Next Article in Journal
Beyond Destabilizing Activity of SAP11-like Effector of Candidatus Phytoplasma mali Strain PM19
Next Article in Special Issue
Impact of Environmental Pollutants on Gut Microbiome and Mental Health via the Gut–Brain Axis
Previous Article in Journal
Evaluation of Conditions to Improve Biomass Production by Submerged Culture of Ganoderma sp.
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Microorganisms
Volume 10
Issue 7
10.3390/microorganisms10071405
microorganisms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Nasal Microbiota, Olfactory Health, Neurological Disorders and Aging—A Review

by
Subramanian Thangaleela
1,
Bhagavathi Sundaram Sivamaruthi
2,*,
Periyanaina Kesika
1,2,
Muruganantham Bharathi
1 and
Chaiyavat Chaiyasut
1,*
1
Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand
2
Office of Research Administration, Chiang Mai University, Chiang Mai 50200, Thailand
*
Authors to whom correspondence should be addressed.
Microorganisms 2022, 10(7), 1405; https://doi.org/10.3390/microorganisms10071405
Submission received: 12 May 2022 / Revised: 8 July 2022 / Accepted: 11 July 2022 / Published: 12 July 2022
(This article belongs to the Special Issue Host-Associated Microbiome and the Diet-Gut-Brain Axis)
Browse Figures
Versions Notes

Abstract

:
The nasal region is one of the distinct environments for the survival of various microbiota. The human microbial niche begins to inhabit the human body right from birth, and the microbiota survive as commensals or opportunistic pathogens throughout the life of humans in their bodies in various habitats. These microbial communities help to maintain a healthy microenvironment by preventing the attack of pathogens and being involved in immune regulation. Any dysbiosis of microbiota residing in the mucosal surfaces, such as the nasal passages, guts, and genital regions, causes immune modulation and severe infections. The coexistence of microorganisms in the mucosal layers of respiratory passage, resulting in infections due to their co-abundance and interactions, and the background molecular mechanisms responsible for such interactions, need to be considered for investigation. Additional clinical evaluations can explain the interactions among the nasal microbiota, nasal dysbiosis and neurodegenerative diseases (NDs). The respiratory airways usually act as a substratum place for the microbes and can act as the base for respiratory tract infections. The microbial metabolites and the microbes can cross the blood–brain barrier and may cause NDs, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and multiple sclerosis (MS). The scientific investigations on the potential role of the nasal microbiota in olfactory functions and the relationship between their dysfunction and neurological diseases are limited. Recently, the consequences of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) in patients with neurological diseases are under exploration. The crosstalk between the gut and the nasal microbiota is highly influential, because their mucosal regions are the prominent microbial niche and are connected to the olfaction, immune regulation, and homeostasis of the central nervous system. Diet is one of the major factors, which strongly influences the mucosal membranes of the airways, gut, and lung. Unhealthy diet practices cause dysbiosis in gut microbiota and the mucosal barrier. The current review summarizes the interrelationship between the nasal microbiota dysbiosis, resulting olfactory dysfunctions, and the progression of NDs during aging and the involvement of coronavirus disease 2019 in provoking the NDs.

1. Introduction

All humans and other animals are hosts for many unicellular and multicellular microbial communities, such as bacteria, viruses, fungi, and parasites [1]. Microbes are omnipresent in the environment and exist in the human body. They can adapt or adjust themselves as the host or the environment changes. The microbes and their metabolites might be involved in the host’s health and diseases [2]. The microbes can reside on every surface of the human body [3], such as the oropharynx, nasopharynx, respiratory system [4], digestive tract [5], urinary system, genital organs [6], and the skin [7].
Microbial dysbiosis is the alteration in healthy microbiota composition, which causes pathological conditions leading to health issues [8]. The microbiota can be both transient and resident; their diversity is affected by various factors, such as drugs, surrounding environmental microorganisms [9], habitat, nutritional availability, and host factors, such as host hygiene, immunity, and genetics [10], and physical factors, such as oxygen, pH, moisture, and other microbial interactions [11]. The colonization of opportunistic pathogens results in the onset of respiratory infections and changes in the innate immune mediators [12]. The human respiratory passages start from the opening of the nostrils (nose or anterior nares). They lead to the nasopharynx posteriorly and the lung alveoli [13]. The upper respiratory tract (URT) has a constant airflow. It has the highest density of microbial communities, which prevent the localization and spreading of pathogens on the lower respiratory tract’s (LRT) mucosal surface [14].
The nasal microbiota are different from the microbial community in the URT and remain constant throughout adulthood [15]. Changes in the nasal microbiota may initiate in the middle age of adults. At the age of 40–65 years, the nasal microbiota of healthy adults are completely dominated by Staphylococcus, Streptococcus, Veillonella, Cutibacterium and Corynebacterium species [16]. The composition of the nasal and oropharyngeal microbiota changes during aging and becomes similar to that of the microbial community of the oropharyngeal region [16,17]. Roghmann et al. examined the diversity of the nasal microbiota among elderly subjects who resided in nursing homes and independent homes. The study revealed that the elderly individuals showed an abundance of Streptococcus and a relative abundance of other species, such as Lactobacillus reuteri, Staphylococcus epidermidis, and Rothia mucilaginosa, in their nasal passages [18].
The older adults (≥65 years) with respiratory tract infections (RTI) have Corynebacterium, Moraxella, Staphylococcus, Dolosigranulum, Streptococcus, Haemophilus, Peptoniphilus, Cutibacterium, Anaerococcus, Enterobacteriaceae, Pseudomonas, and Neisseria in the nasal passages. Prevotella, Veillonella, Streptococcus, Neisseria, Fusobacterium, Leptotrichia, Haemophilus, Rothia, Porphyromonas, Actinobacillus, Lactobacillus, and Staphylococcus were found in the oropharynx. Compared to the healthy older adults, Moraxella catarrhalis and M. nonliquefaciens were less prevalent in the elderly individuals with lower respiratory tract infections (LRTI), which indicates the association of Moraxella spp. in the respiratory health of the elderly [19]. In contrast, M. catarrhalis and M. nonliquefaciens were reported to cause RTIs in young children [20].
Some evidence suggests that a few bacteria have a major role in linking the nasal cavity and the central nervous system (CNS). Chlamydia pneumonia is an obligate intracellular pathogen responsible for sinusitis and pneumonia and found in the brains of AD patients [21]. The post-mortem studies of AD brains showed an increased load of Propionibacterium acnes belonging to the oral, nasopharyngeal, and skin niches [22]. The diphtheria toxin produced by Corynebacterium diphtheria can enter the CNS and result in sporadic AD [23]. In addition to neuropathological changes, some changes were found in the mucosal sensory nerve terminals of the oropharynx, larynx, upper esophagus [24], and gut [25] in Parkinson’s disease (PD). In the same way as the involvement of the nasal microbiota in neurodegenerative diseases, the gut microbiota link the gut and brain by inducing bidirectional communication through the integration of the gut–brain immunological mediators [26]. PD is mainly characterized by the loss of dopaminergic neurons in the substantia nigra, due to the accumulation of α-synuclein, otherwise known as Lewy bodies, in the central nervous system [27]. In the case of AD, the neuropathological features include the formation of amyloid-β (Aβ; a short peptide found in the amyloid plaques of the AD brain) plaques and the neurofibrillary tangles of the phosphorylated tau proteins, which result in the loss of neurons and synaptic elements [28,29].
The macronutrients and micronutrients of the diet significantly affect the mucosal barrier, gut, lung, and microbiota [30]. A healthy diet helps enhance the gut–brain axis and is possibly involved in preventing mental disorders [31]. Diet and lifestyle have been associated with neurodevelopmental disorders [32]. The dietary fibers are utilized by the members of the gut microbiota (Firmicutes, Bacteroidetes, Bifidobacterium and Prevotella), resulting in the production of short-chain fatty acids (SCFAs) [33], such as acetate, propionate, and butyrate, which are crucial for gut epithelial and immune regulations [34], the intestinal homeostasis, blood–brain barrier (BBB), and the neuroimmunoendocrine functions [35].
The entry site of pathogens and the host’s response affect the disease outcomes. The URT and the nasal barrier play the main role in preventing infection [36]. Even though the nasal mucosa of humans gives rise to varied microbial communities, in the case of the coronavirus disease 2019 (COVID-19) pathogenicity, the URT was acting as the main site of entry [36]. The COVID-19 pathogenesis may be linked to the nasal or respiratory tract microbiota [37]. Yet the role of the microbiota in the upper airways in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection needs to be studied in detail. The current review summarizes the interrelationship between the nasal microbiota dysbiosis, respiratory tract infections, olfactory dysfunctions, and the progression of NDs during aging. The manuscript also highlights the diet–microbiota–brain interrelationship and the involvement of COVID-2019 in provoking the NDs.

