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Supplement: Immunonutrition: Enhancing Tumoricidal Cell Activity

How Are Dietary Signals (Probiotics and Prebiotics) Processed by GI Cells to Effect Measurable Changes in Immune Parameters Systemically?¹

Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI

²To whom correspondence should be addressed. E-mail: hord{at}msu.edu.

KEY WORDS: • probiotic bacteria • commensal bacteria • toll-like receptors • dendritic cells

A primary function of the gastrointestinal (GI)³ tract is the digestion of food and absorption of nutrients. This is accomplished largely by digestive secretions and epithelial cells dispersed across a complex involution of crypt/villi structures in association with gut microflora [500 species of resident (autochthonous) and transient (allochthonous) microorganisms]. A single epithelial-cell layer, some covering specialized structures for transducing antigenic information to mucosal immune cells, separates the host from gut microflora, and forms the first line of defense against invasion. Specific toll-like receptors (TLR) expressed on the surface of epithelial cells provide a mechanism for sensing microbial components required for intestinal homeostasis, innate immunity, and pathogen defense. The pattern of epithelial-cell chemokine and cytokine production stimulated by bacterial ligand is that TLR interactions support barrier function homeostasis and specific communication to subepithelial-localized immune cells, including dendritic cells (DC-professional antigen presenting cells), macrophages, lymphocytes, monocytes, and polymorphonuclear leukocytes (1,2). Alternatively, TLR-equipped DCs can directly sample luminal antigens or, like macrophages, detect soluble molecules originating from bacterial or viral pathogens that transgress the tight junction barrier of epithelial cells. In addition to early bacterial recognition, DCs direct the generation and homing of effector T cell responses. It is noteworthy that DC-mediated suppression of the inflammatory immune response to gut microflora, or tolerance, is mandated to balance immune system reactivity with intestinal homeostasis.

Probiotic bacteria are diet-derived bacteria of commensal origin that must be consumed consistently to maintain measurable colonic populations (3). Prebiotics are dietary substrates that support the growth of probiotic bacteria in vivo. Probiotics are proposed to have multiple mechanisms of action, including prevention of pathogenic bacterial growth, binding to or penetration of pathogens to mucosal surfaces, stimulation of mucosal barrier function, or altering immunoregulation (decreasing proinflammatory and promoting protective molecules).

Specific probiotic bacteria can modulate mucosal and systemic immune activity as evidenced by their efficacy in treating specific health conditions (4). The evidence in support of the efficacy of probiotic bacteria varies from circumstantial to convincing (Level 1) using evidence-based medicine techniques (for definition see Evidence-Based On Call at http://www.eboncall.org/ content/levels.html). Consumption of specific probiotic bacteria results in restoration of normal microfloral spectrum in nasal and vaginal mucosa, the latter being associated with decreased risk of preterm birth. Level I evidence now exists for the therapeutic use of probiotics in infectious diarrhea in children, recurrent Clostridium difficile induced infections, and postoperative pouchitis. Level II evidence is emerging for the use of probiotics in other gastrointestinal infections, prevention of postoperative bacterial translocation, irritable bowel syndrome, and in both ulcerative colitis and Crohn’s disease. The identification of mechanisms has led to new credence for the use of probiotics and prebiotics in clinical medicine. The efficacy of probiotic bacteria is genus, species, and strain specific; it is not possible to generalize beneficial effects of probiotics. Most clinical studies use daily intake levels as high as 10 (8–10) viable cells per day, reflecting 4 1 cup servings of probiotic-containing product, containing 2 x 10⁶ cfu/mL (3).

Despite evidence of efficacy in treating specific diseases and conditions, there is a paucity of mechanistic data linking mucosal exposure to probiotics to systemic immunologic modulation. Newly uncovered functions of DCs have provided pivotal insights into the ability of probiotic bacteria to modulate systemic immune function. Several lines of evidence suggest DC function directly influences intestinal responses to commensal and probiotic bacteria. Following isolation and characterization in vitro, colonic DCs can produce IL-10 and IL-12 when cultured with bacteria (5). Three Lactobacillus species regulated phenotype and functions of myeloid-derived DCs (MDC). MDCs activated with lactobacilli clearly skewed CD4(+) and CD8(+) T cells to T helper 1 and Tc1 polarization, as evidenced by secretion of interferon (IFN) but not IL-4 or IL-13. These results emphasize a potentially important role for lactobacilli in modulating immunological functions of DCs (6). VSL#3 (4 lactobacilli, 3 bifidobacteria, and 1streptococcal strains) was a potent inducer of IL-10 by dendritic cells from blood and intestinal tissue, and inhibited generation of Th1 cells. Individual strains within VSL#3 displayed distinct immunomodulatory effects on dendritic cells; the most marked anti-inflammatory effects were produced by bifidobacteria, strains that upregulated IL-10 production by dendritic cells, decreased expression of the costimulatory molecule CD80, and decreased IFN- production by T cells (7). Probiotic bacteria differ in their immunomodulatory activity and influence polarization of immune responses at the earliest stage of antigen presentation by dendritic cells.

