A Review on the Nasal Microbiome and Various Disease Conditions for Newer Approaches to Treatments

Literature Search

A review was done from PubMed, Medline, and Google with the Mesh terms: nasal microbiome AND diseases. 231 articles and chapters were reviewed, and 127 were chosen, which had proposed some correlation between nasal microbiome and disease.

Outcomes

The review has unraveled eight clinical conditions which correlate with nasal microbiome. The correlation was either in the form of disease development, prediction or expression of the disease phenotype. Table 1.

Nasal Microbiome in Olfactory Function and Dysfunction

As per the National Institute on Deafness and Other Communication Disorders, 1.4% population experiences olfactory dysfunction. Olfactory neuroepithelium, a small area of the nasal mucosa (about 2square cm) in the upper recess. [19] It incorporates a high abundance of lactoferrin, IgM, IgA and lysozyme, which has a protective function. They help in preventing pathogens from getting intracranial access through the cribriform plate. [20] The olfactory receptor cells recognize odour molecules as well as the secondary metabolites of bacteria.[21, 22]

Olfactory loss may occur due to inflammation (due to the viral and bacterial infection), brain injury (due to trauma), senescence or neurodegenerative diseases.[23, 24] Its precedented that dysbiosis of the microbiome may play a major role in olfactory dysfunction as well. [25], [26].

Koshiken et al. in their study on healthy normo-osmic individuals found four archaeal and 23 bacterial phyla in the olfactory area. [26] The typical dermal bacteria, Staphylococcus and Corynebacterium are also found abundant in the nasal cavity. [27]–[31] Dolosigranulum, found in abundance is a commensal inhabitant associated with health. [29] Dolosigranulum pigrum, though an opportunistic pathogen is potent of causing infection in certain conditions. [32, 33].

Various nasal conditions leading to impaired airflow, like allergic rhinitis, rhinosinusitis, atrophic rhinitis, nasal surgery, as well as congenital causes can influence the URT microbiome, indirectly. All these conditions have some form of olfactory dysfunction, which might be due to the altered microbial community architecture of the area. The microbial composition and addressing the dysbiosis through probiotics or other means may be a way to improve the quality of life for people suffering from olfactory dysfunction, which consists of about 20% of the general population. [21], 34−36].

The Respiratory Tract Microbiome of Cystic Fibrosis Patients Follows Clear Patterns and might be Established Already Early in Life

Cystic fibrosis (CF), a hereditary disease caused by the mutation of the gene of Cystic Fibrosis transmembrane conductance regulator (CFTR) affects the quality of life of the patient severely. In most cases, it causes chronic lung disease, though it has the potential to affect multiple organs. [37], [38] The defect in the mucociliary clearance and mucopurulent secretions are the hallmark of this disease. [39, 40].

The ‘typical CF pathogens’ colonize the lungs of these patients, which consists of Streptococcus, Prevotella, Rothia, Veilonella and Actinomyces. [41, 42, 43] Apart to the CF core microbiota, pathogens like the Haemophilus influenzae, Pseudomonas aeruginosa, Burkholderia cepacian and Staphylococcus aureus can also cause chronic lung infection in CF patients. [40, 41, 44] These microorganisms reach lungs from the environment via the URT which reach during inhalation or micro-aspiration. [40, 45].

In infants with CF, the nasal microbiome is significantly different from those of the healthy controls. The Staphylococcaceae is in abundance compared to the normal Corynebacteriaceae and Pastorellaceae signatures. The nasopharyngeal samples have S. mitis, Staphylococcus aureus and Corynebacterium accolens, along with Gram-negative bacteria. [46] The increase in Staphylococcus aureus abundance in early life may be due to impaired early innate immune system. Moreover, the accumulated mucus in the airways of CF patients provides the much needed microaerobic conditions, which leads to better sustenance of the Staphylococcus aureus. [41, 47, 48] The microbiome of the CF children and CF adult patients are similar, indicating the initiation of dysbiosis early in life. [40].

