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Emerging molecular insights into the interaction between probiotics and the host intestinal mucosa

Nature Reviews Microbiology volume 10, pages 66–78 (2012)Cite this article

Subjects

Key Points

  • Probiotics are defined as “live microorganisms which when administered in adequate amounts confer a health benefit on the host” and have been studied by the scientific community for more than a century. The vast majority of marketed probiotics belong to the genera Lactobacillus and Bifidobacterium. Although the scientific evidence for the health-promoting effects of probiotics in specific challenged populations is solid (for example, the prevention of antibiotic-associated and acute infectious diarrhoea), the effectiveness of these organisms in other areas, such as the treatment of inflammatory bowel disease, is less established.

  • Several modes of action have been proposed for probiotics, including the strengthening of intestinal epithelial barrier function by stimulation of mucin secretion or enhancement of tight junction function, the clearance of pathogens by competitive binding to receptors presented by epithelial cells, and the synthesis of antimicrobial substances such as bacteriocins. Another key mode of action by which probiotics are proposed to exert their beneficial effects is through modulation of the host immune system in the intestinal mucosa.

  • The intestinal mucosa contains several specialized cell types involved in immunomodulation, and these cells express a range of pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), NOD-like receptors (NLRs) and C-type lectin receptors (CLRs). Upon exposure to microorganism-associated molecular patterns (MAMPs), PRRs respond by activating associated adaptor proteins that are linked to nuclear factor-κB and mitogen-activated protein kinase signalling cascades, resulting in modulated expression of response genes, including genes encoding cytokines, chemokines and antimicrobial peptides.

  • Multiple conserved, polymeric MAMPs are located in the bacterial cell envelope, including peptidoglycan, capsular polysaccharide, wall teichoic acids and lipoteichoic acids (LTAs). Several MAMP–PRR interactions are well documented. However, the strain- and species-specific probiotic effects that are observed hinder the investigation into general probiotic MAMPs and the effects that they induce. Obtaining insight into strain specificity will require comparative structural analyses of the complex MAMP backbones and their modifications.

  • Strain-specific proteinaceous MAMPs have also been identified, further adding to the complexity of intestinal host–microorganism interactions. Overall, the molecular analysis of MAMPs has led to the perception that their functioning is influenced by the cellular context in which they are expressed, and the overall MAMP profile will lead to an integrated response by the host to maintain or regain intestinal homeostasis.

  • Determination of the changes in the duodenal transcriptomes of healthy volunteers after the consumption of four different lactobacilli revealed species-specific host immunomodulation via distinct signalling pathways, pinpointing the importance of strain selection for specific probiotic applications. Moreover, a remarkably large intrapersonal distance between the transcriptome profiles was observed in comparison to the interpersonal transcriptional changes induced by consumption of different probiotic strains. These observations suggest that, within the concept of the 'bandwidth of human health' that we outline here, different molecular solutions may underlie intestinal homeostasis in healthy individuals, a fact that is likely to affect the physiological consequences of a healthy person's responses to functional foods such as probiotics.

Abstract

Probiotic bacteria can modulate immune responses in the host gastrointestinal tract to promote health. The genomics era has provided novel opportunities for the discovery and characterization of bacterial probiotic effector molecules that elicit specific responses in the intestinal system. Furthermore, nutrigenomic analyses of the response to probiotics have unravelled the signalling and immune response pathways which are modulated by probiotic bacteria. Together, these genomic approaches and nutrigenomic analyses have identified several bacterial factors that are involved in modulation of the immune system and the mucosal barrier, and have revealed that a molecular 'bandwidth of human health' could represent a key determinant in an individual's physiological responsiveness to probiotics. These approaches may lead to improved stratification of consumers and to subpopulation-level probiotic supplementation to maintain or improve health, or to reduce the risk of disease.

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Figure 1: Mechanisms of host defence against and tolerance to intestinal microorganisms.
Figure 2: Microorganism-associated molecular patterns of three Lactobacillus species for which the reciprocal receptors have been identified.
Figure 3: Probiotic molecular interactions of three lactobacilli and of Gram-positive bacteria in general with intestinal epithelial cells and dendritic cells.
Figure 4: Person-to-person variation of the baseline mucosal molecular make-up and the responses to three probiotics.
Figure 5: The molecular 'bandwidth of human health' concept.

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  1. Peter A. Bron and Peter van Baarlen: These authors contributed equally to this work.

Authors and Affiliations

  1. Top Institute Food and Nutrition, Nieuwe Kanaal 9A, Wageningen, 6709 PA, The Netherlands

    Peter A. Bron & Michiel Kleerebezem

  2. NIZO Food Research, Kernhemseweg 2, Ede, 6718ZB, The Netherlands

    Peter A. Bron & Michiel Kleerebezem

  3. Kluyver Centre for Genomics of Industrial Fermentation, Julianalaan 67, Delft, 2628BC, The Netherlands

    Peter A. Bron

  4. Host-Microbe Interactomics, Wageningen University, De Elst 1, Wageningen, 6708 WD, The Netherlands

    Peter van Baarlen

  5. Laboratory for Microbiology, Wageningen University, Dreijenplein 10, Wageningen, 6703HB, The Netherlands

    Michiel Kleerebezem

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Glossary

Necrotizing enterocolitis

An acute inflammatory condition that is seen primarily in premature infants and results in parts of the bowel dying off.

Tight junction

An area in which the cell membranes from two adjacent vertebrate cells are closely and tightly associated, forming a barrier that is impermeable to liquids and particulate compounds.

Follicle centres

Small, spherical groups of cells; these spheres contain a cavity or centre, in which immune cells (B cells and T cells) proliferate and differentiate.

Microfold cells

(M cells). A cell type that is found in the follicle-associated epithelium of Peyer's patches. M cells have the ability to take up antigens, including bacteria, directly from the small intestinal lumen and to deliver these antigens to the immune cells that are located directly underneath the M cells.

Peptidoglycan

An essential cell wall polymer composed of alternating residues of β-1-4-linked N-acetylmuramic acid and N-acetylglucosamine crosslinked by pentapeptide bridges containing immunomodulatory fragments such as diaminopimelic acid.

Lipoteichoic acid

A D-alanyl- and glycosyl-substituted polyglycerolphosphate polymer that is anchored in the bacterial cytoplasmic membrane through glycolipids.

Nutrigenomic approaches

The application of high-throughput genomic tools in nutrition research to decipher how nutrients affect the production and action of specific gene products and how these in turn affect the response to nutrients.

Immunological adjuvant

An agent that modifies the effect of another agent (often a drug or vaccine) but has few, if any, direct effects when given by itself.

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Bron, P., van Baarlen, P. & Kleerebezem, M. Emerging molecular insights into the interaction between probiotics and the host intestinal mucosa. Nat Rev Microbiol 10, 66–78 (2012). https://doi.org/10.1038/nrmicro2690

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