2. Nasal Microbiota and Respiratory Tract Infections

The colonization of the microbes inside the human body is initiated immediately after birth [38]. The first microbial colonization in the nasopharyngeal region of infants resembles the maternal vaginal or skin microbiome [39]. The initial microbial exposure will determine the further successive microbial entries and lead to stable ecosystems during adulthood [40]. With an increase in age, the nasal microbiota are dominated by species of Moraxella. On the contrary, the abundance of Haemophilus and Streptococcus species leads to less stable microbiota [41]. The LRT microbiota of premature infants are dominated by pathogenic Staphylococcus spp. [42], Ureaplasma spp. [43], and Acinetobacter spp. [44]. The microbiota of the URT of infants differs from adults. The nasal microbiome of children is highly dense, with a less diverse population [17,45]. The anterior nares of adults are rich in Actinobacteria and Firmicutes, and less dominated by Bacteroidetes [46,47,48]. Healthy individuals (18 to 65 years old) are rich in Staphylococcus spp., Corynebacterium spp., Dolosigranulum spp., Moraxella spp., Streptococcus spp., or Fusobacterium spp. in their URT. Specifically, Streptococcus spp. and Fusobacterium spp. are colonized in the nasopharynx and completely absent in the nose [49]. The nasal passages of humans are inhabited by commensal pathobionts, such as Staphylococcus aureus, Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis [50]. In older adults (68-96 years old), the nostrils were dominated by the non-pneumococcal Streptococcus [16]. The initial acquisition of microbes and their establishment is a complex multistage process. The microbiota of the nasopharynx, oropharynx, and lungs play an important role in the immune system, metabolism, neuro-regulation, and several respiratory diseases, such as upper respiratory tract infections (URTIs) [51].
The microbial niches in the URT and LRT are different. They are influenced by various factors, such as mode of birth, feeding patterns, lifestyle, immunity, and vaccinations [52,53]. The URTIs include the common cold, laryngitis, pharyngitis/tonsillitis, allergic rhinitis, acute rhinitis, acute rhinosinusitis, and otitis media. Lower respiratory tract infections (LRTIs) include acute bronchitis, bronchiolitis, pneumonia, and tracheitis [54]. The pathogenic microbes colonizing the URT can be relocated into the LRT and lung, causing respiratory diseases [55,56]. Recent techniques, such as next-generation sequencing, show a diverse range of microbial species in the LRT (Table 1). The ambient air and the gastric–esophageal reflux are responsible for the LRT microbial load [57]. Whelan et al. [16] revealed that the discrete microbiota of the nasal and oropharyngeal region are lost during aging and are replaced with an oropharyngeal-like microbial population enriched with Streptococcus spp. It appears that the increase in Streptococci spp., such as S. pneumoniae, causes pneumococcal infections. The different microbial communities that commonly reside in the URT and LRT are summarized in Table 1.
As nasal microbiota are associated with regulating the immune functions, the dysbiosis of nasal microbiota may be responsible for nasal inflammatory diseases [68]. The inflammation in the sinus and nasal mucosal layers is linked with chronic rhinosinusitis (CRS), one of the common inflammatory diseases of the URT, with the symptoms such as congested nose, sinus pain, headaches, and attention difficulties and depression [69,70,71]. The dysbiosis, damaged immune barrier, inflamed mucosal epithelium, and secondary bacterial overgrowth cause a chronic immune response and inflammation, which may trigger CRS [72].

3. Nasal Microbiota and Olfactory Health

The nasal cavity is comprised of different microbes [73]. The respiratory tract is lined with ciliated epithelial cells. The epithelial layer of the nasal cavity acts as a barrier that detects, filters, and helps remove the inhaled microorganisms and dust or unwanted particles [74], and prevents the host system from being infected or the pathogens from reaching the LRT [75]. It clears the airways and the lungs, and the mucus secreted by the interspersed goblet cells hydrates the airways [74,76]. The respiratory mucosa and the motile cilia in the respiratory tract play a major role in protecting the host from the invasion of pathogens [74].
The epithelial cells are involved in immune defense mechanisms through the secretion of lysozyme, lactoferrin, IgM, and IgA [77], preserving a healthy nasal environment, and preventing infection and inflammation [78]. The nasal commensal bacteria inhibit the growth and colonization of the pathogens by releasing antagonistic chemicals, and through nutrition and space deprivation. On the other hand, dysbiosis can result in infections such as influenza [36]. The nasal microbial community reflects the health status and functionality, and can be used as an assessment tool for disease diagnosis [8,79].
The prime function of the human olfactory system is to discriminate between odors [80]. The olfactory function is facilitated by over 6,000,000 bipolar olfactory receptors, which are of central nervous system origin [81], and are present in the olfactory epithelium. The olfactory function is significant for human well-being and health; any dysfunction in olfaction can cause serious ailments, such as negative effects on mood, safety, the enjoyment of food, personal hygiene, social interactions, and sexual relations [82,83,84], and are associated with weight gain [85] and weight loss [86].
The microbiota are essential for normal olfactory epithelium development. Koskinen et al. studied the interrelationship between the nasal microbiome and the olfactory function. They revealed that the Faecalibacterium spp. and Porphyromonas spp. were involved in the decline in the olfactory function, and the Corynebacterium members were associated with a reduction in odor discrimination and threshold [78]. The high risk of olfactory dysfunction increases with age and other diseases, such as chronic diseases in the sinonasal regions (about the sinus and nasal regions), head trauma, URTIs, or neurological diseases. The microbiota of the lungs are likely to resemble that of the mouth. Streptococcus, Prevotella and Veronica spp. are most common in the lungs and the mouth [87]. Comparable to middle-aged adults, children and older adults are most susceptible to infections initiated from the URT, such as pneumonia [88] and influenza [89]. Towards the stage of middle-aged adults, the susceptibility rate decreases, with an increase in the immune responses of the mature URT [90,91]. Older adults are more susceptible to infections, due to the decline in the immune system [92] and the decrease in muconasal clearance [36].
The olfactory circuit was studied by exposing experimental subjects to specific olfactory tasks based on emotion, memory, and identification parameters. The results showed that an odor enters the olfactory system and travels to various brain regions, such as the entorhinal cortex, hippocampus, amygdala, orbitofrontal cortex, thalamus, and piriform cortex [93]. The piriform cortex and amygdala regions showed strong activation with odor stimuli and were found to be important for recognizing odor and strong emotional stimuli. All of the odors are initially encoded as objects in the piriform cortex [93]. Volunteers with hyposmia have reduced olfactory discrimination, and their nasal microbiota are rich in Actinobacteria, Bacilli, Clostridia, Bacteroidia, and Proteobacteria. Corynebacterium and Faecalibacterium are also involved in reduced odor discrimination. In addition, the nasal microbiota of subjects with a reduced odor threshold have an abundance of Comamonadaceae and Enterobacteriaceae. Butyrate-synthesizing Porphyromonas are associated with reduced olfactory function [94].

