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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">Culture-independent techniques have revealed the composition of a stable microbiota within the distal airways&#59; and although normality criteria have not yet been established&#44; atypical compositions linked to certain respiratory diseases have been detected&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">1</span></a> Dysbiosis is typically detected surrounding tumours tissues&#44; and this trait has been poorly explored in the respiratory airway tissues&#44;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">2&#44;3</span></a> mostly using surgical samples&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">4&#8211;8</span></a> An understanding of the microbiota is necessary to decipher its possible causal role in cancer&#44; and also to elucidate the prognosis and response to immunomodulatory therapies&#44; because microorganisms and&#47;or their metabolites shape the local microenvironment&#44; influence the immune response&#44; and impact the final battle against cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">9</span></a> Finally&#44; the presence and&#47;or abundance of specific bacteria could be used as a biomarker&#44; as occurs with <span class="elsevierStyleItalic">Streptococcus gallolyticus</span> sbsp&#46; <span class="elsevierStyleItalic">gallolyticus</span> in the colorectal cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">10</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The aims of the present study were to define the bacterial and fungal microbiota of central lung cancer&#44; in relation to the corresponding contralateral bronchus and compared with controls without cancer history&#44; also defining the core of those microbiotas&#59; and to correlate the pulmonary microbiota in lung cancer with the salivary and faecal compartments&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Patients and samples</span><p id="par0015" class="elsevierStylePara elsevierViewall">Twenty-five patients &#40;24 men&#44; mean age of 68 years&#41; diagnosed with central lung cancer&#44; directly visible and biopsied by bronchoscopy&#44; were recruited &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; The exclusion criteria included the intake of antibiotics&#44; pre or probiotics&#44; and systemic corticoids during the previous 4 weeks&#59; acute infection&#59; radio or chemotherapy in the last year&#44; and immunodeficiency&#46; Tumours were histologically classified into non-small cell lung cancer &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>18&#44; including 10 squamous&#44; 4 adenocarcinoma&#44; and 4 undifferentiated&#41;&#59; and small cell lung cancer &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#41;&#46; Each patient contributed with 4 samples&#58; &#40;i&#41; saliva collected from a rinse with sterile distilled water&#44; prior to the bronchoscopic procedure&#44; &#40;ii&#41; biopsies of affected&#44; and &#40;iii&#41; contralateral bronchi&#44; and finally &#40;iv&#41; a faecal sample &#40;provided by 18 out of the 25 patients&#41;&#46; The nasal route&#44; or oral if not possible&#44; with local instillation of lidocaine were used for bronchoscopies&#46; Prior to the tumour sampling&#44; biopsies for microbiota determination were obtained from contralateral non-affected tissues&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Simultaneously&#44; 16 controls without history of cancer were included&#44; and each contributed the following&#58; &#40;i&#41; oral microbiota and &#40;ii&#41; a single biopsy of their healthy bronchi&#46; Controls without respiratory symptoms &#40;except 2 with chronic cough&#41; underwent bronchoscopy for non-cancer related indications &#40;benign tracheal stenosis 9&#44; fake haemoptysis 3&#44; chronic cough 2&#44; control of a previous endobronquial hamartoma resection 1&#44; and dyspnoea 1&#41;&#44; and all of them had normal spirometries&#46; All samples were immediately frozen at &#8722;80<span class="elsevierStyleHsp" style=""></span>&#176;C after collection&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Microbiota composition</span><p id="par0025" class="elsevierStylePara elsevierViewall">Total DNA was obtained by the QiaAmp kit &#40;Qiagen&#41; from the biopsies&#44; from the pellet of saliva after centrifugation&#44; and from 200<span class="elsevierStyleHsp" style=""></span>&#956;l aliquots of a solution of 0&#46;5 gr of faeces in 5<span class="elsevierStyleHsp" style=""></span>ml of water&#46; Bacterial composition was determined by PCR amplification of the 16S rDNA V3-V4 region using published primers&#44;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">11</span></a> whereas the mycobiome was only analyzed in bronchial and saliva of the 16 controls and in a subset of 6 patients by amplification of the ITS-1 region&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">12</span></a> PCR products were submitted to massive sequencing &#40;2&#215; 300<span class="elsevierStyleHsp" style=""></span>bp&#41; on a MiSeq &#40;Illumina&#44; San Diego&#44; CA&#44; USA&#41; platform&#44; at FISABIO &#40;Valencia&#44; Spain&#41;&#46; Raw