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In recent years, research interest in understanding the role that the intestinal microbiota plays in human health has increased exponentially. However, few findings from preclinical models have been translated into clinically meaningful microbiota-targeted therapies for treating physicians. This thesis has aimed to translate the findings obtained through preclinical animal models into human cohort and intervention studies linking antibiotic-induced disturbances of the intestinal microbiome to altered function of the innate immune system. We hypothesized that the collateral effects of disruptions of these commensal intestinal microorganisms contribute to increased susceptibility to systemic infections. Using clinical cohorts and human adult volunteer studies, we were able to demonstrate that alterations of the gut microbiome, specifically a loss of anaerobic butyrate-producing bacteria, are associated with a loss of protection against infectious agents. In addition, we have shown that intestinal bacterial composition is indeed linked with direct innate immune responses. Finally, we show that antibiotic-induced modulation of the bacterial component of the microbiome has implications extending beyond this kingdom alone, enabling the overgrowth of potentially invasive and pathogenic fungi and viruses. While these findings show promise that specific intestinal bacteria are associated with protection against infections, it is clear that we are only beginning to understand the overarching mechanisms by which such microbial metabolites and micro-organisms influence the immune system. Therefore, future studies aimed at elucidating the underlying mechanisms of action will be vital to understanding how best to improve innate immune responses and induce protection against systemic infectious diseases.

Obesity is a major health concern not only in the general population but also in patients with haemophilia. Little is known about the consequences of obesity for haemophilia patients. As obesity is an important risk factor for osteoarthritis, these effects may be even more pronounced in haemophilia patients who are prone to joint damage. The association between obesity and limitations in daily activities as well as the frequency of bleeds and use of factor VIII (FVIII) concentrate in obese and normal weight haemophilia patients was assessed. Fifteen obese (BMI≥30kgm-2) and fifteen normal weight (BMI≤25kgm-2) haemophilia A patients matched for severity and age were analysed. The Hemophilia Activities List (HAL) was used to assess the impairment in daily activities. Compared with the normal weight haemophilia patients, obese haemophiliacs had a significantly lower sum score (88/100 and 98/100, respectively, P=0.02), which was mainly caused by an impaired lower limb function. All other components of the HAL also showed lower scores in the obese patients, but did not reach statistical significance. A higher frequency of bleeds requiring treatment with FVIII concentrate occurred in the obese haemophiliacs (17 bleeds in eight individuals) compared with the controls (three bleeds in three individuals) (P=0.045). Compared with non-obese haemophilia patients, obese haemophiliacs had more joint bleeds and a lower overall HAL score, which was driven by a lower limb function score. Prevention of overweight and weight reduction requires special attention from physicians treating haemophilia patients. © 2011 Blackwell Publishing Ltd.