It is clear that DCs play important roles in tightly regulating intestinal homeostasis in the healthy intestine and in the dysregulated response seen in inflammatory bowel diseases (IBD) and colorectal cancer (8). DCs may be potential targets for probiotic therapies for the prevention of IBDs and GI infections.

Research needs (4,8)

The causal pathway between colonic or subcutaneous exposure to specific probiotic bacteria (e.g., epithelial- and DC-derived signals), antigenic sensing and transduction to lymph nodes (e.g., DC antigen processing, maturation, and migration; DC-directed lymphocyte homing), and phenotypic alterations in colonic and distant tissues is needed;

The identification of intermediate immune cell biomarkers of exposure to probiotic bacteria is needed;

Issues related to human biologic factors: identification of metabolic factors that impair probiotic viability, epithelial factors that determine response to specific probiotic strains, dietary factors efficacious in maintaining new bacterial populations in the gut;

Issues related to probiotic bacteria: selection of appropriate strains, regulation of probiotic quality standardization and processing, and local product unavailability.

FOOTNOTES

¹ Published in a supplement to The Journal of Nutrition. Presented during a workshop entitled: "Immunonutrition: Enhancing Tumoricidal Cell Activity," held in Bethesda, MD, March 23, 2005. This workshop was sponsored by the Division of Cancer Prevention, NCI, NIH, DHHS. Guest editors for the supplement publication were Susan S. Percival, John A. Milner, and Christopher A. Jolly. Guest Editor Disclosure: Susan S. Percival: no relationships to disclose; John A. Milner: no relationships to disclose; Christopher A. Jolly: received reimbursement for travel expenses from NCI.

³ Abbreviations used: DC, dendritic cells; GI, gastrointestinal; IBD, inflammatory bowel diseases; IFN, interferon; MDC, myeloid-derived DC; TLR, toll-like receptors.

LITERATURE CITED

1. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell. 2004;118(2):229-241.[Medline]

2. Kagnoff MF, Eckmann L. Epithelial cells as sensors for microbial infection. J Clin Invest. 1997;100(1):6-10.[Medline]

3. Kopp-Hoolihan L. Prophylactic and therapeutic uses of probiotics: a review. J Am Diet Assoc. 2001;101(2):229-238.[Medline]

4. Fedorak RN, Madsen KL. Probiotics and prebiotics in gastrointestinal disorders. Curr Opin Gastroenterol. 2004;20(2):146-155.[Medline]

5. Mohamadzadeh M, Olson S, Kalina WV, Ruthel G, Demmin GL, Warfield KL, Bavari S, Klaenhammer TR. Lactobacilli activate human dendritic cells that skew T cells toward T helper 1 polarization. Proc Natl Acad Sci U S A. 2005;102(8):2880-2885.[Abstract/Free Full Text]

6. Drakes M, Blanchard T, Czinn S. Bacterial probiotic modulation of dendritic cells. Infect Immun. 2004;72(6):3299-3309.[Abstract/Free Full Text]

7. Hart AL, Lammers K, Brigidi P, Vitali B, Rizzello F, Gionchetti P, Campieri M, Kamm MA, Knight SC, Stagg AJ. Modulation of human dendritic cell phenotype and function by probiotic bacteria. Gut. 2004;53(11):1602-1609.[Abstract/Free Full Text]

8. Stagg AJ, Hart AL, Knight SC, Kamm MA. Microbial-gut interactions in health and disease. Interactions between dendritic cells and bacteria in the regulation of intestinal immunity. Best Pract Res Clin Gastroenterol. 2004;18(2):255-270.[Medline]

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