sequence data were deposited in GenBank &#40;BioProjects PRJNA586753 and PRJNA586768&#46; QIIME2 software suite &#40;2019&#46;1 distribution&#41;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">13</span></a> and LEfSE<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">14</span></a> were used for analysis&#44; and adequate negative sequencing controls were added in each process and run&#46; A computational analysis has developed to define the microbiota core that was present in at least 95&#37; of the individuals&#46; This analysis is available at <a href="https://github.com/JJ-Lab/Cancer_Lung_Microbiota">https&#58;&#47;&#47;github&#46;com&#47;JJ-Lab&#47;Cancer&#95;Lung&#95;Microbiota</a> website&#46;</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Results</span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Sample filtering</span><p id="par0030" class="elsevierStylePara elsevierViewall">Three samples from affected bronchi &#40;patients 23&#44; 24&#44; and 25&#41; and four samples from control bronchi &#40;controls 2&#44; 3&#44; 7&#44; and 16&#41; were excluded of the analysis since they did not reach minimal sequencing depth requirements &#40;&#62;1000<span class="elsevierStyleHsp" style=""></span>reads&#47;sample&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Alpha diversity</span><p id="par0035" class="elsevierStylePara elsevierViewall">Alpha diversity indexes&#44; as Chao1 and Shannon&#44; express the mean diversity in microbial species in a single community&#44; with the highest values corresponding to the greater number of species &#40;richness&#41;&#46; Faeces and saliva had similar alpha diversity values&#44; while bronchi were significantly more diverse according to Faith&#39;s PD index &#40;which specifically assessed phylogenetic diversity&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 1</a>&#41;&#46; The diversity of saliva was comparable in patients and controls&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Microbiota composition</span><p id="par0040" class="elsevierStylePara elsevierViewall">Beta diversity analysis compares the microbiota composition between different samples&#44; and use to be referred to <span class="elsevierStyleItalic">phyla</span> &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 2</a>&#41; and genera levels &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 3</a>&#41;&#46; Patients&#8217; saliva presented a higher density of <span class="elsevierStyleItalic">Firmicutes</span> and <span class="elsevierStyleItalic">Actinobacteria</span> to the clear detriment of <span class="elsevierStyleItalic">Proteobacteria</span>&#44; and this pattern was reproduced in the affected and contralateral bronchi&#46; Faecal samples had a remarkably high proportion of <span class="elsevierStyleItalic">Firmicutes</span> &#40;&#62;75&#37;&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Saliva</span><p id="par0045" class="elsevierStylePara elsevierViewall">Up to 213 genera were detected in saliva samples&#44; with 13 comprising the majoritarian in both controls and patients&#58; <span class="elsevierStyleItalic">Streptococcus</span> &#40;19&#37; and 23&#37;&#44; respectively&#41;&#44; <span class="elsevierStyleItalic">Prevotella</span> &#40;15&#8211;13&#37;&#41;&#44; <span class="elsevierStyleItalic">Rothia</span> &#40;4&#8211;7&#37;&#41;&#44; <span class="elsevierStyleItalic">Veillonella</span> &#40;7&#8211;8&#37;&#41;&#44; <span class="elsevierStyleItalic">Neisseria</span> &#40;6&#8211;4&#37;&#41;&#44; <span class="elsevierStyleItalic">Porphyromonas</span> &#40;6&#8211;4&#37;&#41;&#44; <span class="elsevierStyleItalic">Haemophilus</span> &#40;6&#8211;2&#37;&#41;&#44; <span class="elsevierStyleItalic">Gemella</span> &#40;3&#8211;5&#37;&#41;&#44; <span class="elsevierStyleItalic">Fusobacterium</span> &#40;5&#8211;3&#37;&#41;&#44; <span class="elsevierStyleItalic">Alloprevotella</span> &#40;4&#8211;1&#37;&#41;&#44; <span class="elsevierStyleItalic">Actinomyces</span> &#40;2&#8211;2&#37;&#41;&#44; <span class="elsevierStyleItalic">Granulicatella</span> &#40;1&#8211;2&#37;&#41;&#44; and <span class="elsevierStyleItalic">Leptotrichia</span> &#40;1&#8211;2&#37;&#41;&#46; The remaining genera represented less than 1&#37; of the total microbiota abundance&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Saliva microbiota core from patients and controls were similar&#44; and although significant differences on the bacterial proportions were detected &#40;<a class="elsevierStyleCrossRefs" href="#fig0020">Figs&#46; 3 and 4</a>&#44; and <a class="elsevierStyleCrossRef" href="#sec0095">supplementary material</a>&#41;&#44; that differences are linked to relative abundance of common taxa and no to presence or absence of specific taxa&#46; <span class="elsevierStyleItalic">Streptococcus&#44; Rothia</span>&#44; <span class="elsevierStyleItalic">Gemella</span> and <span class="elsevierStyleItalic">Lactobacillus</span> abundances are capable of distinguishing the saliva of patients from controls&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Bronchi</span><p id="par0055" class="elsevierStylePara elsevierViewall">More than 450 bacterial genera were identified with different distribution among