It would be interesting to further navigate the correlation between microbiome in nose and nasopharynx, in these patients propagating infection control.

Nasal Microbiome and CRS

Chronic rhinosinusitis(CRS) is an inflammatory disorder of the nose and paranasal sinuses, more than 12 weeks, affecting around 16% population[49, 50, 51]. The bacterial infection, however, may be contributing by the initiation of inflammation. [52, 53, 54] It has been hypothesized that inflammatory response is triggered in sinus cavity by a bacterial infection which results in chronic changes and symptoms. [55, 56] A decreased microbial diversity, evenness. and richness in chronic inflammatory diseases elsewhere has been found in CRS patients also.^49,57−60 The decrease in diversity may be because of the increased presence of anaerobic bacteria growing in biofilms. [60, 61] Whereas, the overall bacterial burden and the phylum level abundance are constant, the relative abundance of specific genera of bacteria is found altered in CRS. [60, 61, 62, 63].

A depleted signature of Corynebacterium, Anaerococcus, Peptoniphilus, Finegoldia, Propionibacterium, Peptoniphilus are found in CRS, are actually a mosaic of healthy bacteria of the URT. [59, 64] The shift from the beneficial microbial community may be the reason for the increased inflammatory response (Toll-like receptor responses) as well as the clinical severity. [57, 65].

As studied by Aurora Ret al. CRS patients have a sinus microbiome signature dominated by Pseudomonadaceae, Corynebacteriaceae, Streptococcaceae and Staphylococcaceae. [66] Other studies have shown an overgrowth of Corynebacterium tuberculostearicum and Staphylococcus, in sinuses. [49, 58] along with Curtobacteria, Corynebacterium, Staphylococcus, H. influenza and Pseudomonas in the middle meatal area. [66, 67] The microbiome of CRS patients have Pseudomonas aeruginosa, S aureus and coagulase-negative Staphylococcus, as per some studies. [58], [68]–[72].

In a recent study by Lal et al. they compared the microbiota of middle and inferior meatus of CRS patients with healthy controls. They found that the CRS patients without nasal polyps had an abundance of Haemophilus, Streptococcus and Fusobacterium sp., but a loss of bacterial diversity compared to controls. In patients with CRS without polyp, the study found the abundance of Alloiococcus, Staphylococcus and Corynebacterium. [73] Copeland et al. in their study found that CRS has a negative correlation with six OTUs, affiliated to Corynebacterium, Dolosigranulum and Staphylococcus. Furthermore, the Corynebacterium OTU410908 signature correlated negatively with the SNOT-22 score, giving an idea about the severity of the disease. [8].

Usually, the genera which are anaerobic like the Anerococcus, Finegoldia, Lactobacillus and Peptoniphilus are more abundant in patients with CRS compared to healthy individuals. [8].

CRS is generally categorized into CRS with polyp (CRSwNP) and CRS without polyp (CRSsNP). [8, 49, 50] CRSwNP is usually associated with aspirin intolerance and asthma. [67] When compared, it was noted that CRSwNP had abundant signatures of Staphylococcus, Corynebacterium and Alloiococcus. In contrast, CRSsNP had an abundance of anaerobes Haemophilus, Fusobacteria and Streptococcus, with depletion of Alloiococcus, Rothia, Corynebacterium and Finegoldia.

The severity of inflammation in CRS has a positive correlation with the presence of phylum Proteobacteria (Pseudomonas) and phylum Bacteroidetes (Prevotella). [74] It has also found that CRS patients have altered taste molecule response, with less sensitive to bitter taste and more sensitive to sweet. [75].

The bitter receptors play a role in bacterial detection and defence; hence it is evident that the CRS patients would have decreased bitter sensation. Due to these changes, CRS patients have reduced ciliary beating stimulation in URT, showing altered NO levels. [76, 77] The functional capacity of the taste receptors in the URT correlates with CRS.[75,78−80]

Cope et al. collected samples during sinus surgery of CRS patients. They determined that depending on the bacterial colonization and divided CRS patients into three subgroups.

