By Marko Kalliomäki, Seppo Salminen, Heikki Arvilommi, Pentti Kero, Pertti Koskinen, Erika Isolauri

Condensed Version Of Original Landmark Lancet Article

More than half the developing countries have allergy problems in their children.(1)

The authors propose that specific microbes in the gut microflora are more important than sporadic infections in allergy prevention. Gastrointestinal microflora promote potentially antiallergenic processes:

Probiotics have been previously proven effective in allergic inflammation (4) and food allergy.(8)

Confrontation between microbes and their antigens in the gastrointestinal tract begins instantly after birth, and the viable cells of fully established gut microflora outnumber those of the human host by a factor of ten. (9) Consequently, gastrointestinal microbes are the earliest and biggest stimulus for development of gut-associated lymphoid tissue.

Probiotics also enhance gut-specific IgA responses,(10) which are often defective in children with food allergy.(11)

They also help to promote gut barrier function and restore normal gut microecology,(9) alterations in which have been shown in allergic individuals.(12)

Some probiotics alleviate changes related to allergic inflammation in vitro and in vivo. (5, 12, 13)

Use of probiotics in allergy prevention is further lent support by results of studies (14,15) showing that oral lactobacilli in atopic children enhance transforming growth factor ß and interleukin (4) production in vivo.

Findings from clinical and experimental studies (6,16) suggest that these anti-inflammatory cytokines have a crucial role, possibly more essential than that of T-helper-1-type inducers, in prevention and treatment of atopy and atopic diseases.

Thus, specific strains in indigenous gut microflora have profound effects on the physiology and immunology of the host.

At birth, the human gastrointestinal tract is sterile, but in the first months and years of life a rapid sequential colonisation occurs until a stable indigenous gut microflora is established.(9)

Simultaneously, the T-helper-2-dominant immunity of newborn babies is intensified in atopic individuals, with the subsequent expression of atopic disease.(17)

In support of an essential role for indigenous gut microflora in this process, a reduced ratio of bifidobacteria to clostridia in early gut microflora precedes the development of atopy and atopic disease.(18)

Dietary antigens also strongly affect the neonatal gastrointestinal system. Results from work in animals indicate that these antigens might provoke atopic-type immunity at mucosal and systemic level.(19)

Therefore, treatment for counter-regulation of allergy must work in infancy, and preferably in the first encounters with dietary antigens. Probiotics are appropriate for the task, not only with respect to timing, but also in their ability to reduce dietary antigen load by degradation and modification of macromolecules.(20)

This process of antigen degradation is necessary in development of non-responsiveness to dietary antigens.(21)

Our results suggest that gut microflora have unique, yet largely unexplored, endogenous immunomodulatory properties. These properties might be indispensable in the fight against the increasing frequency of atopic, and possibly other, immunological diseases.

The Lancet 2001; 357: 1076-79

References

1 Holgate ST. The epidemic of allergy and asthma. Nature 1999; 402 (6760 suppl): B2-4.

2 Martinez FD, Holt PG. Role of microbial burden in aetiology of allergy and asthma. Lancet 1999; 354 (suppl 2): 12-15

3. Sanfilippo L, Li CK, Seth R, Balwin TJ, Menozzi MG, Mahida YR. Bacteroides fragilis enterotoxin induces the expression of IL-8 and transforming growth factor-beta (TGF-beta) by human colonic epithelial cells. Clin Exp Immunol 2000; 119: 456-63.

4. Isolauri E, Arvola T, Sütas Y, Salminen S. Probiotics in the management of atopic eczema. Clin Exp Allergy 2000; 30: 1605-10.

5. Hansen G, McIntire JJ, Yeung VP, et al. CD4(+) T helper cells engineered to produce latent TGF-beta1 reverse allergen-induced airway hyperreactivity and inflammation. J Clin Invest 2000; 105: 61-70.

6. Sudo N, Sawamura S, Tanaka K, Aiba Y, Kubo C, Koga Y. The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction. J Immunol 1997; 159: 1739-45.

7. Gaskins HR. Immunological aspects of host/microbiota interactions at the intestinal epithelium. In: Mackie RI, White BA, Isaacson RE, eds. Gastrointestinal microbiology. New York: International Thomson Publishing, 1997: 537-87.

8. Majamaa H, Isolauri E. Probiotics: a novel approach in the management of food allergy. J Allergy Clin Immunol 1997; 99: 179-85

9. Salminen S, Bouley C, Boutron-Ruault MC, et al. Functional food science and gastrointestinal physiology and function. Br J Nutr 1998; 80 (suppl 1): 147-71

10. Isolauri E, Majamaa H, Arvola T, Rantala I, Virtanen E, Arvilommi H. Lactobacillus casei strain GG reverses increased intestinal permeability induced by cow milk in suckling rats. Gastroenterology 1993; 105: 1643-50

11. Isolauri E, Suomalainen H, Kaila M, et al. Local immune response in patients with cow milk allergy: follow-up of patients retaining allergy or becoming tolerant. J Pediatr 1992; 120: 9-15

12. Björksten B, Naaber P, Sepp E, Mikelsaar M. The intestinal microflora in allergic Estonian and Swedish 2-year-old children. Clin Exp Allergy 1999; 29: 342-46.

13. Pessi T, Sütas Y, Hurme M, Isolauri E. Interleukin-10 generation in atopic children following oral Lactobacillus rhamnosus GG. Clin Exp Allergy 2000; 30: 1804-08.

14. Isolauri E, Arvola T, Sütas Y, Salminen S. Probiotics in the management of atopic eczema. Clin Exp Allergy 2000; 30: 1605-10.

15. Pessi T, Sütas Y, Hurme M, Isolauri E. Interleukin-10 generation in atopic children following oral Lactobacillus rhamnosus GG. Clin Exp Allergy 2000; 30: 1804-08.

16. van den Biggelaar AHJ, van Ree R, Rodrigues LC, et al. Decreased atopy in children infected with Schistosoma haematobium: a role for parasite-induced interleukin-10. Lancet 2000; 356: 1723-27

17. Prescott SL, Macaubas C, Smallacombe T, Holt BJ, Sly PD, Holt PG. Development of allergen-specific T-cell memory in atopic and normal children. Lancet 1999; 353: 196-200.

18. Kalliomäki M, Kirjavainen P, Eerola E, Kero P, Salminen S, Isolauri E. Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing. J Allergy Clin Immunol 2001; 107: 129-34

19. Sato M, Iwakabe K, Kimura S, Nishimura T. The influence of dietary protein antigen on Th1/Th2 balance and cellular immunity. Immunol Lett 1999; 70: 29-35.

20. Pessi T, Sütas Y, Marttinen A, Isolauri E. Probiotics reinforce mucosal degradation of antigens in rats: implications for therapeutic use of probiotics. J Nutr 1998; 128: 2313-18.

21. Barone KS, Reilly MR, Flanagan MP, Michael JG. Abrogation of oral tolerance by feeding encapsulated antigen. Cell Immunol 2000; 199: 65-72.