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Probiotics in functional intestinal disorders and IBS: proof of action and dissecting the multiple mechanisms
  1. Philippe Marteau
  1. Correspondence to Professor Philippe Marteau, Medicosurgical Department of Digestive Diseases, AP-HP Lariboisière Hospital, & Paris 7 Denis Diderot University, Paris, France; philippe.marteau{at}lrb.aphp.fr

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Probiotics are widely consumed and the widespread advertising is often not really justified by the evidence. Many products were never studied as such and some companies use studies performed with other (and different) products for advertising even during medical conventions. Evidence of benefit is still patchy and the clinician has to take into account the variability of the strains, the doses, the quality of the trials and clinical relevance of end points.

In this issue of Gut, Mohayyedi and colleagues (see page 325) have made an interesting systematic analysis on the randomised controlled trials testing various probiotics in patients with irritable bowel syndrome (IBS).1 They show that many trials are of good quality, that positive results were obtained with some strains, or products combining several strains, but also that studies are heterogeneous and that funnel plot asymmetry suggests biases in the publications (ie, there are more reports on the positive studies than of the negative ones). I agree with the authors that meta-analysis is not wise as the active ingredients and mechanisms of action of various probiotics are very likely to differ. Indeed, the phenotypes and genome of probiotics differ greatly between each other.2 Important differences exist between bacteria (or yeasts) not only at the genus or species levels but also inside a single species at the strain level (for example between two Lactobacillus casei or two Bifidobacterium longum). Clearly, demonstrations were recently published and this has direct consequences for the clinician. For example, L johnsonii strains NCC533 and ATCC 33200 differ significantly in their gut residence time after oral feeding to mice. Denou et al identified genes that were specific for the long-gut-persistence strain using hybridisation of DNA of the ATCC 33200 strain against a microarray of the sequenced NCC533 strain.3 The authors determined the genes that were expressed in the intestine of mice mono-associated with NCC533, and finally by fusion of the two microarray data sets they were able to identify three gene loci that were both expressed in vivo and specific to the long-gut-persistence isolate. Knockout mutants were constructed and proved to have indeed modified gut residence time in vivo. Medina et al studied the ability of different strains of B longum to induce cytokine production by peripheral blood mononuclear cells.4 B longum W11 stimulated strongly the production of Th1 cytokines while B longum NCIMB 8809 and BIF53 induced low levels of Th1 cytokines and high levels of IL-10. As last example, L plantarum 299v increased the transcription and excretion of the mucins MUC2 and MUC3 in goblet cells but strain Lp6 did not.5 As a consequence and as stressed by the FAO/WHO joint report the benefits of one probiotic ‘cannot be extrapolated to other probiotic strains without experimentation’.6 On the other hand, it is also likely that group specific properties exist and that identifying them would help considerably in the strain selection. Comparative genomic analysis can be of great help in highlighting strain-specific or group-specific genes.2

A probiotic contains thousands of genes which may potentially influence the clinical effects. Furthermore, interaction with the host, food components or endogenous substrates or the endogenous microbiota inside the gastrointestinal lumen may generate by-products or end-products with functional properties. There is a great hope that new (molecular combined with biostatistical) methods including metagenomics and metabolomics will help to dissect the complexicity.7 These methods should, for example, allow the discovery of novel genes and gene products, with novel properties which could be later used as drugs (eg, small molecules or proteins with antimicrobial activities, immunomodulating properties or interacting with intestinal functions).

Numerous mechanisms are involved in the action of probiotics. New discoveries which may have an impact on the understanding of the clinical effects in IBS include the demonstration of the presence of anti-inflammatory microorganisms in the endogenous microbiota (especially the phylum Firmicutes),8 and that of the action of probiotics on intestinal motility and visceral sensivity.9–14 For example, Bär et al reported that conditioned media from the probiotic strain Escherichia coli Nissle 1917 modulates contractility of muscle strips isolated from humans.9 Four controlled studies in humans showed that B lactis DN-173-010 shortened the colonic transit time and two trials also showed reduction of bloating in patients IBS or functional disorders.10 11 Previous studies showed that L farciminis CIP 103136 suppresses stress-induced hypersensitivity in response to colorectal distension and it was recently reported that pretreatment with this probiotic was associated with a decreased expression of Fos protein (a marker of neuronal activation) in the spinal cord of stressed female rats.12 Conditioned media from L paracasei NCC2461 reduced visceral hypersensitivity associated with antibiotic treatment in mice and normalised substance P expression in the myenteric and submucosal plexuses.13 Last but not least, L acidophilus NCFM has also been reported to increase the visceral threshold in rats (as effectively as morphine), and to induce opioid or cannabinoid receptors on HT29 cells (a property which was not shared by a variety of other bacterial strains).14

It is thus now clear that some but not all probiotics exhibit modulating properties on the gastrointestinal functions and may improve physiological disturbances and IBS. Clinicians should know that only functional claims are allowed for probiotic food in Europe, and that extrapolation between strains is not sound.

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Footnotes

  • Linked articles 167270.

  • Competing interests Philippe Marteau has received consultancy fees and invitations to speak at conventions by Danone, Nestlé, Biocodex, Merck Médication familiale, Rosel Lallemand, and PiLeJe.

  • Provenance and peer review Commissioned; externally peer reviewed.

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