Pulmonary Aspergillus fumigatus infection in rats affects gastrointestinal homeostasis
Introduction
At late seventies the term “common mucosal immunological system” (CMIS) was coined to describe similarities in lymphoid tissues associated with bronchus and intestine (McDermott and Bienenstock, 1979). From then mechanisms underlying immune responses to pathogens in the gastrointestinal and respiratory tract have been established (Mowat and Agace, 2014; Sato and Kiyono, 2012). Growing body of evidence suggests that two mucosal sites communicate and interact in health and disease what brought suggestion that mucosal immune system is system wide-organ (Gill et al., 2010). Pulmonary involvement seen in patients with chronic gastrointestinal diseases such as inflammatory bowel disease and irritable bowel syndrome as well as association of gastrointestinal symptoms observed in patients with pulmonary infections depict cross-talk between gastrointestinal and pulmonary defences (Samuelson et al., 2015; Tulic et al., 2016).
Much interest in investigation of gut and lung communication was given to gut microbiota (Dickson et al., 2013). The use of animals treated with antibiotics or which differ in intestinal microbiota composition showed that gut microbiota is essential for promoting optimal pulmonary response to allergens (Kim et al., 2014), against viruses (Abt et al., 2012; Ichinohe et al., 2011; Wu et al., 2013) and bacteria (Chen et al., 2011; Fagundes et al., 2012; Gauguet et al., 2015; Schuijt et al., 2016).
Changes in gut microbiota were also found to be involved in settings of pulmonary immune responses. Infection of mice with Influenza A (IA) (Deriu et al., 2016; Groves et al., 2018; Wang et al., 2014; Yildiz et al., 2018; Zhang et al., 2015) or respiratory syncytial (RSV) viruses (Groves et al., 2018) resulted in altered diversity of gut bacterial microbiota and was associated with intestinal injury and inflammation. Presence of the virus in the intestine was responsible for tissue injury only in one study (Zhang et al., 2015). Intestinal injury is thought to be induced by virus-specific T cells recruited from the lung (Wang et al., 2014), though innate pulmonary responses might be responsible judging by data which showed that administration of agents which induce pulmonary inflammation such are poly I:C (Deriu et al., 2016) and LPS (Sze et al., 2014) also affected gut microbiota. Alterations of gut microbiota were detected in patients (Luo et al., 2017) and mice with pulmonary M. tuberculosis infection (Winglee et al., 2014).
Gut microbiota has the potential to influence host response to fungi as well. Treatment of mice with antibiotics and oral C. albicans thereafter, prime mice for allergic T-cell based response to Aspergillus (Noverr et al., 2004). More recently, the influence of intestinal bacterial microbiota on the generation of pulmonary IL-17 response to A. fumigatus was noted in mice (McAleer et al., 2016). There are, however no data concerning the effects of pulmonary fungal infections on gut homeostasis.
In the view of above cited studies which showed the impact of pulmonary viral and bacterial infections on gut homeostasis, we hypothesized that pulmonary immune response to fungi might affect gut homeostasis as well. Among variety of rat models of aspergillosis (Chandenier et al., 2009; Desoubeaux and Cray, 2017) we used rat model of pulmonary Aspergillus fumigatus infection in immunocompetent rats (El-Muzghi et al., 2013; Mirkov et al., 2015) to investigate the effect of A. fumigatus infection on gut homeostasis. Signs of intestinal damage, intestinal and gut-associated lymphoid tissue cytokine responses as well as gut bacterial microbiota diversity were examined at different time points following infection, shown previously by us to be accompanied with marked changes in fungal load resulting from inflammatory/immune activity in the lungs (El-Muzghi et al., 2013; Mirkov et al., 2015). Data that were obtained showed for the first time that lung infection with A. fumigatus is associated with intestinal damage and pro-inflammatory cytokine response in small intestine and major-gut draining (mesenteric) lymph nodes. Decrease in diversity of intestinal bacterial microbiota was observed during pulmonary infection, with appearance of new bacterial species, not noted in non-infected controls, what might have contributed to intestinal inflammation. Disruption of gut homeostasis during pulmonary infection might render gastrointestinal tract more susceptible to variety of physiological and pathological stimuli.
Section snippets
Rats
Male Dark Agouti (DA) rats, ten to twelve weeks old, bred and conventionally housed at the Institute for Biological Research “Sinisa Stankovic” (Belgrade, Serbia) were used in the study. Animals were fed commercial chow and received no medication prior experimental procedure. Four individuals were assigned per group for each time point in two independent experiments. All animal procedures were complied with the Directive 2010/63/EU on the protection of animals used for experimental and other
Pulmonary infection of rats with A. fumigatus: general information
No differences in body weight were observed between sham infected and rats administered with A. fumigatus throughout the investigated period (Table 1). In line with our previously published data, pulmonary A. fumigatus infection induced lung leukocyte infiltration, predominantly neutrophils, (starting from day one) and proinflammatory cytokine lung response (IFN-γ from post infection day three to day seven; IL-17 from day one to day seven).
Intestinal injury in rats with pulmonary A. fumigatus infection
Histological examination of intestine revealed edema of
Discussion
The effect of lung A. fumigatus infection on gut homeostasis was examined in this study. Data obtained showed for the first time that pulmonary infection with the fungus is associated with intestinal damage and inflammation and was accompanied by cytokine response of major gut-draining lymph nodes. It is not result of intestinal response to A. fumigatus, since fungus was not detected in the gut, judging by highly sensitive and rapid method (seminested PCR specifically amplifying internal
Conflict of interest
The authors declare no conflict of interest.
Acknowledgement
This study was supportedby the Ministry of Education, Science and Technological Development of the Republic of Serbia (Grants #173039 and #173019).
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