OCCASIONAL REVIEW Does environmental endotoxin exposure prevent asthma? J Douwes, N Pearce, D Heederik ............................................................................................................................. Thorax 2002;57:86–90 The evidence as to whether exposure to environmental airborne endotoxin plays a protective or an inducing role in the development of asthma is reviewed. Studies of endotoxin and atopy, endotoxin and asthma, and farming and asthma are considered and, in each instance, a distinction is made between evidence of primary causation and evidence of secondary causation. It is concluded that, although it is plausible that bacterial endotoxin may protect against the development of asthma, there is considerable reason for caution regarding this hypothesis. .......................................................................... I t has recently been suggested that exposure to environmental endotoxin might protect against the development of atopy and asthma. 1–5 This hypothesis has been prompted by various recent studies that reported a reduced risk of atopy (determined by skin prick tests, IgE serology or questionnaire), hay fever and, to a lesser extent, asthma in farmers’ children and adolescents 6–10 and in first year university students with a farm- ing background. 11 It was indicated that contact with livestock reduced the risk. 7 8 10 This is consistent with previous observations that pigs and cattle in the home in Guinea-Bissau 12 and Nepal, 13 respectively, and the presence of pets in the home early in life in Europe 14 15 were negatively associated with atopy. Although no specific protective factors were determined in these studies, it has been speculated that respira- tory exposure to endotoxin (particularly in livestock farming) may play an important role 23 since it is well known, especially from occupa- tional studies, that keeping animals is associated with strongly increased exposures to bacterial endotoxin. The suggestions by Thomas 16 that endotoxins are “read by our tissues as the very worst of bad news” and that in response to these molecules “we are likely to turn on every defence at our dis- posal” elaborate well the toxic potential of these macromolecules. 17 Endotoxin is composed of lipopolysaccharides and is a non-allergenic cell wall component of Gram negative bacteria with strong pro-inflammatory properties. It is com- monly present in many occupational environments 18 and also in the general environ- ment, particularly in house dust, as was first demonstrated by Peterson et al 19 and more recently by others. 20–22 There is ample evidence, mainly from studies in the work environment, that very high levels of exposure to endotoxin occur in farming, particularly livestock farming. 23 Increased endotoxin levels were also found in homes where children had regular contact with farm animals 2 and in those where pets were present. 22 It therefore seems plausible that bacterial endotoxin may account for the lower risk of atopy and perhaps asthma itself in farmers’ children and, more generally, in the wider population. This hypothesis is appealing since it would not only account for the striking finding in farmers’ children, but is also consistent with the “hygiene hypothesis” 1 24 and would offer potential practical methods of asthma prevention. However, there is considerable reason for caution. In particular, although endotoxin exposure may protect against the development of atopy, at most only 50% of asthma cases appear to be attributable to mecha- nisms involving atopy. 25 Moreover, it is well known from occupational health studies that exposure to endotoxin may induce asthma rather than protect against it (see below). Finally, there are many other factors that may explain the reduction of atopy in farmers’ children—for example, high allergen exposure that may reduce the risk of sensitisation, infant infections, diet, and other lifestyle factors. These two aspects of the (potential) effects of endotoxin—namely, the protective effect with regard to atopy and endotoxin as an inducer of (occupational) asthma—have often not been carefully consid- ered in discussing these issues. In this review we therefore consider the evidence as to whether environmental airborne endotoxin exposure plays a protective or inducing role in the development of asthma. In doing so, we distinguish between studies of endotoxin and atopy, endotoxin and asthma, and farming and asthma. Furthermore, in each instance we distinguish between evidence of primary causation and evidence of secondary causation. For clarity, we will only focus on the role of respiratory endotoxin exposure and will not discuss the potential immunomodulating role of gastrointestinal endotoxin. The latter may, however, be significant since it has been sug- gested that the intestinal microflora may be a very important source for microbial pressure poten- tially enhancing Th1 type responses. 26 DEFINITIONS In this review we consider “atopy” as IgE mediated sensitisation to “common allergens” such as house dust mite, pets, and various other indoor and outdoor allergens. Asthma is defined as a chronic inflammatory disorder of the airways involving airflow limitation that is at least partly reversible and which results in recurrent episodes of symptoms such as wheezing, breathlessness, chest tightness, and cough. Allergic asthma represents asthma with an underlying atopic air- way inflammation involving IgE sensitisation and eosinophils whereas non-allergic asthma is char- acterised by non-atopic airway inflammation (not involving IgE and eosinophils). See end of article for authors’ affiliations ....................... Correspondence to: Dr J Douwes, IRAS, PO Box 80176, 3508 TD, Utrecht, The Netherlands; j.douwes@iras.uu.nl Accepted 19 September 2001 ....................... 86 www.thoraxjnl.com