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THE NEGLECTED ORGAN: BACTERIAL FLORA HAS A CRUCIAL IMMUNOSTIMULATORY ROLE VELIO BOCCI* Introduction Most people are surprised to hear that a normal human being hosts a mass of bacteria equivalent to about 1.2 kilograms; the bulk are in the gut lumen and the remaining mainly dispersed among the skin, the rhino-oral-pharyngeal cavities, and the genital mucosae. Their weight almost equals that of the liver, and because they are smaller than our cells, their total number (about 10H) exceeds that of our own cells [I]. It is also almost incredible that over 400 species, mostly anaerobic or microaerophilic gram-negative and gram-positive bacteria [2], live on strictly aerobic animals and are well adapted to particular environments such as gingival crevices, and the intestinal and vaginal niches, enjoying the wealth of nutrients and the constancy of temperature. Another outstanding feature is that, although during fetal life we are sterile, from the moment of being born by passing through the vagina, by breathing, sucking, and being caressed, we begin to pick up bacteria present in the air, nipples, and hands, so that they colonize all available cutaneous and mucosal surfaces in a matter of days, even though the final flora becomes firmly established after weaning. The number and types of bacteria on the earth surface vary depending on geographic location, climate, and hygienical and social conditions, but they are ubiquitous. No living eukaryote can avoid bacterial colonization unless it is born and maintained in absolutely sterile conditions after cesarean delivery. Therefore it has been proved beyond any doubt that the absence of bacterial flora This work was supported by grants from M.URST, Project 40%, and by contract 91.00089, PFAI of the National Research Council (CNR), Rome, targeted Project "Prevention and Control Disease Factors" Subproject 02. The author thanks Miss P. Marrocchesi for preparing the manuscript. *Institute of General Physiology and Nutritional Sciences, University of Siena, Via Laterina 8, 53100 Siena, Italy.© 1992 by The University of Chicago. AU rights reserved. 0031-5982/92/3502-0765$01.00 Perspectives in Biology and Medicine, 35, 2 ¦ Winter 1992 | 251 in germ-free animals does not hinder their existence, and, although constrained in a closed environment, they can have a normal, possibly longer, life span, provided an adequate amount of sterilized foodstuff is supplied [I]. But here I do not want to engage in a futile discussion about whether we can live better and longer without the bacterial flora. With a few exceptions caused by severe genetic deficiencies, no one would choose to live in a sterile chamber eating sterilized food and unable to communicate directly with other human beings. Therefore we must live with the bacterial flora. Prokaryotes have lived on Earth for about 3 billion years earlier than the eukaryotes, many of which (e.g., the ruminants) still depend on them for the availability of essential nutrients. During evolution, both prokaryotes and eukaryotes have had to find the most suitable conditions for living harmoniously most of the time, and they have, with some risks and reciprocal advantages. They exist together in such an intimate way; how do they interact with each other? The object of this article is to point out that the main bacterial signals are represented by constituents of the outer membrane of gram-negative bacteria, namely, lipopolysaccharides (LPS). Most eukaryotes, and of course human beings, have evolved an immune system with appropriate receptors, effector cells, and molecules such as the cytokines, immunoglobulins (Ig), and complement factors that, directly or indirectly, most of the time are able to check invading microorganisms. I shall summarize the main structure and characteristics of LPS. Then I shall sum up data indicating that most of the LPS are by various means kept from entering the internal environment and that only traces can reach the body fluids and interact with a variety ofcells. A consideration of their topography, the main reactive sites, and biological effects makes this apparent. Third, I shall emphasize that normally LPS act as a physiological stimulus and, by inducing the production of cytokines, maintain the immune system in a state of alertness. Finally, I would like to speculate on the importance of LPS in mood and sleep...