4. Olfactory Dysfunction and Neurological Disorders

Humans with olfactory impairment face many difficulties in their day-to-day lives [95]. Olfaction is one of the vital senses associated with human health and well-being. Olfactory dysfunction is an indicator of serious illnesses. The olfactory identification follows a different pathway, such as when the odor material binds to the olfactory receptors; the chemical binding elicits the electrochemical signals inside the olfactory neurons, the signals that are transmitted to the olfactory regions of the brain, later the autonomic nervous system and endocrine system are stimulated, which finally results in the emotional response [96]. Age is an important factor in olfactory dysfunction [97]. The olfactory ability declines mostly in middle-aged and older adults [98]. Schubert et al. [99] studied the risk of aging in olfactory dysfunction. Their results demonstrated that the risk of olfactory dysfunction was 4.1%, 21%, and 47.1% among 53–59 years, 70–79 years, and 80–97 years old, respectively. The results showed that the olfactory function deteriorates upon aging. Olfactory dysfunction is a primary indicator of the NDs [100]. A study about changes in olfaction during aging, and in certain neurological disorders, stated that olfaction is a complex sensory system known to affect cognitive abilities and mood. The neurophysiological features of the olfactory system and the odorant can lead to strong olfactory and emotional memories [101,102].
In addition to other external factors, the commensal organisms residing in the nasal cavity are also involved in developing the olfactory epithelium (OE). Evaluating the olfactory functions of the nasal microbiota proved that olfactory identification was not linked with the nasal microbiota. On the contrary, the olfactory threshold and olfactory discrimination are associated with the nasal microbial community [78]. Healthy volunteers were studied for their nasal microbiota and olfactory functions. The volunteers were categorized as per their olfactory ability, such as normal olfactory function, a good sense of smell, and hyposmia. The results indicated, surprisingly, that the microbial community in the nasal cavity differs between each group. The results showed that the nasal microbiota have a role to play in olfactory functions [78].
The microbes modulate the olfactory epithelium and influence the olfactory function [93]. The microbiome of the olfactory area is predominated by the phyla Actinobacteria, Firmicutes, Proteobacteria, and Bacteroidetes. Specifically, the species of Corynebacterium, Staphylococcus, and Dolosigranulum are abundant [68]. When the normal nasal microbiota get disturbed and are dominated by the commensal inhabitant, Dolosigranulum pigrum, olfactory infections occur [103]. The nasal microbiota and metabolites enter the brain through the olfactory system. The olfactory nerve from the nasal cavity enters the CNS bypassing the BBB, which results in the microbiota and its products accessing the olfactory bulb (OB) through the olfactory neuro epithelium [104]. The BBB is an interface for the blood–brain exchange [105], comprised of endothelial cells, astrocytes, neurons, and peripheral immune cells. Complex tight junctions regulate the movement of ions and macromolecules from systemic circulation at the inter-endothelial cleft. The microbial pathogens entry into the CNS is routed through the transcellular paracellular permeability [106].
When microbes from aerosols or air enter the nasal cavity via the nostrils, it contacts the olfactory receptor cells (Orc). The axons of the Orc protrude into the neuroepithelium of the nasal cavity through the perforations in the cribriform plate (CP), and form synaptic connections with the neurons in the OB (Figure 1A) [104]. The tuft of olfactory nerve fibers receives connections from the neurotransmitter system and the olfactory cortices (OC). Olfactory signaling is a complex network where another set of olfactory neurons projects their nerve endings into the OC, hippocampus (HC), amygdala (AG), entorhinal cortex (EC), hypothalamus (HT), and locus coeruleus [106], and reaches the reticular formation system (RFS), which creates the visceral responses of smell (Figure 1B) [107]. Hence, the olfactory neuronal fibers extend their connection over the brain and enable the person to identify, discriminate, and correlate odors with emotions. The inflammatory cytokines and other immune regulators of the nasopharynx enter the brain’s extracellular fluid and the CNS [104] and can influence the olfactory function.
Olfactory dysfunction is common during aging, and, due to the structural changes in the nostrils, age-related alterations in the OE and OB [108]. Other reasons, such as chronic infections, age-related atrophy of the nasal epithelium, decreased mucosal blood flow, sympathetic and parasympathetic imbalance, nasal engorgement, abnormalities in the olfactory cortex (OC), sensory loss in the receptor cells, reduced mucosal enzymes, and changes in the neurotransmitter systems may induce olfactory impairment, which might cause cognitive and memory decline during aging and NDs, such as AD and PD [97]. Loss of integrity of the OE can occur during aging, due to a loss of the sensory responses in receptor cells, air-borne agents, smoking, and genetic factors [109]. Immunohistochemical studies revealed the presence of Aβ and paired helical tau elements in the OE of AD patients [110].
Microbial pathogens can enter the CNS by penetrating the BBB, blood–cerebrospinal fluid barrier (BCSFB), and the olfactory and trigeminal nerves (Figure 2) [111]. The BCSFB is formed by endothelial and choroid plexus epithelial cells, producing CSF [112]. The pathogens cross the BBB either transcellularly or paracellularly or with the help of infected phagocytes using the Trojan-horse mechanism (Figure 2C–E). Thus, the pathogens disturb the BBB function, resulting in increased permeability, encephalopathy, or pleocytosis [113].
As a result of chronic inflammation and CRS, the homeostasis of the local microbiota gets altered, which could lead to the development of AD and dementia [114,115]. Hedner et al. analyzed the olfactory dysfunctions concerning cognitive demands using three parameters: odor threshold; odor discrimination; and odor identification using the Sniffin’ Sticks test [116]. The odor tests are effective as the odor representation is stored as a long-term memory. Hence, the brain can reveal and retrieve the odor later [117]. The smell helps perceive the external environment and other behaviors, such as decision-making, eating, detecting danger, etc. [117,118]. Anosmia, the complete loss of olfactory function, and hyposmia, decreased olfactory function, are common in neurological disorders [119,120]. Anosmia or hyposmia can result from various other reasons, such as head injury, cranial surgery, allergies, medication, cranial surgery, URTIs, and chemicals that cause nasal irritation. The available relevant investigations regarding olfactory and memory deficits showed that these are prevalent in NDs, such as AD, PD, MS, Huntington’s disease, and motor neuron disease [100].
The studies have examined the relationship between dementia and chronic rhinitis (CR), and CR is also related to other conditions, such as stroke, vasculopathy, and vascular dementia [121,122,123]. The patients with mild cognitive impairment and CR were more susceptible to the development of dementia than the patients without CR [124]. Chronic inflammation can be considered the key factor that bridges CR and AD. The dysregulated immune system in CR initiates inflammation. The pathology of CR involves a decrease in immunoglobulin J chain, antileukoproteinase, surfactant protein A [125], and an increase in the immune cells, eosinophils and basophils [126], which produce inflammatory cytokines IL-13, IL-5, IL-4 [127], IL-6, IL-12, IL-18, tumor necrosis factor-α (TNF-α), and transforming growth factor-β (TGF-β) in the mucosal region of CR patients. Thus, the increase in inflammatory cytokines, which disrupts the nasal epithelial cell regeneration by inhibiting the neural progenitor cell proliferation and provoking CR [128], might also lead to the disruption of neural integrity in the CNS and cause neurodegeneration [50]. The progression of CR pathology with aging causes damage to the olfactory neural epithelium [129,130].
Memory loss and cognitive impairments are the signature characteristics associated with AD. The main cause of dementia has been a global concern, due to the high risk of AD in the elderly [131]. Depression and cognitive impairment are the initial symptoms of AD, which consequently lead to severe memory loss, behavioral and personality changes, difficulties in executing day-to-day tasks, reduced communication capabilities [132], weakened immune function, and difficulties in movement and swallowing [133,134]. Currently, no direct evidence supports the association between AD pathology and the inflammatory responses of the nasal microbiota. However, in some cases, the cognitive dysfunction was improved through sinus therapies and CR treatments [135]. In addition to the OB infections, C. pneumonia was also found in the microglia, astrocytes, and neurons of patients who died of AD. Thus, the defensive functions of the astrocytes and microglia cells have deteriorated due to C. pneumonia invasion, which can consequently increase AD pathogenesis. C. pneumonia is a pneumonia-causing pathogen that has been one of the reasons for mortality in AD patients [136]. These studies support the involvement of respiratory pathogens in AD pathogenesis.
Olfactory dysfunction is one of the biomarkers of physiological decline [137], heart failure, stroke, diabetes, hypertension, liver damage, and even cancer [100], and is also predicted as a high-risk marker of psychosis [138] and other neurological diseases, such as MS and epilepsy [84]. The oral and nasal regions are two important entry points for pathogens; they later spread to the CNS and lead to PD pathogenesis [139]. The link between PD and nasal microbiota has been examined. The results indicated that the dysbiosis of the nasopharyngeal microbiota creates the inflammatory response to α-synuclein that ends in neurodegenerative disorders [140,141]. The accumulation and aggregation of α-synuclein in the dopaminergic substantia nigra of the CNS cause a neuronal loss in PD [142]. Most PD patients showed olfactory deficits in the early period of the disease before the occurrence of the motor symptoms [143]. Clinically, PD patients experience non-motor symptoms (NMS), such as decreased salivation, drooling, dysphagia, and hyposmia. These NMS are related to the pathological changes in the olfactory system [144]. These studies suggested the involvement of the nasal microbial community in the progression of PD. In contrast, the relative abundance of non-inflammatory bacteria, such as Blautia wexlerae, Lachnospira pectinoschiza, and Propionibacterium humerusii, were reduced in the nasal sinus cavity of PD patients (Figure 3) [145].

5. Diet–Microbiota–Brain Interrelationship

Over the past few decades, a greater priority has been given to studying the gut microbiota–diet–brain interrelationship. The changes in the neurochemical profile and abnormal behaviors recorded in the animal model showed that the gut microbiota are involved in the brain development and functions [146,147]. The gut microbiota composition of an individual could modulate the diet-dependent gut microbiota metabolites [148].
The gastrointestinal (GI) tract wall is innervated with the CNS through the enteric nervous system (ENS) [149]. It is predominantly colonized by Bacteroidetes and Firmicutes [150], Actinobacteria, Cyanobacteria, Fusobacteria, Proteobacteria, and Verrucobacteria [151], which can directly or indirectly influence the host immune responses [152]. Firmicutes comprise genera, such as Clostridium, Bacillus, Lactobacillus, Enterococcus, and Ruminococcus. The Bacteroidetes consist of genera Bacteroides and Prevotella [67]. In the same way as the gut, the phyla Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria are members of healthy nasal microbiota [16,67,72,153]. The adequate moist environment in the nasal passage has been termed as an access point for microbes from the environment. Proteobacteria and Actinobacteria are the most predominant in the brain; any disruption may cause CNS disorders [154].
MS is a demyelinating inflammatory disorder linked with CNS dysbiosis. The studies in the frozen and autopsied brain samples of MS patients revealed the presence of the dominant phylum, Proteobacteria [155]. AD brains showed an increased number of Actinobacteria compared to the controls [22]. The proofs exist for the gut and CNS dysbiosis and their impact on neurodegeneration. However, the in vivo studies on the dysbiosis of other mucosal surfaces, such as the nasal region, related to neurological disorders is limited [104]. However, the direct relationship between mucosal dysbiosis and neurodegenerative disease processes, and the data on how the microbiota at these mucosal surfaces trigger CNS inflammation and neurodegeneration, require further investigation [104]. The axons of the ORc enter the cribriform plate and form synapses with the OBs neurons. As the lymphatics of the posterior paranasal sinuses drain into the extracellular fluid of the brain, the by-products of the nasal microbiota can access the CNS [104]. Gut dysbiosis causes the accumulation of lipopolysaccharides (LPS), pro-inflammatory cytokines, Helper T cells and monocytes, which in turn lead to the loss of integrity of the intestine and the BBB, which subsequently results in the pro-inflammatory conditions, and the pathogenesis of NDs [156]. A diet rich in highly processed carbohydrates can produce high levels of inflammatory cytokines [157]. On the contrary, a diet rich in fibers can help reduce gut and systemic inflammation, lower the inflammatory cytokines, and enhance the synthesis of SCFAs, such as butyrate, acetate, and propionate, which help maintain gut microbiota diversity [158].
Bacteroidetes and Firmicutes produce acetate and propionate, and Firmicutes produce butyrate. These metabolites maintain gut homeostasis and anti-inflammatory actions. The microbial metabolites depend on the diet and baseline microbiota composition [159,160]. They also act as a driving force for intestinal epithelial cells and enhance the gut barrier functions [34]. Butyrate acts as the main energy source for colonocytes [161]. The gut microbes, Faecalibacterium prausnitzii, Clostridium leptum, Eubacterium rectale and Roseburia spp., are known to produce butyrate [162,163]. The lactate-dependent bacteria, Eubacterium hallii, and Anaerostipes caccae, synthesize both butyrate and acetate [164].
SCFAs, such as propionate, inhibit interleukin-17 (IL-17) production in mice and humans [165]. The interplay between the microbiota in the mucosal surfaces, such as the gut, nasal cavity, and immune cells, is complex and organized as a circuit, where the signals transmit between the microbes–nervous system–immune system. This circuit undoubtedly depends upon the dietary composition ingested by the individuals. Hence, the interrelationship among the diet–gut–nasal microbiota–brain is considerable in the case of immune and neuro functions and pathogenesis. The diet is a key to maintaining a safe and healthy life in coordination with the gut microbiome. Even though studies about the diet–microbiome–mucus interactions are budding here and there, the understanding of the linear interactions of diet–gut microbiome–mucus with inflammatory infections and neurological diseases needs more clinical evaluation [30].
Healthy diets could restore the beneficial microbiota and promote health. The diet predominantly influences the gut microbiota and strongly correlates with food-associated health issues [166]. The influence of the diet on the immune system during COVID-19 was reported [167]. COVID-19 patients could lose their nutritional status due to anorexia, vomiting, nausea, diarrhea, hypermetabolism, and nitrogen loss. The dietary components may interact with the ACE-2 receptor, the hallmark entry point of SARS-CoV-2, and reduce the inflammatory response caused by SARS-CoV-2 [167]. Respiratory infections, such as COVID-19, can stimulate the synthesis of inflammatory cytokines in the host system. To balance the host immune system, dietary practices, such as limiting the carbohydrate-rich diet and a including a fiber-containing diet, can be initiated in the case of COVID-19 infection, to control the synthesis and circulation of the inflammatory cytokines [167].