patients and controls&#44; while the microbiota of the cancer-affected bronchus was almost identical to its contralateral counterpart &#40;<a class="elsevierStyleCrossRefs" href="#fig0020">Figs&#46; 3 and 4</a>&#44; and <a class="elsevierStyleCrossRef" href="#sec0095">Supplementary material</a>&#41;&#46; Particularities depending on the histological type of cancer were not detected&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Lung cancer-related genera were <span class="elsevierStyleItalic">Streptococcus</span> &#40;19&#37; in affected bronchus and 24&#37; in contralateral&#41;&#44; <span class="elsevierStyleItalic">Prevotella</span> &#40;9&#8211;9&#37;&#41;&#44; <span class="elsevierStyleItalic">Blautia</span> &#40;5&#8211;4&#37;&#41;&#44; <span class="elsevierStyleItalic">Veillonella</span> &#40;4&#8211;5&#37;&#41;&#44; <span class="elsevierStyleItalic">Rothia</span> &#40;3&#8211;4&#37;&#41;&#44; <span class="elsevierStyleItalic">Neisseria</span> &#40;2&#8211;3&#37;&#41;&#44; <span class="elsevierStyleItalic">Gemella</span> &#40;2&#8211;2&#37;&#41;&#44; and <span class="elsevierStyleItalic">Porphyromonas</span> &#40;2&#8211;2&#37;&#41;&#46; Health bronchi from control group was dominated by <span class="elsevierStyleItalic">Pseudomonas</span> &#40;21&#37;&#41;&#44; followed by <span class="elsevierStyleItalic">Streptococcus</span> &#40;8&#37;&#41;&#44; <span class="elsevierStyleItalic">Actinobacter</span> &#40;6&#37;&#41;&#44; <span class="elsevierStyleItalic">Veillonella</span> &#40;4&#37;&#41;&#44; <span class="elsevierStyleItalic">Prevotella</span> &#40;3&#37;&#41;&#44; <span class="elsevierStyleItalic">Delftia</span> &#40;3&#37;&#41;&#44; <span class="elsevierStyleItalic">Janthinobacterium</span> &#40;3&#37;&#41;&#44; <span class="elsevierStyleItalic">Escherichia-Shigella</span> &#40;2&#37;&#41;&#44; <span class="elsevierStyleItalic">Haemophilus</span> &#40;2&#37;&#41;&#44; and <span class="elsevierStyleItalic">Neisseria</span> &#40;2&#37;&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Streptococcal abundance characterizes the microbiota of patients</span><p id="par0065" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Streptococcus</span> is a genus within the <span class="elsevierStyleItalic">Firmicutes</span> phylum that has a complex taxonomy&#46; Our results showed that bronchial streptococcal abundance systematically distinguished patients from controls Up to 95 different amplicon sequence variants &#40;ASV&#41; assigned to <span class="elsevierStyleItalic">Streptococcus</span> were identified among all samples&#44; and their particular distribution allowed us to hypothesize an exchange between oral and bronchial ecosystems &#40;<a class="elsevierStyleCrossRef" href="#sec0095">Supplementary material</a>&#41; Faeces were the most remote niche&#44; with saliva and bronchi also distant&#46; It is important to note that &#62;95&#37; of the ASV detected in the patients&#8217; bronchi were also present in their saliva&#44; while on the contrary only 36&#37; from saliva were also in the lung&#44; indicating that saliva is the main source of pulmonary <span class="elsevierStyleItalic">Streptococcus</span>&#46; An ROC curve representing <span class="elsevierStyleItalic">Streptococcus</span> bronchial abundance distinguished patients from controls&#44; particularly when a relative abundance<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>14&#46;6&#37; predicted lung cancer with 90&#46;9&#37; sensitivity and 83&#46;3&#37; specificity &#40;AUC<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;897&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0030">Fig&#46; 5</a>&#41;&#46; Unfortunately&#44; this result was not reproduced in saliva&#46;</p><elsevierMultimedia ident="fig0030"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">The comparison of the whole microbiota in samples within each individual revealed that saliva and bronchi of patients with lung cancer were significantly the closest ecosystems &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0030">Fig&#46; 5</a>&#41;&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Mycobiome composition</span><p id="par0075" class="elsevierStylePara elsevierViewall">Fungal characterization through ITS1 sequencing was determined in the 16 controls &#40;saliva and bronchus&#41; and a subset of 6 patients &#40;saliva&#44; affected and contralateral bronchi&#41;&#46; Regarding to alpha diversity&#44; differences in Chao1 index were not observed&#44; whereas Shannon was significantly higher in affected bronchi from patients compared to controls &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;03&#41; in accordance with the results obtained for bacteria &#40;<a class="elsevierStyleCrossRef" href="#sec0095">Supplementary material</a>&#41;&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Affected bronchi and saliva from patients have similar fungal composition&#44; but different from both their contralateral bronchi &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;006&#41;&#44; and the bronchi &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and saliva &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;007&#41; from controls&#46; This trend supports the