152 Chapter 7 Introduction While the pathophysiology of asthma is complex, perturbation of the gut microbiota has been associated with an increased risk of asthma development in childhood [1]. Disruption and subsequent dysregulation of gut microbiota-related immunological processes have also been linked to disease severity and response to treatment [2]. Murine studies have suggested that products derived from gut commensals, such as short chain fatty acids and microbe-associated molecular patterns, can modulate systemic immunity and local lung inflammation by priming immune effector cells [3]. The so-called gut-lung-axis, referring to the hypothesized interaction between the gut microbiota and the lungs, might be of importance in patients with allergic asthma but mechanistic data from humans is lacking [4]. This current human intervention trial was designed as a proof-of-concept study, addressing the following question: does modulation of the gut microbiome of adults with allergic asthma influence lung inflammation in a house dust mite (HDM) plus lipopolysaccharide (LPS) provocation model? Methods We recruited twenty patients (aged 18-45 years) with asthma and HDM allergy who were randomized into two groups, which received either broad-spectrum antibiotics orally (ciprofloxacin 500 mg q12h, vancomycin 500 mg q8h, metronidazole 500 mg q8h) for 7 days in order to disrupt the intestinal microbiota or no treatment. After a 36-hour washout period of antibiotics all patients were challenged through HDM/LPS installation in one lung segment by bronchoscopy, after instillation of normal-saline in a contralateral lung segment (Figure 1A). Bronchoalveolar lavage fluid (BALF) was obtained from both instilled lung segments during a second bronchoscopy seven hours later. Primary outcome was influx of eosinophils and neutrophils, defined as number of cells/mL, into the bronchoalveolar space. Secondary outcomes were differences in microbiome diversity and differences in BALF inflammatory mediators. For details on study design, patient selection, sample handling, assays, and statistical analysis see Methods section in online supplementary text (ClinicalTrials.gov identifier NCT03051698). Results Baseline characteristics were similar across groups (Supplementary Table 1). The concentration methacholine bromide required to achieve 20% in Forced-ExpiratoryVolume in 1-second (FEV1), corresponding with increased airway hyperresponsiveness, was 2.71 [1.79, 4.90] (median [IQR]) in the control group and 2.08 [1.71, 2.98] in the group treated with broad-spectrum antibiotics. In the antibiotics group, most patients experienced mild and transient gastro-intestinal complaints. The effect of the seven-day course of ciprofloxacin, vancomycin and metronidazole on the intestinal microbiota was profound and resulted in a loss of diversity and a shift in fecal community composition, as determined by sequencing of bacterial 16S rRNA genes. Alpha diversity was lower after antibiotic treatment compared to baseline (before antibiotics: median Shannon Index (SI) 3.8, IQR 3.6-4.0; following antibiotic treatment: SI 1.5, IQR 0.5-1.6; Wilcoxon P<.001; Figure 1B). Controls did not differ from
RkJQdWJsaXNoZXIy MTk4NDMw