6. Nasal Microbiota and COVID-19

COVID-19 is an RTI, resulting in high mortality and morbidity worldwide, and the survivors are at a high risk of developing neurological disorders [168]. Some studies evaluated that the SARS-CoV-2 virus may cross the BBB and OB and enter the CNS [169,170]. The human URT is the major entry route for SARS-CoV-2 [171] and is transmitted through sneezing, coughing, or speaking with an infected person at a close distance. COVID-19 may evoke severe neurodegeneration, which could reduce the overall survival of COVID-19 patients with AD [172]. Few studies report the association between CoVs with CNS diseases, such as MS, acute disseminated encephalomyelitis [173,174,175], febrile seizures, and encephalitis epilepsy [176]. SARS-CoV-2 can enter the host through the upper airways. The viral replication occurs in the upper respiratory epithelia and is transmitted through ACE-2, resulting in immune responses [177]. SARS-CoV-2 infection results in a systemic increase in the pro-inflammatory cytokines, virtually resulting in neuroinflammation [178]. The SARS-CoV-2 enters the CNS by binding to the ACE-2 receptor in the endothelial cells of the BBB, and bypassing the BBB protection by targeting the CNS macrophages and monocytes [179].
De Maio et al. reported that the microbiota in the nasopharynx were not altered in COVID-19 patients, especially the phyla Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, and Fusobacteria which were found in both SARS-CoV-2 infected and uninfected subjects [180]. The members of the phyla Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria, and genera Streptococcus, Prevotella, Veillonella, Haemophilus, and Moraxella were abundantly present in the nasopharynxes of COVID-19 patients [181].
Usually, the genus Prevotella is considered commensal, but some strains rarely cause infections [182]. In the COVID-19 pathological condition, Prevotella induces the production of cytokines and inflammation through T helper 17 cells [183]. The Prevotella proteins promote viral infection and COVID-19 severity through NF-κB signaling [184]. A good balance in the URT is maintained with the help of healthy nasal microbiota. In the case of COVID-19, the gut and LRT microbiota are altered because of therapeutic interventions [185,186,187].
The COVID-19 infection is associated with neurological manifestations. Nowadays, studies are emerging to decode the role of SARS-CoV-2 in CNS pathophysiology. Experimental evidence showed that the human CoVs could infect the neurons, microglia, astrocytes, and glial cells and confirmed the presence of CoVs in the autopsies of MS, PD, and AD patients [188]. A study reported that about 20% of the COVID-19 patients admitted to intensive care units (ICU) showed neurological complications, including stroke, encephalopathy, acute inflammatory demyelinating polyneuropathy, and encephalitis [189]. Strokes commonly occur as a COVID-19 complication in a few older, hypertensive, and hemorrhagic cases [190]. Dementia patients are at an increased risk of COVID-19 infection [191]. PD patients are at a higher risk of COVID-19-associated mortality than non-PD patients [192]; they also showed worsening PD symptoms, such as rigidity, fatigue, tremor, and pain [193], and an increase in depression, insomnia, and irritability [193,194]. Other neurological conditions, such as confusion, unconsciousness, agitation, seizure, and altered mental states, were observed in COVID-19 patients [195,196]. Neuropsychiatric complications, such as symptoms of post-traumatic stress disorder, depression, anxiety, obsessive-compulsive disorder, and insomnia were also reported in the hospitalized COVID-19 patients [197].

7. Conclusions

Microbes survive within the host either as commensals or as opportunistic pathogens. The mucosal membranes provide shelter for the microbes, and the microbiota are involved in various functions, such as metabolism, immune responses, and pathogen resistance. Maintaining healthy mucosal environments is essential to sustaining healthy microbiota. The nasal microbiota are potentially connected with the olfactory function by modulating the physiology of the olfactory epithelium. The incidence of olfactory dysfunction increases during aging, due to the loss of olfactory NE and the reduced activity of the olfactory cortex. Respiratory infections may cause olfactory dysfunction. The invasive pathogens enter the nasal cavity and bind to the olfactory receptors of the olfactory NE. They could result in inflammatory changes, olfactory impairment, and even temporary or permanent olfactory dysfunction.
Diet plays an indomitable role in shaping the human microbiota and maintaining interactions between the microbiota–host–mucosal environments. Dietary changes affect the mucosal barriers with or without the involvement of the microbiota. The diet’s macro- and micronutrients, lipids, proteins, and carbohydrates may differentially regulate the prevalence of microbiota. A diet rich in fiber can limit the production of inflammatory cytokines by the gut microbiota. Hence, maintaining a healthy microenvironment for gut functioning during respiratory infection is necessary. The increase in respiratory, inflammatory, and neurological diseases has been a more alarming health threat globally. The involvement of nasal–gut microbiota in inflammatory diseases is explained through various studies, but the etiology of neurological diseases is not clearly stated. Thus, more studies are necessary to unveil the correlation between the nasal microbiota and the nervous system.

Author Contributions

Conceptualization, C.C., B.S.S. and P.K.; methodology, S.T. and B.S.S.; validation, C.C., B.S.S. and P.K.; formal analysis, S.T.; investigation, S.T. and B.S.S.; resources, C.C.; data curation, S.T.; writing—original draft preparation, S.T., B.S.S., P.K., M.B. and C.C.; writing—review and editing, S.T., B.S.S., P.K. and C.C.; supervision, C.C. and B.S.S.; project administration, C.C.; funding acquisition, C.C. All authors have read and agreed to the published version of the manuscript.

Funding

This project was supported by the Fundamental fund research, Chiang Mai University, Chiang Mai, Thailand.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available within the article.