aforementioned bacterial findings&#44; which also suggest an interconnection between both anatomical ecosystems in lung cancer patients&#46; A differential abundance analysis between affected bronchi from patients and from controls showed an enrichment of <span class="elsevierStyleItalic">Malassezia</span> in patients&#44; whereas controls had a higher abundance of <span class="elsevierStyleItalic">Candida</span> &#40;<a class="elsevierStyleCrossRef" href="#fig0035">Fig&#46; 6</a>&#41;&#46;</p><elsevierMultimedia ident="fig0035"></elsevierMultimedia></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Discussion</span><p id="par0085" class="elsevierStylePara elsevierViewall">The role of microbiota in carcinogenic processes has not yet been elucidated and will probably be different for each tumour and localization&#46; Recent data clearly indicate that the microbiota contributes to the prognosis of cancer and determines the response to treatments&#44; particularly responses to the new immunomodulation therapies&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">9&#44;15</span></a> Criteria for the normal composition of lung microbiota have not yet been established&#44; but the available data indicate that their composition in cancer patients differs considerably from that of healthy individuals&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">2&#8211;8</span></a> Sampling in the respiratory system requires invasive methods&#44; and here we have characterized the respiratory microbiota surrounding central lung cancer by direct sampling of the tumour tissue by bronchoscopy&#46; Our results reinforce the previously known particularities of the lung microbiota&#44; which considerably differ from oral and stool microbial communities&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">16</span></a> Our results also allowed us to rule out significant contamination with the upper microbiota during the bronchoscopy&#44; as other authors had previously suggested&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">17&#8211;19</span></a> Moreover&#44; we considered strict inclusion criteria to avoid the possible bias of antibiotic or corticosteroid therapy&#44; and the bacterial exchange between the anatomically separated niches such as saliva and faeces&#46; Finally&#44; the mycobiome composition of central lung cancer was studied&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Lung microbiota has been described based on health status or a lung cancer diagnosis in sputum&#44;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">20</span></a> bronchoalveolar lavage&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">5</span></a> protected specimen brushing&#44;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">6</span></a> cytological brushing&#44;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">21</span></a> and surgical tissue&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">7&#44;8&#44;22</span></a> Our major contribution is the depiction of the microbiome surrounding central cancer via direct sampling&#44; but our results are not necessarily applicable to the microbiota of the distal airway&#46; Curiously&#44; higher diversity indexes have been detected in bronchi than in faecal or oral compartments&#44; contrarily to the biomass decreases from upper to lower tract described in healthy people&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">19</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">We found significantly higher alpha diversity values in cancer than in the control group&#44; whereas other authors have published analogous<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">8</span></a> and opposing results&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">5&#44;6&#44;22</span></a> Moreover&#44; advanced cancer stages<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">16</span></a> and reduced recurrence-free survival and disease-free survival<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">22</span></a> have been associated with higher values of alpha diversity&#46; In that sense&#44; 80&#37; of our patients were at tumour stage III or IV&#44; and their mean survival was only of 198 days in the follow up&#46; Furthermore&#44; other factors such as environmental exposure&#44; residence in high-population density areas&#44;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">4&#44;16</span></a> and pack-years of tobacco smoking&#44; can increase the biodiversity of the lung microbiota&#44; whereas chronic bronchitis reduces it&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">16</span></a> All our patients had been smokers&#44; while most of the controls &#40;56&#37;&#41; had not &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">In terms of beta diversity&#44; cancer affected and contralateral bronchi had very similar compositions&#44; probably reflecting the environmental influence which is not restricted to the cancer area&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">2&#44;6&#44;21&#44;22</span></a> Although the limited size of our sample prevents us from reaching solid conclusions&#44; no differences were detected in the composition of the bronchial microbiota as