Coming full circle: From antibiotics to probiotics and prebiotics.

1Departments of Pathology and Laboratory Medicine, Medicine, and Microbiology and Infectious Diseases, University of Calgary, Calgary, Alberta; 2Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia Correspondence: Dr John Conly, Departments of Pathology and Laboratory Medicine, Medicine, and Microbiology and Infectious Diseases, Room 930, 9th Floor, North Tower, 1403 29th Street Northwest, Calgary, Alberta T2N 2T9. Telephone 403-944-8222, fax 403-944-1095, e-mail jconly@ucalgary.ca Received and accepted for publication May 25, 2004 Antibiotics are used as agents to prevent and treat infections caused by pathogenic bacteria and other microbes, and rank as one of the most important developments of modern medicine. The word ‘antibiotic’ is derived from the Greek term ‘biotikos’ and may be literally translated as ‘against life’. Antibiotics were first used centuries ago by the Chinese in the form mouldy soybean curd applied to carbuncles and furuncles. (1) The ancient Greeks, including Hippocrates, routinely used agents with antimicrobial properties such as myrrh and inorganic salts in their treatment of infected wounds (1). The discovery of penicillin by Fleming in 1928, followed by the discovery and clinical use of sulphonamides in the 1930s, heralded the age of modern antibiotherapy (1,2). Penicillin usage became widespread in the 1940s during the war years and by the 1950s the ‘golden era’ of antibiotic development and use was well underway. Probiotics are live microbes that are used as agents to alter the composition or metabolic activities of the microbiota, or to modulate immune system reactivity in a way that benefits health (3,4). The word ‘probiotic’ is also derived from the same Greek term ‘biotikos’ which may be literally translated as ‘for life’. Probiotics have been used for many years in the animal feed industry, but they are now being increasingly made available in many forms and can be purchased over the counter as freeze-dried preparations in health food stores. Prebiotics are food ingredients, usually oligosaccharides, that escape digestion in the upper gastrointestinal tract and selectively stimulate the growth of selective bacterial genera such as bifidobacteria and lactobacilli in the colon (4,5). It is believed that modulation of the normal microflora to benefit the host can be achieved through the use of prebiotics and probiotics. There is now increasing evidence that selected probiotic strains can provide health benefits to their human hosts and it is noteworthy that the Food and Agriculture Organization of the United Nations and the World Health Organization have stated that there is adequate scientific evidence to indicate that there is potential for probiotics to provide health benefits (6). Given these recent developments, it was considered timely to review the background and conceptual framework of the use of these agents and the evidence for their effectiveness in clinical settings. The human intestine contains a complex, dynamic and diverse number of bacteria, that may be differentiated into native inhabitants and transient flora (7). These microorganisms colonize the mucosal surface of the oral cavity, the upper respiratory tract, much of the gastrointestinal tract and the urogenital tract. Although the gastrointestinal tract is sterile at birth, microflora colonize the mucosal surfaces of infants during an ecological succession of organisms that differ from the adult microflora (7). The composition of the flora is influenced heavily by the receipt of oral formula or breast milk. Breastfed infants have been found to have an increased number of Bifidobacteria but rarely have Clostridium species, whereas formulafed infants have large numbers of Lactobacilli, Bacteroides and Clostridium, and relatively few Bifidobacterium species. As solid foods are added to the infant’s diet, the microflora becomes similar regardless of breast feeding status, with Bacteroides and anaerobic Gram-positive cocci appearing in the flora. After the infant reaches two years of age, a conversion to normal adult flora begins, and populations of Bacteroides and anaerobic cocci increase until they equal or exceed those of Bifidobacterium. The number of Gram-negative anaerobes increases to adult levels, whereas coliform, clostridial and streptococcal populations decrease to the levels found in healthy adults. The development of the microflora from the neonatal to the adult composition is very important with respect to the development of the intestinal mucosal immune system and its ability to discriminate between pathogenic microorganisms and the vast array of antigens to which it is exposed over a lifetime. The intestinal mucosa thus has the unique properties of tolerance to environmental antigens (which may include probiotics) and specific immunological responsiveness to mucosal pathogenic microorganisms. The phenomenon of tolerance is thought to occur through clonal deletion, clonal anergy of antigen-specific T cells, or immune deviation medicated via Class I restricted CD4+ T cells and cytokines such as interleukin (IL)-10, or transforming growth factor-β (7).The process is dependent on the normal indigenous flora because germ free animals are defective with respect to tolerance. The immunological response of the gut is mediated through lymphocytes within the lamina propria and both T helper cell 1 (Th-1; IL-12, IFN-γ) and T helper cell-2 (IL-10, IL-4, IL-5) responses