Acknowledgments

The authors gratefully acknowledge the Faculty of Pharmacy and Chiang Mai University: Chiang Mai, Thailand. S.T acknowledges the CMU-Postdoctoral fellowship for its support.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Ryan, M.J.; Schloter, M.; Berg, G.; Kostic, T.; Kinkel, L.L.; Eversole, K.; Macklin, J.A.; Schelkle, B.; Kazou, M.; Sarand, I.; et al. Development of microbiome biobanks-challenges and opportunities. Trends Microbiol. 2021, 29, 89–92. [Google Scholar] [CrossRef] [PubMed]
  2. Nicholson, J.K.; Holmes, E.; Kinross, J.; Burcelin, R.; Gibson, G.; Jia, W.; Pettersson, S. Host-gut microbiota metabolic interactions. Science 2012, 336, 1262–1267. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Segata, N.; Haake, S.; Mannon, P.; Lemon, K.P.; Waldron, L.; Gevers, D.; Huttenhower, C.; Izard, J. Composition of the adult digestive tract bacterial microbiome based on seven mouth surfaces, tonsils, throat and stool samples. Genome Biol. 2012, 13, R42. [Google Scholar] [CrossRef] [Green Version]
  4. Proctor, D.M.; Relman, D.A. The Landscape Ecology and Microbiota of the Human Nose, Mouth, and Throat. Cell Host Microbe 2017, 21, 421–432. [Google Scholar] [CrossRef] [Green Version]
  5. Ahern, P.P.; Maloy, K.J. Understanding immune-microbiota interactions in the intestine. Immunology 2020, 159, 4–14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Stapleton, A.E. The vaginal microbiota and urinary tract infection. Microbiol. Spectr. 2016, 4, 79–86. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Chen, Y.E.; Fischbach, M.A.; Belkaid, Y. Skin microbiota-host interactions. Nature 2018, 553, 427–436. [Google Scholar] [CrossRef]
  8. Hartstra, A.V.; Bouter, K.E.C.; Bäckhed, F.; Nieuwdorp, M. Insights into the role of the microbiome in obesity and type 2 diabetes. Diabetes Care 2015, 38, 159–165. [Google Scholar] [CrossRef] [Green Version]
  9. Anwar, H.; Iftikhar, A.; Muzaffar, H.; Almatroudi, A.; Allemailem, K.S.; Navaid, S.; Saleem, S.; Khurshid, M. Biodiversity of gut microbiota: Impact of various host and environmental factors. Biomed Res. Int. 2021, 2021, 5575245. [Google Scholar] [CrossRef]
  10. Gupta, V.K.; Paul, S.; Dutta, C. Geography, ethnicity or subsistence-specific variations in human microbiome composition and diversity. Front. Microbiol. 2017, 8, 1162. [Google Scholar] [CrossRef] [Green Version]
  11. Faust, K.; Sathirapongsasuti, J.F.; Izard, J.; Segata, N.; Gevers, D.; Raes, J.; Huttenhower, C. Microbial Co-occurrence Relationships in the Human Microbiome. PLoS Comput. Biol. 2012, 8, e1002606. [Google Scholar] [CrossRef] [PubMed]
  12. Khan, A.A.; Khan, Z.; Warnakulasuriya, S. Cancer-associated toll-like receptor modulation and insinuation in infection susceptibility: Association or coincidence? Ann. Oncol. 2016, 27, 984–997. [Google Scholar] [CrossRef] [PubMed]
  13. Brugger, S.D.; Bomar, L.; Lemon, K.P. Commensal-Pathogen Interactions along the Human Nasal Passages. PLoS Pathog. 2016, 12, e1005633. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Man, W.H.; de Steenhuijsen Piters, W.A.; Bogaert, D. The microbiota of the respiratory tract: Gatekeeper to respiratory health. Nat. Rev. Microbiol. 2017, 15, 259–270. [Google Scholar] [CrossRef]
  15. Bomar, L.; Brugger, S.D.; Lemon, K.P. Bacterial microbiota of the nasal passages across the span of human life. Curr. Opin. Microbiol. 2018, 41, 8–14. [Google Scholar] [CrossRef]
  16. Whelan, F.J.; Verschoor, C.P.; Stearns, J.C.; Rossi, L.; Luinstra, K.; Loeb, M.; Smieja, M.; Johnstone, J.; Surette, M.G.; Bowdish, D.M. The loss of topography in the microbial communities of the upper respiratory tract in the elderly. Ann. Am. Thorac. Soc. 2014, 11, 513–521. [Google Scholar] [CrossRef]
  17. Schenck, L.; Surette, M.G.; Bowdish, D.M.E. Composition and immunological significance of the upper respiratory tract microbiota. FEBS Lett. 2016, 590, 3705–3720. [Google Scholar] [CrossRef]
  18. Roghmann, M.C.; Lydecker, A.D.; Hittle, L.; DeBoy, R.T.; Nowak, R.G.; Johnson, J.K.; Mongodin, E.F. Comparison of the Microbiota of Older Adults Living in Nursing Homes and the Community. mSphere 2017, 2, e00210-17. [Google Scholar] [CrossRef] [Green Version]
  19. Van den Munckhof, E.; Hafkamp, H.C.; de Kluijver, J.; Kuijper, E.J.; de Koning, M.; Quint, W.; Knetsch, C.W. Nasal microbiota dominated by Moraxella spp. is associated with respiratory health in the elderly population: A case control study. Respir. Res. 2020, 21, 181. [Google Scholar] [CrossRef]
  20. Biesbroek, G.; Tsivtsivadze, E.; Sanders, E.A.; Montijn, R.; Veenhoven, R.H.; Keijser, B.J.; Bogaert, D. Early respiratory microbiota composition determines bacterial succession patterns and respiratory health in children. Am. J. Respir. Crit. Care Med. 2014, 190, 1283–1292. [Google Scholar] [CrossRef]
  21. Tsai, M.H.; Huang, Y.C.; Chen, C.J.; Lin, P.Y.; Chang, L.Y.; Chiu, C.H.; Tsao, K.C.; Huang, C.G.; Lin, T.Y. Chlamydial pneumonia in children requiring hospitalization: Effect of mixed infection on clinical outcome. J. Microbiol. Immunol. Infect. 2005, 38, 117–122. [Google Scholar] [PubMed]
  22. Emery, D.C.; Shoemark, D.K.; Batstone, T.E.; Waterfall, C.M.; Coghill, J.A.; Cerajewska, T.L.; Davies, M.; West, N.X.; Allen, S.J. 16S rRNA Next Generation Sequencing Analysis Shows Bacteria in Alzheimer’s Post-Mortem Brain. Front. Aging Neurosci. 2017, 9, 195. [Google Scholar] [CrossRef] [PubMed]
  23. Shibuya, Y.; Kawakatsu, S.; Hayashi, H.; Kobayashi, R.; Suzuki, A.; Sato, C.; Otani, K. Comparison of entorhinal cortex atrophy between early-onset and late-onset Alzheimer’s disease using the VSRAD, a specific and sensitive voxel-based morphometry. Int. J. Geriatr. Psychiatry 2013, 28, 372–376. [Google Scholar] [CrossRef]
  24. Mu, L.; Chen, J.; Sobotka, S.; Nyirenda, T.; Benson, B.; Gupta, F.; Sanders, I.; Adler, C.H.; Caviness, J.N.; Shill, H.A. Alpha-Synuclein Pathology in Sensory Nerve Terminals of the Upper Aerodigestive Tract of Parkinson’s Disease Patients. Dysphagia 2015, 30, 404–417. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Scheperjans, F.; Aho, V.; Pereira, P.A.B.; Koskinen, K.; Paulin, L.; Pekkonen, E.; Haapaniemi, E.; Kaakkola, S.; Eerola-Rautio, J.; Pohja, M.; et al. Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov. Disord. 2015, 30, 350–358. [Google Scholar] [CrossRef] [PubMed]
  26. Kesika, P.; Suganthy, N.; Sivamaruthi, B.S.; Chaiyasut, C. Role of gut-brain axis, gut microbial composition, and probiotic intervention in Alzheimer’s disease. Life Sci. 2021, 264, 118627. [Google Scholar] [CrossRef]
  27. Malek, N.; Swallow, D.; Grosset, K.A.; Anichtchik, O.; Spillantini, M.; Grosset, D.G. Alpha-synuclein in peripheral tissues and body fluids as a biomarker for Parkinson’s disease—A systematic review. Acta Neurol. Scand. 2014, 130, 59–72. [Google Scholar] [CrossRef]
  28. Crews, L.; Masliah, E. Molecular mechanisms of neurodegeneration in Alzheimer’s disease. Hum. Mol. Genet. 2010, 19, R12–R20. [Google Scholar] [CrossRef]
  29. Knowles, R.B.; Wyart, C.; Buldyrev, S.V.; Cruz, L.; Urbanc, B.; Hasselmo, M.E.; Stanley, H.E.; Hyman, B.T. Plaque-induced neurite abnormalities: Implications for disruption of neural networks in Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 1999, 96, 5274–5279. [Google Scholar] [CrossRef] [Green Version]
  30. Alemao, C.A.; Budden, K.F.; Gomez, H.M.; Rehman, S.F.; Marshall, J.E.; Shukla, S.D.; Donovan, C.; Forster, S.C.; Yang, I.A.; Keely, S.; et al. Impact of diet and the bacterial microbiome on the mucous barrier and immune disorders. Allergy 2021, 76, 714–734. [Google Scholar] [CrossRef]
  31. Jacka, F.N. Targeting the gut to achieve improved outcomes in mood disorders. Bipolar Disord. 2019, 21, 88–89. [Google Scholar] [CrossRef] [PubMed]
  32. Sivamaruthi, B.S.; Suganthy, N.; Kesika, P.; Chaiyasut, C. The Role of Microbiome, Dietary Supplements, and Probiotics in Autism Spectrum Disorder. Int. J. Environ. Res. Public Health 2020, 17, 2647. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Adamberg, K.; Kolk, K.; Jaagura, M.; Vilu, R.; Adamberg, S. The composition and metabolism of faecal microbiota is specifically modulated by different dietary polysaccharides and mucin: An isothermal microcalorimetry study. Benef. Microbes 2018, 9, 21–34. [Google Scholar] [CrossRef] [PubMed]
