Immune Signalling by Orally Delivered Probiotics

The first point of contact for orally delivered probiotics with intestinal tissues occurs as the microorganisms form lectin-like attachments to epithelial cells of the intestinal tract, as they begin to colonize the mucosa (Fuller, 1992). Recent research has shown that human intestinal epithelial cells are immunocompetent and can transcribe cytokine messenger RNA in response to contact with probiotic bacteria (Delneste et al., 1998). This response is heightened in cells that have been subjected to cytokine activation (e.g. during an inflammatory reaction) and is accompanied by an up-regulation of cell surface receptors.

Table 13.1. Clinical evidence of immune stimulation by probiotic microorganisms.

Microorganism

Immunological effect

Subjects

Reference

Lactobacillus acidophilus La1/Lactobacillus johnsonii ; Lactobacillus rhamnosus HN001; Bifidobacterium bifidum Bb12; Bifidobacterium lactis HN019

Lactobacillus casei Shirota; Bifidobacterium lactis HN019

Lactobacillus brevis Labre; Bifidobacterium lactis HN019

Lactobacillus rhamnosus GG; Bifidobacterium breve YIT4064

Lactobacillus rhamnosus GG

  • Phagocytic activity of blood mononuclear and polymorphonuclear cells
  • Tumoricidal activity of blood mononuclear cells
  • Production of interferons (cytokines) by peripheral blood mononuclear cells in vitro and pro-interferon enzymes in circulation
  • Anti-rotavirus antibody responses during infection
  • Specific antibody responses following vaccination

Healthy adult and elderly volunteers

Healthy adult and elderly volunteers; patients with colorectal cancer

Healthy adult and elderly volunteers

Children with rotavirus diarrhoea

Volunteer adult vaccinees

Schiffrin et al. (1995, 1997); Donnet-Hughes et al. (1999); Arunachalam et al. (2000); Chiang et al. (2000); Gill and Rutherfurd (2001); Gill et al. (2001a, b); Sheih et al. (2001)

Sawamura et al. (1994); Chiang et al. (2000); Gill et al. (2001a,b,c); Sheih et al. (2001)

de Simone et al. (1989, 1993); Kishi et al. (1996); Aattouri and Lemonnier (1997); Arunachalam et al. (2000)

Kaila et al. (1992); Majamaa et al. (1995); Yasui et al. (1999b)

Link-Amster et al. (1994); Isolauri et al. (1995); Fangac et al. (2000)

During the regulation of potential inflammatory events, it now seems that bacterial signalling from the gut microflora plays an important role in the communication between gut epithelial cells and associated intraepithelial lymphocytes. In vitro studies with the CaCo-2 human intestinal epithelial cell line have shown that fermentative (Lactobacillus sakei) and probiotic (Lactobacillus john-sonii) species can induce the expression of the anti-inflammatory mediator transforming growth factor (TGF)-p, but not pro-inflammatory cytokines, such as tumour necrosis factor (TNF)-a or interleukin (IL)-1p. Addition of leucocytes to CaCo-2 Lactobacillus co-cultures promotes the production of pro-inflammatory molecules by the epithelial cells, but also induces secretion of the leucocyte-derived anti-inflammatory mediator IL-10 (Haller et al., 2000). Thus, the picture that emerges is that gut microflora and/or probiotic microbes play an active role in the maintenance of gut homoeostasis by inducing the release of anti-inflammatory mediators and that, under pro-inflammatory conditions, the cross-talk between epithelial cells and leucocytes augments this regulatory role via additional cytokine mediation. In this context, contact between gut-dwelling bacteria and intestinal cells may be considered part of the routine microbial signalling processes of a healthy gut microflora, forming a homoeostatic mechanism for the regulation of intestinal inflammation. Indeed, removal of these routine signals at the gut epithelial surface can lead to a breakdown in these regulatory immune mechanisms and consequently promote aggressive and uncontrolled inflammatory responses (Kuhn et al., 1993; Kulkarni and Karlsson, 1993).

While it has been suggested that routine signalling between resident/pro-biotic microbes and gut epithelial cells plays a maintenance role for gut homoeostasis, it is arguably direct immunostimulation by an interaction of the microbes with lymphoid foci that has received most research attention. In this situation, the interactions are quite different: microbes traverse the epithelial boundary and contact leucocytes directly (e.g. in the organized capsular foci of Peyer's patches), enabling direct immunoactivation. Evidence for this direct interaction has been obtained experimentally in animal models (de Simone et al., 1987; Yasui et al., 1989; Herias et al., 1999; Perdigon et al., 1999), and has an important consequence: unlike immunoinflammatory events that take place solely in the common mucosal immune system, immunostimulation via lymphoid foci facilitates ready access of messenger cells to the systemic circulation, via drainage to the mesenteric lymph node and thoracic duct. Thus, the consequence of an interaction between probiotic bacteria and lymphoid foci in the GI tract could include effects on systemic immune responses involving circulating leucocytes (Perdigon et al., 1988, 1995). Several Gram-positive bacterial cell-wall components (including lipoteichoic acid, peptidoglycan and muramyl dipeptide) have been shown to bind leucocyte pattern-recognition receptors, including the endotoxin receptor (CD14), Toll 2 and type I macrophage scavenger receptor (Dunne et al., 1994; Cleveland et al., 1996; Cauwels et al., 1997; Dziarski et al., 1998), and this could represent the mechanism by which probiotics are able to stimulate the immune system directly.

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