antioxidant system and the adaptive response of enterocytes are all responsible for the lack of toxicity. However we must keep in mind that Eliakim et al., (2001), after repeated enema in rats with ozonated water (20mcg/ml), have reported the appearance of a microscopic colitis. Although gas insufflation is probably less irritating than the enema, this result reinforces my suggestion to use low doses of ozone at least initially for inducing the tolerance phenomemon. 53 Chapter 6 In Chapter 9, we will briefly examine the pathogenesis of the diseases where RI is best employed, but here it may be useful to speculate about the local effects of ozone. These may be as follows: a) Biochemical effects. In the studies already cited (Leon et al., 1998; Barber et al., 1999; Peralta et al., 1999, 2000; Borrego et al., 2004; Gonzalez et al., 2004), RI in rats upgraded the enzymatic antioxidant response in liver and kidney but the viability of enterocytes was not examined. b) Bactericidal effects. The human colon-rectum contains up to 600 g of about 400 species of mostly anaerobic bacteria, and ozone may partly change the environment for a short while. Except in particular conditions, like clindamycin-associated enterocolitis (Schulz, 1986), bactericidal activity per se is probably unimportant but may cause the release of LPSs and muramyl peptides. These compounds are among the most potent cytokine inducers and in large amounts are responsible for the toxic shock syndrome and likely death. However, in physiological conditions, the daily absorption of traces of LPSs bound to specific proteins and to lipoproteins is considered essential for maintenance of the basic cytokine response and an alert immune system (Bocci, 1981b, 1988b, 1992c). Particularly in the last paper, it was postulated that the somewhat neglected gut flora has a crucial immunostimulatory role. This idea remains valid today and it is possible that RI favours a slight increase of LPS absorption with the consequence of enhanced activation of intrahepatic lymphocytes, Ito’s and Kupffer’s cells (O’Farrelly and Crispe, 1999), which may change the evolution of chronic hepatitis. c) Modification of the bacterial flora equilibrium. Owing to the multiplicity of bacterial species, this remains a complex area. However, the normal flora contains Lactobacillus (Lb) acidophilus, Lb. bifidus, Lb. fermentum, Lb. casei, Streptococcus faecalis, S. thermophilus, S. bulgaricus, Escherichia coli, Proteus and a variety of enterocci. The bacteria and their products interact with each other and with the enterocytes, goblet and enteroendocrine cells (producing a myriad of hormones) and the gutassociated lymphoid tissue, GALT (Hooper and Gordon, 2001). On the other hand, it is well known that contaminated food, water and antibiotics can subvert this dynamic symbiosis by allowing the establishment of pathological bacteria and fungi like Candida albicans, C. tropicalis, Torulopsis glabrata, etc. The successive dysmicrobism usually has farreaching deleterious consequences, ranging from transient to chronic enterocolitis and to autoimmune reactions and therefore we must try to correct it in order to restore normal homeostasis. Whether RI with a daily input of oxygen-ozone can re-equilibrate the bacterial flora and lead to normal immunoreactivity remains to be demonstrated (and explained), although anecdotal results suggest a beneficial effect. d) Effects on the GALT. The gastrointestinal compartment represents almost 40% of the whole immune system. Besides the famous plaques 54 The Actual Six Therapeutic Modalities