1. Subgroup which contained Streptococcaceae evoked pro-inflammatory TH1 responses encoding ansamysin biosynthesis gene pathway. [81].

2. The subgroup contained Pseudomonadaceae generated pro-inflammatory TH1 responses but instead encoded tryptophan metabolism gene pathways. [81].

3. The subgroup containing Corynebacteriaceae encoded the peroxisome proliferator-activated receptor – c signalling pathways. They have enhanced IL5 expression with an increased incidence of nasal polyps. [81].

Thus, the nasal microbiome not only influences the phenotype of CRS but is also capable of modulating the immune response. Therefore, dysbiosis plays a role in CRS and polyp formation. [81].

It has also been proposed that nasal washes and, steroids and sinus surgery influence the URT microbiome significantly. Nasal microbiome manipulation has been attempted using probiotics with promising results.

Nasal Microbiome and Allergic Rhinitis

Allergic Rhinitis (AR) is an immune (IgE) mediated inflammatory disease of the nasal airway causing sneezing, itchiness, rhinorrhoea and nasal obstruction. [82] It is widely prevalent across the globe, affecting about 25% of the Canadian population. [82, 83].

Nasal microbiome holds a vital role in the local immune response modulation; therefore, dysbiosis has a potential role in the pathophysiology and development of AR. Choi et al.compared the microbiome of Seasonal Allergic Rhinitis(SAR) patients, with those of healthy controls. [84] They found that the SAR patients had increased bacterial diversity during the pollen season with a positive correlation with nasal eosinophilia as compared to the non-allergic control group. [84] However, the two groups SAR patients and control, showed no significant differences in microbiome profile taken before the pollen season. Increased bacterial diversity is associated with health, as per ‘theory of biodiversity and microflora’. So the study results are confusing. [85, 86] Lal et al., however, did not find increased biodiversity in their group of patients suffering from AR. Which may be due to small sample size and also the study not being conducted during the pollen season. [73].

Ruokolainen et al. did a study on allergic diseases with skin and nasal microbiota, on Finnish and Russian Karelia children who have relatively similar geographic features. While Russian Karelia had a more rural set up the Finnish Karelia was a modern set up. The Finnish Karelia reported a 3 to 10 times more symptoms of AR, atopic sensitization, atopic eczema, and self-reported rhinitis than the Russian population. The bacterial and fungal communities understudy had significantly greater diversity in the Russian people than the Finnish subjects. This study proved that early exposure to environmental microbes has a significant influence on allergic disease development. [87].

Microbiome dysbiosis has a pivotal role in the development of AR; however, it has not been ascertained for sure how is this role played.

Nasal Microbiome and Asthma

The severity and phenotype of asthma and the nasal microbiome have a close association. Studies corroborate that nasal microbiome significantly contributes towards the onset, severity and development of asthma. [88]–[91] The nasal microbiota of the asthma patients have enriched taxa from the Proteobacteria and the Bacteroidetes of which the Gardnerella vaginalis and Prevotella buccalis have are in abundance. [92]–[94] G. vaginalis, P. buccalis, Alkanindiges hongkongensis and Dialister invisus were abundant differentially, which depended on the asthma activity of the patient. [94].

Early asymptomatic colonization of the nasopharynx by Streptococcus, is a strong indicator of the development of asthma in future. [88].

The structure and composition of the nasal microbiome in adolescents and children who have asthma are significantly different from healthy controls. A study also found a difference in the nasal microbiome in different asthma phenotypic clusters. [95] The nasopharyngeal microbiome in asthmatic children is dominated by Staphylococcus, Moraxella, Corynebacterium, Fusobacterium, Haemophilus, Dolosigranulum and Prevotella. [91].

Further studies are suggested by researchers to understand how nose and nasopharynx influence asthma. So that personalized therapy for the disease can be achieved targeted to resolve the dysbiosis. Early microbiome assay also has the potential to identify high-risk children and give them targeted therapy to prevent the development of asthma or prevent its severity.