a function of the histological variants of the cancer&#46; The abundance of <span class="elsevierStyleItalic">Firmicutes</span> to the clear detriment of <span class="elsevierStyleItalic">Proteobacteria</span> was the most noticeable result in our patients&#44; and this result was consistent in all samples&#46; <span class="elsevierStyleItalic">Proteobacteria</span> dominance in health lung microbiota&#44; especially <span class="elsevierStyleItalic">Pseudomonas</span>&#44; has been also previously corroborated&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">5&#44;6&#44;23</span></a> Higher concentrations of <span class="elsevierStyleItalic">Streptococcus&#44; Blautia&#44; Akkermansia&#44;</span> and <span class="elsevierStyleItalic">Rothia</span> were observed in patients&#44; but <span class="elsevierStyleItalic">Streptococcus</span> abundance was consistently the major marker linked to lung cancer&#46; This fact has been previously reported in saliva&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">5</span></a> sputum&#44;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">20&#44;24</span></a> bronchoalveolar lavage&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">5</span></a> lung tissue&#44;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">7</span></a> and protected specimen brushing&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">6&#44;21</span></a> The exhaustive phylogenetic analysis of ASVs allows us to suggest that the streptococcal variants present in lung tissue are similar to those found in saliva or faeces&#46; New studies including <span class="elsevierStyleItalic">Streptococcus</span> cultures and molecular characterization of the species are needed to decipher whether oral lineages are different from those found in the lungs or faeces and thus establish whether there are any markers truly associated with lung cancer&#44; as occurs with <span class="elsevierStyleItalic">Streptococcus gallolyticus</span> subsp&#46; <span class="elsevierStyleItalic">gallolyticus</span> and colorectal carcinoma&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">10&#44;25</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">There is increasing evidence of a link between <span class="elsevierStyleItalic">Streptococcus</span> and lung cancer&#46; Recently&#44; Tsay et al&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">21</span></a> detected <span class="elsevierStyleItalic">Streptococcus</span> and <span class="elsevierStyleItalic">Veillonella</span> enrichment in the lower airways with ERK and PI3K pathways upregulation &#8211; an early event that contributes to cell proliferation&#44; survival and tissue invasion &#8211; combining microbiome and transcriptomic signatures&#46; The major question that a remains to be answered is whether the abundance of streptococci is a cause or consequence of the tumour process&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">26</span></a><span class="elsevierStyleItalic">Streptococcus</span> is a natural inhabitant of the oral cavity&#44; which is connected to the lower respiratory tract by the larynx and trachea&#44; and the oral&#47;lung bacterial exchange could occur via microaspirations&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">6&#44;21&#44;23</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Microaspiration events are common&#44; but their frequency is significantly increased in chronic inflammatory airway diseases&#44;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">23</span></a> inducing Th17 lymphocytes&#44; as well as expression of inflammatory cytokines &#40;as IL-1&#945;&#44; IL-1&#946; and IL-17&#41;&#46; IL-23&#47;IL-17 axis alteration is well known in the pathogenesis of both autoimmune diseases and tumours&#44; and <span class="elsevierStyleItalic">Streptococcus mitis</span> facilitate the cancer development and expansion by induction of IL-1&#946;&#44; IL-6&#44; IL-10 and IL-23 transcription&#44; Th17 activation&#44; and an increased immune checkpoint PD-L1 expression&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">27</span></a> Lung resident &#947;&#948; T cells with protective roles or pro-tumorigenic functions in cancer have been recently discovered&#44; and local lung microbiota&#44; including <span class="elsevierStyleItalic">Streptococcu</span>s&#44; can provoke inflammation and tumour cell proliferation via lung resident &#947;&#948; T cells activation&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">28</span></a> Our results demonstrated a global streptococcal enrichment in patients with cancer that affected more than just the respiratory tract&#44; supporting the idea that microorganisms can orchestrate the balance between tumour-promoted inflammation and anti-tumour immunity depending on the specific microenvironment&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Streptococcal relative abundance in bronchial biopsies was a good predictor of lung cancer&#44; but unfortunately was not reproducible in saliva&#46; ROC curves suggested the contralateral bronchi as the best sample &#40;90&#46;9&#37; sensitivity and 83&#46;3&#37; specificity&#59; AUC<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;897&#41;&#46; Other