with other medicines.¹⁵,¹⁶,¹⁷,¹⁸

Given their potentially high safety profile, the use of probiotics for maintaining CD remission induced by drugs or surgery is particularly appealing. It is suggested that luminal bacteria are the main cause of recurrent lesions after operation.³ Moreover, preventing recurrent lesions in CD after surgery has removed all of the macroscopic inflamed tracts is the best test for any type of drug.

Consequently, LGG, which has been shown to survive and colonise the human intestine by adhering to intestinal cells, has been challenged in two randomised placebo controlled trials for its efficacy in preventing recurrence after surgery²¹ and relapse after medically induced remission.²²

In the first study, 45 patients operated on for CD were randomly allocated to receive 12 billion LGG or identical placebo for one year.²¹ Clinical recurrence was ascertained in 16.6% on Lactobacillus and in 10.5% on placebo. Sixty per cent of patients in clinical remission on Lactobacillus had endoscopic recurrence in comparison with 35.3% on placebo. There were no significant differences in the severity of lesions between the two groups.

The second trial involved 75 children in medically induced remission.²² They were randomised to receive 10¹⁰ LGG bacteria or placebo for two years as an adjunct to standard maintenance treatment. The average time to relapse was 9.8 months in the LGG group and 11 months in the placebo group; 31% and 17% of children on LGG and placebo, respectively, relapsed during the study period. Neither study showed any statistically significant differences between the active and placebo groups.

In this issue of Gut, Marteau and colleagues²³ have reported the results of a trial with Lactobacillus johnsonii (LA1) for prophylaxis of postoperative recurrence in CD (see page 842). Ninety eight adult patients were randomised in a double blind, placebo controlled study in which they received 4×10⁹ LA1 or placebo for six months. At the end of this period, 64% of patients on placebo and 49% on probiotic had endoscopic recurrence. Endoscopic scores and clinical recurrences did not differ between the two groups.

Unfortunately, this study is neither decisively negative nor decisively positive. In fact, the lack of statistically significant difference between Lactobacillus and placebo might be due either to an insufficiently large sample size or to the follow up period of six months, which may have been too short to demonstrate a larger difference. However, the cumulative result of these three studies is not encouraging, and at the moment probiotics are not a therapeutic option for CD patients either in the acute phase or for maintenance.

Is it curtains, then, for probiotics in CD?

Before dropping the curtain we have to take into account some important points.

• CD is a complex entity. Diverse locations and different disease behaviours may well condition the response to probiotics—for example, colonic location seems to respond better to antibiotics and, consequently, might be more susceptible to flora manipulation.

• The course of CD follows different phases; probiotics might be more effective in the early ones.

• There are many species of probiotic. One type might be more effective than another because strain specific properties might influence the efficacy in different cases and situations.

• The quantity of bacterial content may condition the effectiveness of the probiotic.

In short, it seems advisable to wait for results from some larger controlled trials, some of which are already underway.

Setting aside the question of probiotic effectiveness however, is their use absolutely safe? In CD, antigenic stimuli contribute towards maintaining gut inflammation, and any bacteria can become a stimulus. In the two studies with LGG, recurrence rates were lower in the placebo groups than in the groups treated with probiotics.²¹,²²

Moreover, some anecdotal reports of infections probably caused by probiotics have been published.²⁴,²⁵ Probiotic strains adhering to the intestinal mucosa could translocate, inducing bacteraemia and sepsis. This risk can be increased in patients with severe disease or deeply immunosuppressed.

So, in conclusion, is all news about probiotics in CD negative? A possible future scenario on probiotics use in this disease has come from data extrapolated from allergic paediatric patients. In children with atopic dermatitis, probiotics seem to stabilise intestinal barrier function and decrease gastrointestinal symptoms.²⁶,²⁷,²⁸,²⁹

In CD, enhanced mucosa permeability may play a pivotal role in causing and perpetuating intestinal inflammation.³⁰ It is possible therefore that administration of probiotics in the very early phases of CD may limit pathological damage and aggravation of symptoms by stabilising the intestinal barrier.

We can also speculate that children with IBD familiarity, who are at risk of developing CD, could be treated by probiotics to reduce intestinal permeability and counterbalance the hypothetical “harmful” species. For this purpose, identification of subjects at risk of developing CD could be done by analysis of genetic characteristics, such as NO2 and other genes still to be identified. In this case, genetic studies in IBD could be promoted from the laboratory to practical usefulness.