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Increasing awareness of the role of intestinal commensal bacteria in the development and mod-
ulation of the immune system has led to great interest in the therapeutic potential of probiotics
and other bacteria-based strategies for a range of immune-related disorders. Studies in animal
models have identified strong immunomodulatory effects of many nonpathogenic bacteria and
provided evidence that intestinal microbes can activate a common mucosal immune response and,
thus, influence sites distant to the intestine, including the respiratory tract. Respiratory effects of
probiotics in animal models have included attenuating allergic airway responses and protecting
against respiratory pathogens. Dendritic cells appear central to directing the beneficial immune
response to probiotic bacteria and in translating microbial signals from the innate to the adaptive
immune system, whereas regulatory T cells are emerging as potentially key effectors of probiotic-
mediated responses, particularly in the reduction of allergic inflammation. Despite progress in
basic research, clinical trials of probiotics in allergy/asthma and respiratory infection have been
highly variable at best, leading to an undermining of confidence in this potential therapeutic
strategy. It is clear that there is still much to learn regarding the determinants of the diverse
immune responses elicited by different bacterial strains. A deeper knowledge of the interactions
between administered probiotics and the existing microbiota, together with an understanding
of how the dialogue between microbes and the innate immune system is translated into ben-
eficial/protective responses, will be required before we can achieve clinically effective bacteria-
based strategies that maintain and promote respiratory health. CHEST 2011; 139(4):901–908
Abbreviations: DC 5 dendritic cell; GALT 5 gut-associated lymphoid tissue; IDO 5 indoleamine 2,3-dioxygenase;
IFN 5 interferon; LAB 5 lactic acid bacteria; NK 5 natural killer; OVA 5 ovalbumin; Th 5 T helper; TLR 5 toll-like
receptor; Treg 5 regulatory T cell
Figure 1. Proposed gut-lung axis of probiotic action. Microbes in the intestine are sampled by DCs either directly from the lumen or
following translocation through M cells to the GALT. A combination of signals from the microbes results in phenotypic changes in the DCs
and the production of Th1 type and/or regulatory mediators. IL-12 promotes Th1 cells and activation and IFN-g production by NK cells.
Regulatory cytokines such as IL-10, TGF-b, and the activation of IDO and subsequent production of immunoactive KYNs promotes
Tregs and depletes Th2 cells. Following immune challenge in the airway, cells activated in the GALT and MLN traffic to the respiratory
mucosa where they promote protective and antiinflammatory responses. AHR 5 airway hyperresponsiveness; BALT 5 bronchus-associated
lymphoid tissue; DC 5 dendritic cell; GALT 5 gut-associated lymphoid tissue; IDO 5 indolamine 2,3 dioxygenase; IFN 5 interferon;
Kyn 5 kynurenine; MLN 5 mesenteric lymph node; NK 5 natural killer; TGF 5 transforming growth factor; Th 5 T helper; Treg 5 regulatory
T cell.
Figure 2. The probiotic-DC dialogue. Probiotic bacteria can interact with DCs via various surface molecules, which act to signal through
microbe-associated molecular pattern (MAMP) receptors such as TLRs that can be extracellular or associated with endosomes such as
TLR-9, and lectins, including the C-type lectin DC-SIGN. Important MAMPs include LTAs, PGNs, LPSs, and a range of CPSs including
PSA. In addition to cell surface components, secreted products of bacteria may also influence DCs, including AHLs, part of the quorum
sensing system of gram-negative bacteria. It is likely that specific combinations of signals instigated by these interactions determine the
response of DCs and thus the immunoregulatory capacity of individual bacterial strains. 1ve 5 gram-positive bacteria; −ve 5 gram-negative
bacteria; AHL 5 acyl-homoserine lactone; CPS 5 cell wall-associated polysaccharide; DC-SIGN 5 DC-specific intercellular adhesion mol-
ecule 3-grabbing non-integrin; LPS 5 lipopolysaccharide; LTA 5 lipoteichoic acid; PGN 5 peptidoglycan; PSA 5 polysaccharide A;
TLR 5 toll-like receptor. See Figure 1 legend for expansion of the other abbreviation.