authors found similar results in protected specimen brushing samples &#40;87&#46;5&#37; of sensitivity and 55&#46;6&#37; specificity&#44; AUC<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;693&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">6</span></a> The proportional abundance of <span class="elsevierStyleItalic">Streptococcus</span> should be validated in the early stages of lung cancer with subsequent follow-up to corroborate their potential use as biomarker&#46; Along these lines&#44; the intestinal enrichment of <span class="elsevierStyleItalic">Streptococcus</span> should be exhaustively explored to identify lung cancer markers in faeces&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">The intestinal and the respiratory ecosystems harbour a diverse and abundant microbiota&#44; but some particularities distinguish both ecosystems&#46; Food intake favours a higher rate of microbial reproduction increasing the total mass that is significantly reduced after defecation&#46; On the contrary&#44; nutritional sources for bacteria in the airway are limited to mucus and cellular debris&#44; while clearance is carried out by the ciliary system and the immune system&#44; particularly by macrophages&#46; Lung microbiota core&#44; which is composed by those taxa that are present in &#62;95&#37; of individuals&#44; had not yet been defined&#46; We have implemented new computational strategies to define the lung microbiota core&#44; which had not previously been defined&#46; Our main results are the elevated alpha-diversity of the bronchial microbiota in comparison with saliva or faeces&#44; and the dominance of <span class="elsevierStyleItalic">Pseudomonas</span> in controls&#46; Presence of this particular genus is linked to cystic fibrosis&#44; being the major pathogen that decreases the respiratory functionality within a pathogenic colonization in those patients&#46; However&#44; the lack of respiratory symptoms reduces the potential pathogenic role of <span class="elsevierStyleItalic">Pseudomonas</span> in healthy individuals&#44; although more studies are needed in that line&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">The mycobiome results were consistent with those obtained for bacteria&#46; The fungal community was slightly richer and more diverse in patients than in controls&#44; although the contralateral bronchus was more similar to controls than to the affected counterpart&#46; The mycobiome of saliva and the affected bronchus from patients matched perfectly&#44; but differed in controls&#44; again suggesting that in patients with cancer the bronchial microbiota is the result of a continuous exchange with that of the oral niche&#46; In terms of taxonomy&#44; affected bronchi from patients had an enrichment of the <span class="elsevierStyleItalic">Basidiomycota phylum</span> with higher populations of <span class="elsevierStyleItalic">Malassezia</span> genus&#44; whereas the enriched taxon in healthy individuals was the <span class="elsevierStyleItalic">Ascomycota phylum</span> and the genera <span class="elsevierStyleItalic">Candida</span> and <span class="elsevierStyleItalic">Saccharomyces&#44;</span> as previously described&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">29</span></a> Although the public databases are increasing exponentially&#44; it is important to note that a major limitation to describing the mycobiome is the lack of available taxonomic records&#46; As far as we know&#44; this is the first description of the lung mycobiome&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">The main limitation of our work is that we cannot estimate the contribution effect of lung cancer factors on the bronchial microbiota&#44; mainly tobacco &#40;all patients had been smokers but only the half of the controls were&#41;&#44; and COPD &#40;12&#47;25 patients&#41;&#46; However&#44; it has not been established yet if tobacco has a significant influence on lung microbiota composition&#44; and some important studies have shown contradictory results&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">16&#44;30&#44;31</span></a> Whereas severe COPD has been linked with significant alterations in the lung microbiota composition&#44;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">32&#44;33</span></a> mild and moderate COPD &#40;92&#37; of our COPD patients&#41; has been associated with <span class="elsevierStyleItalic">Streptococcus</span> enrichment&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">33</span></a> This finding might explain the association of mild&#47;moderate COPD and lung cancer&#44;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">34</span></a> although further studies are needed to confirm this association&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Additional limitations are the small number of patients&#44; all of them from the same hospital&#44; and the lack of other -omic analyses based on genetic expression&#46; On the other hand&#44; our strengths include performing the first study of microbiota combined with mycobiome of bronchial tissue obtained directly from tumour and contralateral bronchi &#40;not adjacent to a resected tumour&#41;&#44; as