  34. Parada Venegas, D.; De la Fuente, M.K.; Landskron, G.; González, M.J.; Quera, R.; Dijkstra, G.; Harmsen, H.; Faber, K.N.; Hermoso, M.A. Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and Its Relevance for Inflammatory Bowel Diseases. Front. Immunol. 2019, 10, 277. [Google Scholar] [CrossRef] [Green Version]
  35. van der Hee, B.; Wells, J.M. Microbial Regulation of Host Physiology by Short-chain Fatty Acids. Trends Microbiol. 2021, 29, 700–712. [Google Scholar] [CrossRef]
  36. Di Stadio, A.; Costantini, C.; Renga, G.; Pariano, M.; Ricci, G.; Romani, L. The Microbiota/Host Immune System Interaction in the Nose to Protect from COVID-19. Life 2020, 10, 345. [Google Scholar] [CrossRef]
  37. Rueca, M.; Fontana, A.; Bartolini, B.; Piselli, P.; Mazzarelli, A.; Copetti, M.; Binda, E.; Perri, F.; Gruber, C.; Nicastri; et al. Investigation of Nasal/Oropharyngeal Microbial Community of COVID-19 Patients by 16S rDNA Sequencing. Int. J. Environ. Res. Public Health. 2021, 18, 2174. [Google Scholar] [CrossRef]
  38. Khoruts, A. First microbial encounters. Nat. Med. 2016, 22, 231–232. [Google Scholar] [CrossRef]
  39. Biesbroek, G.; Bosch, A.A.; Wang, X.; Keijser, B.J.; Veenhoven, R.H.; Sanders, E.A.; Bogaert, D. The impact of breastfeeding on nasopharyngeal microbial communities in infants. Am. J. Respir. Crit. Care Med. 2014, 190, 298–308. [Google Scholar] [CrossRef]
  40. Sampaio-Maia, B.; Monteiro-Silva, F. Acquisition and maturation of oral microbiome throughout childhood: An update. J. Dent. Res. 2014, 11, 291–301. [Google Scholar]
  41. Teo, S.M.; Mok, D.; Pham, K.; Kusel, M.; Serralha, M.; Troy, N.; Holt, B.J.; Hales, B.J.; Walker, M.L.; Hollams, E.; et al. The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development. Cell Host Microbe 2015, 17, 704–715. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Payne, M.S.; Goss, K.C.; Connett, G.J.; Kollamparambil, T.; Legg, J.P.; Thwaites, R.; Ashton, M.; Puddy, V.; Peacock, J.L.; Bruce, K.D. Molecular microbiological characterization of preterm neonates at risk of bronchopulmonary dysplasia. Pediatr. Res. 2010, 67, 412–418. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Mourani, P.M.; Harris, J.K.; Sontag, M.K.; Robertson, C.E.; Abman, S.H. Molecular identification of bacteria in tracheal aspirate fluid from mechanically ventilated preterm infants. PLoS ONE 2011, 6, e25959. [Google Scholar] [CrossRef] [PubMed]
  44. Lohmann, P.; Luna, R.A.; Hollister, E.B.; Devaraj, S.; Mistretta, T.A.; Welty, S.E.; Versalovic, J. The airway microbiome of intubated premature infants: Characteristics and changes that predict the development of bronchopulmonary dysplasia. Pediatr. Res. 2014, 76, 294–301. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Camarinha-Silva, A.; Jáuregui, R.; Chaves-Moreno, D.; Oxley, A.P.A.; Schaumburg, F.; Becker, K.; Wos-Oxley, M.L.; Pieper, D.H. Comparing the anterior nare bacterial community of two discrete human populations using Illumina amplicon sequencing. Environ. Microbiol. 2014, 16, 2939–2952. [Google Scholar] [CrossRef] [PubMed]
  46. Camarinha-Silva, A.; Wos-Oxley, M.L.; Jáuregui, R.; Becker, K.; Pieper, D.H. Validating T-RFLP as a sensitive and high-throughput approach to assess bacterial diversity patterns in human anterior nares. FEMS Microbiol. Ecol. 2011, 79, 98–108. [Google Scholar] [CrossRef] [Green Version]
  47. Oh, J.; Byrd, A.L.; Deming, C.B.; Conlan, S.; Kong, H.H.; Segre, J.A. Biogeography and individuality shape function in the human skin metagenome. Nature 2014, 514, 59–64. [Google Scholar] [CrossRef] [Green Version]
  48. Zhou, Y.; Gao, H.; Mihindukulasuriya, K.A.; Rosa, P.S.L.; Wylie, K.M.; Vishnivetskaya, T.; Podar, M.; Warner, B.; Tarr, P.I.; Nelson, D.E.; et al. Biogeography of the ecosystems of the healthy human body. Genome Biol. 2013, 14, R1. [Google Scholar] [CrossRef] [Green Version]
  49. De Boeck, I.; Wittouck, S.; Wuyts, S.; Oerlemans, E.F.; Van den Broek, M.F.; Vandenheuvel, D.; Vanderveken, O.; Lebeer, S. Comparing the healthy nose and nasopharynx microbiota reveals continuity as well as niche-specificity. Front. Microbiol. 2017, 8, 2372. [Google Scholar] [CrossRef] [Green Version]
  50. de Steenhuijsen Piters, W.A.; Sanders, E.A.; Bogaert, D. The role of the local microbial ecosystem in respiratory health and disease. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2015, 370, 20140294. [Google Scholar] [CrossRef] [Green Version]
  51. Wenfang, H.; Yueyun, M.; Zhou, L.; Hao, X. The role of microbiome in respiratory disease. Chin. J. Lab. Med. 2016, 39, 322–325. [Google Scholar]
  52. Unger, S.A.; Bogaert, D. The respiratory microbiome and respiratory infections. J. Infect. 2017, 74 (Suppl. S1), S84–S88. [Google Scholar] [CrossRef]
  53. Kumpitsch, C.; Koskinen, K.; Schopf, V.; Moissl-Eichinger, C. The microbiome of the upper respiratory in health and disease. BMC Biol. 2019, 17, 87. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Ashworth, M.; Charlton, J.; Ballard, K.; Latinovic, R.; Gulliford, M. Variations in antibiotic prescribing and consultation rates for acute respiratory infection in UK general practices 1995–2000. Br. J. Gen. Pract. 2005, 55, 603–608. [Google Scholar]
  55. Feinberg, M.J.; Knebl, J.; Tully, J.; Segall, L. Aspiration and the elderly. Dysphagia 1990, 5, 61–71. [Google Scholar] [CrossRef]
  56. Scannapieco, F.A. Role of oral bacteria in respiratory infection. J. Periodontol. 2013, 70, 793–802. [Google Scholar] [CrossRef]
  57. Bassis, C.M.; Erb-Downward, J.R.; Dickson, R.P.; Freeman, C.M.; Schmidt, T.M.; Young, V.B.; Beck, J.M.; Curtis, J.L.; Huffnagle, G.B. Analysis of the upper respiratory tract microbiotas as the source of the lung and gastric microbiotas in healthy individuals. mBio 2015, 6, e00037. [Google Scholar] [CrossRef] [Green Version]
  58. Frank, D.N.; Feazel, L.M.; Bessesen, M.T.; Price, C.S.; Janoff, E.N.; Pace, N.R. The human nasal microbiota and Staphylococcus aureus carriage. PLoS ONE 2010, 5, e10598. [Google Scholar] [CrossRef]
  59. Zhou, Y.; Mihindukulasuriya, K.A.; Gao, H.; La Rosa, P.S.; Wylie, K.M.; Martin, J.C.; Kota, K.; Shannon, W.D.; Mitreva, M.; Sodergren, E.; et al. Exploration of bacterial community classes in major human habitats. Genome Biol. 2014, 15, R66. [Google Scholar] [CrossRef]
  60. Wos-Oxley, M.L.; Chaves-Moreno, D.; Jáuregui, R.; Oxley, A.P.; Kaspar, U.; Plumeier, I.; Kahl, S.; Rudack, C.; Becker, K.; Pieper, D.H. Exploring the bacterial assemblages along the human nasal passage. Environ. Microbiol. 2016, 18, 2259–2271. [Google Scholar] [CrossRef]
  61. Bosch, A.A.T.M.; Levin, E.; van Houten, M.A.; Hasrat, R.; Kalkman, G.; Biesbroek, G.; de Steenhuijsen Piters, W.A.A.; de Groot, P.C.M.; Pernet, P.; Keijser, B.J.F.; et al. Development of Upper Respiratory Tract Microbiota in Infancy is Affected by Mode of Delivery. EBioMedicine 2016, 9, 336–345. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Charlson, E.S.; Chen, J.; Custers-Allen, R.; Bittinger, K.; Li, H.; Sinha, R.; Hwang, J.; Bushman, F.D.; Collman, R.G. Disordered microbial communities in the upper respiratory tract of cigarette smokers. PLoS ONE 2010, 5, e15216. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Eidi, S.; Kamali, S.A.; Hajari, Z.; Fata, F.; Hosseini, R.F.; Naseri, A.; Bakhshaee, M. Nasal and indoors fungal contamination in healthy subjects. Health Scope 2016, 5, e30033. [Google Scholar] [CrossRef]
  64. Wang, Y.; Zhu, N.; Li, Y.; Lu, R.; Wang, H.; Liu, G.; Zou, X.; Xie, Z.; Tan, W. Metagenomic analysis of viral genetic diversity in respiratory samples from children with severe acute respiratory infection in China. Clin. Microbiol. Infect. 2016, 22, 458.e1–458.e9. [Google Scholar] [CrossRef] [Green Version]
  65. Marsh, R.L.; Kaestli, M.; Chang, A.B.; Binks, M.J.; Pope, C.E.; Hoffman, L.R.; Smith-Vaughan, H.C. The microbiota in bronchoalveolar lavage from young children with chronic lung disease includes taxa present in both the oropharynx and nasopharynx. Microbiome 2016, 4, 37. [Google Scholar] [CrossRef] [Green Version]
  66. Segal, L.N.; Alekseyenko, A.V.; Clemente, J.C.; Kulkarni, R.; Wu, B.; Gao, Z.; Chen, H.; Berger, K.I.; Goldring, R.M.; Rom, W.N.; et al. Enrichment of lung microbiome with supraglottic taxa is associated with increased pulmonary inflammation. Microbiome 2013, 1, 19. [Google Scholar] [CrossRef] [Green Version]