Nasal Microbiome and ARTI

The nasal microbiome has a significant impact on the immunity and protection of its host. They offer protection against pathogens like Staphylococcus aureus, influenza and rhinovirus. [96]–[99] Influenza A virus is known to modify the microbiome structure with an increase in pathogenic bacterial environment. [97]–[102].

In a trial, Salk et al. administered live attenuated influenza vaccine intranasally, in healthy adults. They found an increase in richness in the taxa and a variation in Immunoglobulin A antibody generation which is specific against the influenza virus. [103] De Lastours et al. in their study, found that adults having influenza virus infection had increased carriage of Staphylococcus aureus and Streptococcus pneumoniae in their nasal mucosa. [104] S pneumoniae has a symbiotic relationship with the influenza virus. Studies propose that influenza A virus enhances the transmission of S pneumoniae. [105, 106] S pneumoniae in turn, secrete proteases that have the potential to activate viral haemagglutinin and modulate the innate immune response of the host facilitating influenza A infection. [105]–[108].

Other viruses also have the potential to change the nasal microbiome. The taxonomic composition between infants infected with rhinovirus and the respiratory syncytial virus was found to be significantly different. [109] Fan et al. observed an increased density of Pneumococcus following rhinovirus infection. [110] Influenza virus, rhinovirus or the adenovirus infection, increased the density of S. pneumoniae colonization. Hence, the risk of invasive pneumococcal pneumonia increases following viral infections. [111] Toinoven et al. observed that infection by different rhinovirus species is dependant on the microbiome composition of the nasopharynx. [112].

Infants with a predominant profile of Haemophilus are prone to be infected with rhinovirus A species. And with a dominant Moraxella profile are likely to be infected with the rhinovirus C species. [112] Mansbach et al. found that infants hospitalized for bronchiolitis with delayed clearance of RSV have a dominant Moraxella profile. [113].

These studies open up the opportunity of developing therapeutic and prophylactic interventions with probiotics to deal with a similar infection.

Nasal Microbiome and Otitis Media

In Otitis Media, increased carriage of pathogenic organisms increases the risk of invasive disease caused by the migration of the pathogens to the middle ear cleft via Eustachian tube. [114]–[116].The nasal microbiome has been a stimulus in the development of Otitis Media. Hilty et al. found that infants with acute otitis media harboured less commensal bacteria compared to their healthy counterparts. Streptococcus, Moxaxella and Pasteurella spp. were found in abundance in Acute Otitis Media patients, compared to controls. [117].

Colonization with S. pneumoniae was more frequent in children with Otitis media (OM) according to the study done by Laufer et al. Colonization, of the nose with Actinomyces, Haemophilus, Rothia, Veillonella and Neisseria, is associated with increased risk for OM too. While colonization with Dolosigranulum, Corynebacterium, Lactococcus, Propionibacterium and Staphylococcus decreases the risk of Pneumococcal colonization as well as OM. [118] Patients suffering from recurrent OM had an abundance of Gemella and Neisseria in their nasopharynx compared to healthy controls. The controls had a Corynebacterium and Dolosigranulum signature in their nasopharyngeal microbiome. [119] Chonmaitree et al. found that the patients with acute otitis media had an abundance of 3 pathogenic genera: Haemophilus, Moraxella and Streptococcus, and the samples had a low bacterial diversity. During acute episodes of OM, the mentioned pathogens increased in abundance, with a decrease in Myroides, Yersinia, Pseudomonas and Sphingomonas. [120].

Nasal Microbiome Composition Linked to Neurological Diseases

It has been proposed that the failure of the innate immune system to prime the microbiome of the nasopharynx initiates an inflammatory response to α synuclein. The oxidative stress precedes cross seeded misfolding, leading to the development of neurodegenerative diseases. [121]–[124] Thus, clearly stating that the resident microbiome is responsible for the initiation of Parkinson’s Disease. [125, 126, 127] The importance and involvement of the microbiome in the pathogenesis of PD is in its nascent stage and requires more investigation.

Conflict of Interest

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