well as performing analysis of the connected ecosystems including saliva and faeces&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">In summary&#44; patients with central lung cancer have a significantly different bronchial microbiota from controls&#44; not restricted to tumour-involved tissue&#44; and probably conditioned by continuous microaspiration events from the oral cavity&#44; more than by the carcinogenic process&#46; Lung cancer was associated with a considerable enrichment of <span class="elsevierStyleItalic">Streptococcus</span> and we propose that this feature could be used for the screening&#44; diagnosis of this pathology&#46; Lung mycobiota differ considerably in control individuals&#44; and there are dissimilarities in patients between the affected and the contralateral bronchi&#46; An innovative bioinformatics strategy used in this study has allowed us to define healthy individuals&#8217; the bronchial core microbiota&#44; which is dominated by a non-pathogenic colonization of <span class="elsevierStyleItalic">Pseudomonas</span>&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Ethics approval</span><p id="par0145" class="elsevierStylePara elsevierViewall">The Ethics Committee &#8220;CEIC Arag&#243;n&#8221; approved this project in 2016 with the reference 15&#47;2016&#44; and all participants signed the informed consent after receiving all the information from the clinical researchers&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Authors&#8217; contributions</span><p id="par0150" class="elsevierStylePara elsevierViewall">SB conceived the study&#46; JJV&#44; ALF&#44; EM&#44; and AR contributed to the patients&#8217; selection and sample collection&#46; JMP&#44; JG carried out the computational analysis for core microbiota definition&#46; MPA and RdC determined the microbiota composition&#46; AR&#44; PG&#44; JMP&#44; JG&#44; and SB participated in the analysis and interpretation of data&#46; SB&#44; RdC&#44; and MPA wrote and reviewed the manuscript&#44; and finally all authors read and approved the final version&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Funding</span><p id="par0155" class="elsevierStylePara elsevierViewall">This work was partially supported by the project PI17&#47;00115 which recipient is RdC&#46; MPA was supported by the <span class="elsevierStyleGrantSponsor" id="gs1">Programa Operativo de Empleo Juvenil</span>&#44; co-financed by the <span class="elsevierStyleGrantSponsor" id="gs2">European Social Fund Investing in your future &#40;ESF&#41; and ERDF</span> &#40;<span class="elsevierStyleGrantNumber" refid="gs2">PEJD-2018-PRE&#47;BMD-8237</span>&#41;&#44; and by a <span class="elsevierStyleGrantSponsor" id="gs3">Rio Hortega</span> contract &#40;<span class="elsevierStyleGrantNumber" refid="gs3">CM19&#47;00069</span>&#41; from the Instituto de Salud Carlos III&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Conflict of interest</span><p id="par0160" class="elsevierStylePara elsevierViewall">RdC is the recipient of a Vertex grant IIS-2017-106179 for cystic fibrosis research&#46; The remaining authors declare that they have no competing interest&#46;</p></span></span>"
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              "titulo" => "Streptococcal abundance characterizes the microbiota of patients"
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            1 => "Bronchoscopy"
            2 => "Lung cancer"
            3 => "Microaspirations"
            4 => "<span class="elsevierStyleItalic">Streptococcus</span>"
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            1 => "AUC"
            2 => "COPD"
            3 => "FISABIO"
            4 => "IL"
            5 => "LDA"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Background</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Dysbiosis in lung cancer has been underexplored&#46; The aim of this study was to define the bacterial and fungal microbiota of the bronchi in central lung cancer and to compare it with that of the oral and intestinal compartments&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Twenty-five patients with central lung cancer and sixteen controls without antimicrobial intake during the previous month were recruited&#46; Bacterial and fungal distribution was determined by massive sequencing of bronchial biopsies and saliva and faecal samples&#46; Complex computational analysis was performed to define the core lung microbiota&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Affected and contralateral bronchi of patients have almost identical microbiota dominated by <span class="elsevierStyleItalic">Streptococcus&#44;</span> whereas <span class="elsevierStyleItalic">Pseudomonas</span> was the dominant genera in controls&#46; Oral and pulmonary ecosystems were significantly more similar in patients&#44; probably due to microaspirations&#46; Streptococcal abundance in the bronchi differentiated patients from controls according to a ROC curve analysis &#40;90&#46;9&#37; sensitivity&#44; 83&#46;3&#37; specificity&#44; AUC<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;897&#41;&#46; The saliva of patients characteristically showed a greater abundance of <span