  67. Stearns, J.C.; Davidson, C.J.; McKeon, S.; Whelan, F.J.; Fontes, M.E.; Schryvers, A.B.; Bowdish, D.M.; Kellner, J.D.; Surette, M.G. Culture and molecular-based profiles show shifts in bacterial communities of the upper respiratory tract that occur with age. ISME J. 2015, 9, 1246–1259. [Google Scholar] [CrossRef] [Green Version]
  68. Tai, J.; Han, M.S.; Kwak, J.; Kim, T.H. Association Between Microbiota and Nasal Mucosal Diseases in terms of Immunity. Int. J. Mol. Sci. 2021, 22, 4744. [Google Scholar] [CrossRef]
  69. Anand, V.K. Epidemiology and economic impact of rhinosinusitis. Ann. Otol. Rhinol. Laryngol. Suppl. 2004, 193, 3–5. [Google Scholar] [CrossRef]
  70. Gliklich, R.E.; Metson, R. The health impact of chronic sinusitis in patients seeking otolaryngologic care. Otolaryngol. Head Neck Surg. 1995, 113, 104–109. [Google Scholar] [CrossRef]
  71. Harrass, S.; Yi, C.; Chen, H. Chronic Rhinosinusitis and Alzheimer’s Disease-A Possible Role for the Nasal Microbiome in Causing Neurodegeneration in the Elderly. Int. J. Mol. Sci. 2021, 22, 11207. [Google Scholar] [CrossRef] [PubMed]
  72. Mahdavinia, M.; Keshavarzian, A.; Tobin, M.C.; Landay, A.L.; Schleimer, R.P. A comprehensive review of the nasal microbiome in chronic rhinosinusitis (CRS). Clin. Exp. Allergy 2016, 46, 21–41. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Andualem, Z.; Gizaw, Z.; Bogale, L.; Dagne, H. Indoor bacterial load and its correlation to physical indoor air quality parameters in public primary schools. Multidiscip. Respir. Med. 2019, 14, 2. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Ridley, C.; Thornton, D.J. Mucins: The frontline defence of the lung. Biochem. Soc. Trans. 2018, 46, 1099–1106. [Google Scholar] [CrossRef] [Green Version]
  75. Jones, N. The nose and paranasal sinuses physiology and anatomy. Adv. Drug Deliv. Rev. 2001, 51, 5–19. [Google Scholar] [CrossRef]
  76. Ballester, B.; Milara, J.; Cortijo, J. Mucins as a New Frontier in Pulmonary Fibrosis. J. Clin. Med. 2019, 8, 1447. [Google Scholar] [CrossRef] [Green Version]
  77. Mellert, T.K.; Getchell, M.L.; Sparks, L.; Getchell, T.V. Characterization of the immune barrier in human olfactory mucosa. Otolaryngol. Head Neck Surg. 1992, 106, 181–188. [Google Scholar] [CrossRef]
  78. Koskinen, K.; Reichert, J.L.; Hoier, S.; Schachenreiter, J.; Duller, S.; Moissl-Eichinger, C.; Schöpf, V. The nasal microbiome mirrors and potentially shapes olfactory function. Sci. Rep. 2018, 8, 1296. [Google Scholar] [CrossRef] [Green Version]
  79. Gevers, D.; Kugathasan, S.; Denson, L.A.; Vázquez-Baeza, Y.; Van Treuren, W.; Ren, B.; Schwager, E.; Knights, D.; Song, S.J.; Yassour, M. The treatment-naive microbiome in new-onset Crohn’s disease. Cell Host Microbe 2014, 15, 382–392. [Google Scholar] [CrossRef] [Green Version]
  80. Bushdid, C.; Magnasco, M.O.; Vosshall, L.B.; Keller, A. Humans can discriminate more than 1 trillion olfactory stimuli. Science 2014, 343, 1370–1372. [Google Scholar] [CrossRef] [Green Version]
  81. Moran, D.T.; Rowley, J.C., III; Jafek, B.W.; Lovell, M.A. The fine structure of the olfactory mucosa in man. J. Neurocytol. 1982, 11, 721–746. [Google Scholar] [CrossRef] [PubMed]
  82. Blomqvist, E.H.; Brämerson, A.; Stjärne, P.; Nordin, S. Consequences of olfactory loss and adopted coping strategies. Rhinology 2004, 42, 189–194. [Google Scholar] [PubMed]
  83. Frasnelli, J.; Hummel, T. Olfactory dysfunction and daily life. Eur. Arch. Otorhinolaryngol. 2005, 262, 231–235. [Google Scholar] [CrossRef] [PubMed]
  84. Kollndorfer, K.; Reichert, J.; Braunsteiner, J.; Schöpf, V. Assessment of olfactory memory in olfactory dysfunction. Perception 2017, 46, 516–529. [Google Scholar] [CrossRef]
  85. Ferris, A.M.; Duffy, V.B. Effect of olfactory deficits on nutritional status. Does age predict persons at risk? Ann. N. Y. Acad. Sci. 1989, 561, 113–123. [Google Scholar] [CrossRef]
  86. Deems, D.A.; Doty, R.L.; Settle, R.G.; Moore-Gillon, V.; Shaman, P.; Mester, A.F.; Kimmelman, C.P.; Brightman, V.J.; Snow, J.B., Jr. Smell and taste disorders, a study of 750 patients from the University of Pennsylvania Smell and Taste Center. Arch. Otolaryngol. Head. Neck Surg. 1991, 117, 519–528. [Google Scholar] [CrossRef]
  87. Morris, A.; Beck, J.M.; Schloss, P.D.; Campbell, T.B.; Crothers, K.; Curtis, J.L.; Flores, S.C.; Fontenot, A.P.; Ghedin, E.; Huang, L.; et al. Comparison of the respiratory microbiome in healthy non-smokers and smokers. Am. J. Respir. Crit. Care Med. 2013, 187, 1067–1075. [Google Scholar] [CrossRef] [Green Version]
  88. Jokinen, C.; Heiskanen, L.; Juvonen, H.; Kallinen, S.; Karkola, K.; Korppi, M.; Kurki, S.; Ronnberg, P.R.; Seppa, A.; Soimakallio, S. Incidence of community-acquired pneumonia in the population of four municipalities in eastern Finland. Am. J. Epidemiol. 1993, 137, 977–988. [Google Scholar] [CrossRef]
  89. Ahmed, R.; Oldstone, M.B.A.; Palese, P. Protective immunity and susceptibility to infectious diseases: Lessons from the 1918 influenza pandemic. Nat. Immunol. 2007, 8, 1188–1193. [Google Scholar] [CrossRef]
  90. Benten, I.J.; Drunen, C.M.; Koopman, L.P.; Middelkoop, B.C.; Hop, W.C.J.; Osterhaus, A.D.M.E.; Neijens, H.J.; Fokkens, W.J. Age- and infection related maturation of the nasal immune response in 0–2-year-old children. Allergy 2005, 60, 226–232. [Google Scholar] [CrossRef]
  91. Oh, J.; Conlan, S.; Polley, E.C.; Segre, J.A.; Kong, H.H. Shifts in human skin and nares microbiota of healthy children and adults. Genome Med. 2012, 4, 77. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  92. Franceschi, C.; Bonafè, M.; Valensin, S.; Olivieri, F.; De Luca, M.; Ottaviani, E.; De Benedictis, G. Inflamm-aging: An evolutionary perspective on immunosenescence. Ann. N. Y. Acad. Sci. 2000, 908, 244–254. [Google Scholar] [CrossRef] [PubMed]
  93. Royet, J.P.; Plailly, J. Lateralization of Olfactory Processes. Chem. Sens. 2004, 29, 731–745. [Google Scholar] [CrossRef] [PubMed]
  94. Summanen, P.; Finegold, S.M.; Summanen, P.; Finegold, S.M. Bergey’s Manual of Systematics of Archaea and Bacteria 1–14; John Wiley & Sons, Ltd.: Hoboken, NJ, USA, 2015. [Google Scholar] [CrossRef]
  95. Croy, I.; Hoffmann, H.; Philpott, C.; Rombaux, P.; Welge-Luessen, A.; Vodicka, J.; Konstantinidis, I.; Morera, E.; Hummel, T. Retronasal testing of olfactory function: An investigation and comparison in seven countries. Eur. Arch. Oto-Rhino-Laryngol. 2014, 271, 1087–1095. [Google Scholar] [CrossRef] [PubMed]
  96. Thangaleela, S.; Sivamaruthi, B.S.; Kesika, P.; Bharathi, M.; Kunaviktikul, W.; Klunklin, A.; Chanthapoon, C.; Chaiyasut, C. Essential Oils, Phytoncides, Aromachology, and Aromatherapy—A Review. Appl. Sci. 2022, 12, 4495. [Google Scholar] [CrossRef]
  97. Attems, J.; Walker, L.; Jellinger, K.A. Olfaction and aging: A mini-review. Gerontology 2015, 61, 485–490. [Google Scholar] [CrossRef]
  98. Markovic, K.; Reulbach, U.; Vassiliadu, A.; Lunkenheimer, J.; Lunkenheimer, B.; Spannenberger, R.; Thuerauf, N. Good news for elderly persons: Olfactory pleasure increases at later stages of the life span. J. Gerontol. A Biol. Sci. Med. Sci. 2007, 62, 1287–1293. [Google Scholar] [CrossRef] [Green Version]
  99. Schubert, C.R.; Cruickshanks, K.J.; Klein, B.E.; Klein, R.; Nondahl, D.M. Olfactory impairment in older adults: Five-year incidence and risk factors. Laryngoscope 2011, 121, 873–878. [Google Scholar] [CrossRef] [Green Version]
  100. Barresi, M.; Ciurleo, R.; Giacoppo, S.; Foti Cuzzola, V.; Celi, D.; Bramanti, P.; Marino, S. Evaluation of olfactory dysfunction in neurodegenerative diseases. J. Neurol. Sci. 2012, 323, 16–24. [Google Scholar] [CrossRef]
  101. Bianchi, A.J.; Guépet-Sordet, H.; Manckoundia, P. Changes in olfaction during ageing and in certain neurodegenerative diseases: Up-to-date. Rev. Med. Interne. 2015, 36, 31–37. [Google Scholar] [CrossRef]
  102. François, A.; Grebert, D.; Rhimi, M.; Mariadassou, M.; Naudon, L.; Rabot, S.; Meunier, N. Olfactory epithelium changes in germfree mice. Sci. Rep. 2016, 6, 24687. [Google Scholar] [CrossRef] [PubMed]
