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The influence of the commensal microbiota on intestinal and extra-intestinal development has been evident since the first studies of germ-free animals over a half-century ago. Microbial signals from the lumen of the gut are trophic for the digestive, immune and other systems, including the developing brain.1 2 In later life, reciprocal host–microbe interactions remain critical for mucosal homeostasis. Probiotic therapy is, in essence, an attempt to harness the beneficial effects of the commensal microbiota for the host.3 In most instances, the molecular underpinning of these exchanges remains to be defined but represents an intriguing strategy for identifying therapeutic targets and drug discovery.4 While the therapeutic potential of immunomodulatory molecules from pathogens is well recognised, the pursuit of bioactive molecules from the commensal gut microbiota is a more recent venture; examples include the discovery of bacteriocins with activity against Clostridium difficile and bacterial-derived immunomodulatory molecules.4 However, much more remains to be mined from the commensal microbiota.
The study by Fernandez and colleagues published in this issue of Gut (see page 1050) has linked a bacterial effector molecule with an anti-inflammatory host response in mice and provides supporting evidence for the likely mechanism.5 The anti-inflammatory property of Lactobacillus salivarius Ls33 on experimental murine colitis induced by trinitrobenzene sulfonic acid (TNBS) was found to be dependent on NOD2 recognition of the bacterial peptidoglycan (PGN) and derived muropeptides. NOD2 is a member of the NOD-like receptor family, whose members are intracellular sensors of bacteria. NOD2 recognises muramyl dipeptide, a bioactive component of PGN from bacterial cell walls. It is coded for by the Card15 gene, mutations of which are associated with risk of Crohn's disease.
Purified PGN from L salivarius Ls33 was anti-inflammatory in a NOD-dependent and interleukin 10-dependent manner and was associated with induction of regulatory dendritic cells and regulatory T cells. Furthermore, additional muropeptides derived from the purified PGN also displayed anti-inflammatory properties. However, when PGN was purified from a different lactobacillus strain (L acidophilus NCFM) which is not protective in the TNBS model of colitis, it lacked anti-inflammatory activity. Thus, structural differences in PGN and its derived muropeptides may account for some of the strain specificity of the anti-inflammatory properties of lactobacilli in this model.
Numerous other examples of divergent functional properties among closely related strains of commensal organisms, which have a bearing on probiotic selection, have been described. In this respect, the cell envelope of lactobacillus has previously attracted interest. Grangette and colleagues showed that the d-alanine content of lipoteichoic acid modulates the anti-inflammatory effects of Lactobacillus plantarum.6 In addition, the genetic diversity of Lactobacillus johnsonii strains has been associated with variability in gut residence time after oral feeding,7 whereas different strains of L plantarum appear to vary in their effects on mucin gene expression in the host.8 Among commensal bifidobacteria, marked differences in the production of conjugated linoleic acid have been described,9 and Bifidobacterium longum strains exhibit differential immunomodulatory properties.10
Curiously, the anti-inflammatory L salivarius Ls33 and the non-protective L acidophilus NCFM strains used by Fernandez et al have previously been studied in a model of visceral hyperalgesia whereby the latter strain appeared to have greater anti-nociceptive capacity than the former.11 The contrasting results with different strains and with the same strains in different experimental settings highlight the importance of careful selection and of matching function with therapeutic indication and desired outcome. It seems likely that where there is limited or reduced commensal microbial diversity, such as in the pre-term infants or after broad-spectrum antibiotics, a diversity of probiotic strains may provide adequate protection. However, where specific anti-inflammatory, anti-nociceptive, immunoregulatory or other effects are desired, probiotic selection should be based on informed criteria rather than on an empiric basis. To do otherwise, is as absurd as recommending ‘pills’ or ‘tablets’ for ailments without knowledge of the active ingredient or the precise indication.
The report by Fernandez and colleagues leaves several lingering questions. To what degree might NOD2 mutations in the host and the strain specificity of the anti-inflammatory mechanism of L salivarius-derived PGN account for the disappointing results of lactobacillus probiotics in patients with Crohn's disease? How restricted is the anti-inflammatory property of PGN in lactobacilli? Several lactobacilli have been sequenced and one wonders what might be distinctive about the L Salivarius Ls33 genome on comparative analysis? Will an informed search reveal that other Gram-positive elements of the microbiota produce similar bioactive PGN? The field is rich. For now, the work has important implications for devising selection criteria for probiotics and illustrates the value of bioprospecting within the gut microbiota for bioactives suitable as functional foods or a new generation of drugs. The promise of a ‘bugs-to-drugs’ strategy for the discovery of new therapeutic agents has moved another step towards realisation.
Linked article 232918.
Funding FS is supported, in part, by the Science Foundation Ireland in the form of a research centre grant (Alimentary Pharmabiotic Centre) and by a research grant from GlaxoSmithKline Ltd.
Competing interests FS is affiliated with a multi-departmental university campus company, Alimentary Health Ltd, which investigates inter alia host–microbe interactions. The content of this paper was neither influenced nor constrained by that fact.
Provenance and peer review Commissioned; not externally peer reviewed.
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