At parturition, there is colonisation of the previously sterile foetal intestine by a vast microbial inoculum. The establishment of the intestinal microflora is a very dynamic process during the first days of life before stable populations are established in defined regions of the gastrointestinal tract. There is sequential colonisation by first E. coli and Streptococci species (Mata, L. J. and J. J. Urrutia. 1971. Ann N Y Acad Sci 176:93-108) and then a bifidogenic microflora, which is highly dominant in breast-fed babies and offers some protection against potential pathogens (Gibson, G. R. and X. Wang. 1994. J Appl Bacteriol. 77:412-420).
Lactic acid bacteria (LAB) such as lactobacilli and bifidobacteria are normal inhabitants of the human adult gastrointestinal tract. Selected strains from these genus, termed probiotics, have health benefits when administered orally to the host (Brassart, D. and E. J. Schiffrin. 1997. Trends Food Sci Technol 9:321-326). Like commensal LAB, probiotics antagonise pathogenic organisms and stimulate immune defence mechanisms. Although, little is known about the precise mechanisms which underlie these biological effects, it is widely accepted that strains which most likely exert health benefits are those which can transiently adhere to the intestinal epithelium, perhaps through the lipoteichoic acid (LTA) in their cell wall.
LTA is a complex glycero-phosphate polymer linked to a hydrophobic lipid moiety (Fischer, W. 1990. Bacterial phophoglycolipids and lipoteichoic acids. In Glycolipids, phosphoglycolipids and sulfoglycolipids, M. Kates, editor. Hanahan, D. J., New York and London. 123-234). It is a component of the cell wall of most Gram-positive bacteria and although there is great diversity in the LTA from different bacteria, it has structural similarities to LPS found in the cell wall of Gram-negative organisms.
While LPS from Gram-negative organisms are renowned for their pro-inflammatory effects on immune cells, less work has been done using LTA from Gram-positive organisms. It appears nevertheless that only LTA from specific species of bacteria mediate such effects (Suda, Y., et al. 1995, FEMS Immunol Med Microbiol 12:97-112; Arakaki, R., et al. 1998, FEMS Immunol Med. Microbiol 22:283-291)
Although LTAs from Gram-positive bacteria show great diversity from one bacterial strain to another, there is some structural similarity to the LPS present in the cell wall of Gram-negative organisms. Pattern Recognition Receptors (PRR) recognise conserved regions of bacterial structures and signal to the host the presence of a bacterial inoculum. CD14, a glycosylphosphatidyl-inositol (GPI)-anchored glycoprotein present on myeloid cells, is one such receptor. It is now known that it can bind both LTA and LPS. Indeed, the sepsis caused by Gram-negative organisms is through LPS binding to CD14 on the membrane of monocytes-macrophages. There is increasing evidence that a soluble form of the CD14 receptor mediates binding of LPS to CD14-negative cells. However, this molecule also recognises other bacterial components, such as peptidoglycan, lipoarabinomannan and manuronic acid polymers (Dziarski, R., et al., 2000. Chem. Immunol. 74:83-107). We have reported that a soluble form of CD14 (sCD14) present in human breast milk stimulates human intestinal epithelial cells (IECs) to release cytokines after challenge with non-pathogenic E. coli or its LPS (Labeta, M. O., et al. 2000. J Exp Med 191:1807-1812) but not after challenge with live Gram-positive bacteria or their cell wall components.
The present invention aims to provide a composition able to modulate the immune responses involved during bacterial colonisation or infection and prevent or reduce any inflammatory response induced thereby, in the gastrointestinal tract, bone, skin, eye, lung, ear and oral cavity in humans or animals.
USPTO Backgrounds
USPTO Backgrounds