class="elsevierStyleItalic">Streptococcus&#44; Rothia&#44; Gemella</span> and <span class="elsevierStyleItalic">Lactobacillus</span>&#46; The mycobiome of controls &#40;<span class="elsevierStyleItalic">Candida</span>&#41; was significantly different from that of patients &#40;<span class="elsevierStyleItalic">Malassezia</span>&#41;&#46; Cancer patients&#8217; bronchial mycobiome was similar to their saliva&#44; but different from their contralateral bronchi&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">The central lung cancer microbiome shows high levels of <span class="elsevierStyleItalic">Streptococcus</span>&#44; and differs significantly in its composition from that of control subjects&#46; Changes are not restricted to tumour tissue&#44; and seem to be the consequence of microaspirations from the oral cavity&#46; These findings could be useful in the screening and even diagnosis of this disease&#46;</p></span>"
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        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Antecedentes</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">La disbiosis en c&#225;ncer pulmonar no ha sido suficientemente estudiada&#46; Los objetivos de este estudio fueron definir la microbiota bacteriana y f&#250;ngica de bronquios con c&#225;ncer central de pulm&#243;n&#44; y compararla con la del compartimento intestinal en heces y saliva&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">M&#233;todos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se reclutaron 25 pacientes con c&#225;ncer central de pulm&#243;n y 16 controles sin exposici&#243;n antibi&#243;tica durante el mes anterior&#46; Se determin&#243; la composici&#243;n de bacterias y hongos en biopsias de bronquio&#44; saliva y heces&#46; Se realiz&#243; un an&#225;lisis computacional para definir el n&#250;cleo de microbiota del pulm&#243;n&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Resultados</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Los bronquios afectados y contralaterales de pacientes presentaron una microbiota similar dominada por <span class="elsevierStyleItalic">Streptococcus</span>&#44; mientras que <span class="elsevierStyleItalic">Pseudomonas</span> destac&#243; en los controles&#46; Los ecosistemas orales y pulmonares fueron significativamente m&#225;s parecidos en pacientes&#44; probablemente debido a microaspiraciones&#46; La abundancia bronquial de estreptococos permiti&#243; diferenciar a los pacientes de los controles mediante una curva ROC &#40;90&#44;9&#37; de sensibilidad&#44; 83&#44;3&#37; de especificidad&#44; AUC<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;897&#41;&#46; La saliva de los pacientes present&#243; mayor abundancia de <span class="elsevierStyleItalic">Streptococcus&#44; Rothia&#44; Gemella</span> y <span class="elsevierStyleItalic">Lactobacillus</span>&#46; El micobioma de los controles <span class="elsevierStyleItalic">&#40;Candida&#41;</span> fue significativamente diferente al de los pacientes <span class="elsevierStyleItalic">&#40;Malassezia&#41;&#44;</span> con los bronquios afectados por el c&#225;ncer similares a su saliva&#44; pero diferentes de sus bronquios contralaterales&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusiones</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">En el c&#225;ncer de pulm&#243;n central hay enriquecimiento de <span class="elsevierStyleItalic">Streptococcus</span>&#44; y su composici&#243;n es significativamente diferente de sujetos control&#46; Las alteraciones no se limitan al tejido tumoral&#44; y parecen ser consecuencia de microaspiraciones desde la cavidad oral&#46; Estos hallazgos podr&#237;an ser &#250;tiles para la detecci&#243;n e incluso el diagn&#243;stico de esta patolog&#237;a&#46;</p></span>"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Analysis of alpha diversity by sample location using Chao1&#44; Shannon&#44; and Faith&#39;s PD indexes&#46; Significant differences &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; between groups are highlighted by asterisks&#46;</p>"
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Microbiota core of the most abundant genera accounting for 90&#37; of total&#46; The abundance of each genus is represented by the circle size and the numbers of connections were determined by their frequency&#46;</p>"
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          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Statistical differences between the fungal composition of patients and controls bronchi&#46;</p>"
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                  \t\t\t\t"><span class="elsevierStyleItalic">Mild &#40;FEV</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">1</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#62;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">80&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Severe &#40;FEV</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">1</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">50&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>FEV mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&nbsp;\t\t\t\t\t\t\n
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