  103. Lécuyer, H.; Audibert, J.; Bobigny, A.; Eckert, C.; Jannière-Nartey, C.; Buu-Hoï, A.; Mainardi, J.L.; Podglajen, I. Dolosigranulum pigrum causing nosocomial pneumonia and septicemia. J. Clin. Microbiol. 2007, 45, 3474–3475. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Bell, J.S.; Spencer, J.I.; Yates, R.L.; Yee, S.A.; Jacobs, B.M.; DeLuca, G.C. Invited Review: From nose to gut—The role of the microbiome in neurological disease. Neuropathol. Appl. Neurobiol. 2019, 5, 195–215. [Google Scholar] [CrossRef] [Green Version]
  105. Daneman, R.; Prat, A. The blood-brain barrier. Cold Spring Harb Perspect Biol. 2015, 7, a020412. [Google Scholar] [CrossRef] [Green Version]
  106. Shipley, M.T.; McLean, J.H.; Ennis, M. Olfactory system. In Rat Nervous System; Paxinos, G., Ed.; Academic Press: San Diego, CA, USA, 1995; pp. 899–926. [Google Scholar]
  107. Saiz-Sánchez, D.; de la Rosa-Prieto, C.; Úbeda-Bañón, I.; Martínez-Marcos, A. Neural Basis of Hyposmia in Alzheimer’s Disease. In The Clinical Spectrum of Alzheimer’s Disease—The Charge Toward Comprehensive Diagnostic and Therapeutic Strategies; De La Monte, S., Ed.; IntechOpen: London, UK, 2011. [Google Scholar]
  108. Doty, R.L.; Kamath, V. The influences of age on olfaction: A review. Front. Psychol. 2014, 5, 20. [Google Scholar] [CrossRef] [Green Version]
  109. Arnold, S.E.; Lee, E.B.; Moberg, P.J.; Stutzbach, L.; Kazi, H.; Han, L.Y.; Lee, V.M.; Trojanowski, J.Q. Olfactory epithelium amyloid-beta and paired helical filament-tau pathology in Alzheimer disease. Ann. Neurol. 2010, 67, 462–469. [Google Scholar] [CrossRef]
  110. Panitch, H.B. Respiratory implications of pediatric neuromuscular disease. Respir Care. 2017, 62, 826–848. [Google Scholar] [CrossRef]
  111. Kristensson, K. Microbes’ roadmap to neurons. Nat. Rev. Neurosci. 2011, 12, 345–357. [Google Scholar] [CrossRef]
  112. Engelhardt, B.; Sorokin, L. The blood-brain and the blood-cerebrospinal fluid barriers: Function and dysfunction. Semin. ImmunoPathol. 2009, 31, 497–511. [Google Scholar] [CrossRef] [Green Version]
  113. Kim, K.S. Mechanisms of microbial traversal of the blood-brain barrier. Nat. Rev. Microbiol. 2008, 6, 625–634. [Google Scholar] [CrossRef] [Green Version]
  114. Lee, S.; Lane, A.P. Chronic rhinosinusitis as a multifactorial inflammatory disorder. Curr. Infect. Dis. Rep. 2011, 13, 159–168. [Google Scholar] [CrossRef] [Green Version]
  115. Dando, S.J.; Mackay-Sim, A.; Norton, R.; Currie, B.J.; St John, J.A.; Ekberg, J.A.; Batzloff, M.; Ulett, G.C.; Beacham, I.R. Pathogens penetrating the central nervous system: Infection pathways and the cellular and molecular mechanisms of invasion. Clin. Micr. Biol. Rev. 2014, 27, 691–726. [Google Scholar] [CrossRef] [Green Version]
  116. Hedner, M.; Larsson, M.; Arnold, N.; Zucco, G.M.; Hummel, T. Cognitive factors in odor detection, odor discrimination, and odor identification tasks. J. Clin. Exp. Neuropsychol. 2010, 32, 1062–1067. [Google Scholar] [CrossRef]
  117. Croy, I.; Nordin, S.; Hummel, T. Olfactory Disorders and Quality of Life—An Updated Review. Chem. Sens. 2014, 39, 185–194. [Google Scholar] [CrossRef] [Green Version]
  118. Boesveldt, S.; Postma, E.M.; Boak, D.; Welge-Luessen, A.; Schöpf, V.; Mainland, J.D.; Martens, J.; Ngai, J.; Duffy, V.B. Anosmia-A Clinical Review. Chem. Sens. 2017, 42, 513–523. [Google Scholar] [CrossRef]
  119. Miwa, T.; Furukawa, M.; Tsukatani, T.; Costanzo, R.M.; DiNardo, L.J.; Reiter, E.R. Impact of olfactory impairment on quality of life and disability. Arch. Otolaryngol. Head Neck Surg. 2001, 127, 497–503. [Google Scholar] [CrossRef] [Green Version]
  120. Temmel, A.F.P.; Quint, C.; Schickinger-Fischer, B.; Klimek, L.; Stoller, E.; Hummel, T. Characteristics of olfactory disorders in relation to major causes of olfactory loss. AOHNS 2002, 128, 635–641. [Google Scholar] [CrossRef] [Green Version]
  121. Matsui, T.; Arai, H.; Nakajo, M.; Maruyama, M.; Ebihara, S.; Sasaki, H.; Yoshida, Y. Role of Chronic Sinusitis in Cognitive Functioning in the Elderly. J. Am. Geriatr. Soc. 2003, 51, 1818–1819. [Google Scholar] [CrossRef]
  122. Tarasidis, G.S.; De Conde, A.S.; Mace, J.C.; Ashby, S.; Smith, T.L.; Orlandi, R.R.; Alt, J.A. Cognitive dysfunction associated with pain and quality of life in chronic rhinosinusitis. Int. Forum Allergy Rhinol. 2015, 5, 1004–1009. [Google Scholar] [CrossRef]
  123. Jafari, A.; de Lima Xavier, L.; Bernstein, J.D.; Simonyan, K.; Bleier, B.S. Association of Sinonasal Inflammation with functional brain connectivity. JAMA Otolaryngol. Head Neck Surg. 2021, 147, 534–543. [Google Scholar] [CrossRef]
  124. Jung, H.J.; Lee, J.Y.; Choi, Y.S.; Choi, H.G.; Wee, J.H. Chronic rhinosinusitis and progression of cognitive impairment in dementia. Eur. Ann. Otorhino Laryngol. Head Neck Dis. 2021, 138, 147–151. [Google Scholar] [CrossRef] [PubMed]
  125. Brandtzaeg, P. Cells Producing Immunoglobulins and other Immune Factors in Human Nasal Mucosa. In Protides of the Biological Fluids; Peeters, H., Ed.; Elsevier: Amsterdam, The Netherlands, 1985; Volume 32, pp. 363–366. [Google Scholar]
  126. Brescia, G.; Barion, U.; Zanotti, C.; Giacomelli, L.; Martini, A.; Marioni, G. The prognostic role of serum eosinophil and basophil levels in sinonasal polyposis. Int. Forum Allergy Rhinol. 2017, 7, 261–267. [Google Scholar] [CrossRef] [PubMed]
  127. Hulse, K.E.; Stevens, W.W.; Tan, B.K.; Schleimer, R.P. Pathogenesis of nasal polyposis. Clin. Exp. Allergy 2015, 45, 328–346. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  128. Turner, J.H.; Liang, K.L.; May, L.; Lane, A.P. Tumor necrosis factor alpha inhibits olfactory regeneration in a transgenic model of chronic rhinosinusitis-associated olfactory loss. Am. J. Rhinol. Allergy 2010, 24, 336–340. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  129. Kern, R.C. Chronic sinusitis and anosmia: Pathologic changes in the olfactory mucosa. Laryngoscope 2000, 110, 1071–1077. [Google Scholar] [CrossRef]
  130. Litvack, J.R.; Fong, K.; Mace, J.; James, K.E.; Smith, T.L. Predictors of olfactory dysfunction in patients with chronic rhinosinusitis. Laryngoscope 2008, 118, 2225–2230. [Google Scholar] [CrossRef] [Green Version]
  131. Snowdon, D.A.; Greiner, L.H.; Mortimer, J.A.; Riley, K.P.; Greiner, P.A.; Markesbery, W.R. Brain Infarction and the Clinical Expression of Alzheimer Disease: The Nun Study. JAMA 1997, 277, 813–817. [Google Scholar] [CrossRef]
  132. Bature, F.; Guinn, B.-A.; Pang, D.; Pappas, Y. Signs and symptoms preceding the diagnosis of Alzheimer’s disease: A systematic scoping review of literature from 1937 to 2016. BMJ Open 2017, 7, e015746. [Google Scholar] [CrossRef] [Green Version]
  133. Panza, F.; Seripa, D.; D’Onofrio, G.; Frisardi, V.; Solfrizzi, V.; Mecocci, P.; Pilotto, A. Neuropsychiatric Symptoms, Endophenotypes, and Syndromes in Late-Onset Alzheimer’s Disease: Focus on APOE Gene. Int. J. Alzheimers Dis. 2011, 2011, 721457. [Google Scholar] [CrossRef] [Green Version]
  134. Li, X.L.; Hu, N.; Tan, M.S.; Yu, J.T.; Tan, L. Behavioral and psychological symptoms in Alzheimer’s disease. BioMed Res. Int. 2014, 2014, 927804. [Google Scholar] [CrossRef]
  135. Rowan, N.R.; Schlosser, R.J.; Storck, K.A.; Ganjaei, K.G.; Soler, Z.M. The impact of medical therapy on cognitive dysfunction in chronic rhinosinusitis. Int. Forum Allergy Rhinol. 2019, 9, 738–745. [Google Scholar] [CrossRef] [PubMed]
  136. Manabe, T.; Fujikura, Y.; Mizukami, K.; Akatsu, H.; Kudo, K. Pneumonia-associated death in patients with dementia: A systematic review and meta-analysis. PLoS ONE 2019, 14, e0213825. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  137. Pinto, J.M.; Wroblewski, K.E.; Kern, D.W.; Schumm, L.P.; McClintock, M.K. Olfactory dysfunction predicts 5-year mortality in older adults. PLoS ONE 1991, 9, e107541. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  138. Lin, A.; Brewer, W.J.; Yung, A.R.; Nelson, B.; Pantelis, C.; Wood, S.J. Olfactory identification deficits at identification as ultra-high risk for psychosis are associated with poor functional outcome. Schizophr. Res. 2015, 161, 156–162. [Google Scholar] [CrossRef]
  139. Pereira, P.A.B.; Aho, V.T.E.; Paulin, L.; Pekkonen, E.; Auvinen, P.; Scheperjans, F. Oral and nasal microbiota in Parkinson’s disease. Parkinsonism Relat. Disord. 2017, 38, 61–67. [Google Scholar] [CrossRef] [Green Version]
  140. Mulak, A.; Bonaz, B. Brain-gut-microbiota axis in Parkinson’s disease. World J. Gastroenterol. 2015, 21, 10609–10620. [Google Scholar] [CrossRef]
  141. Khan, F.; Oloketuyi, S.F. A Future perspective on neurodegenerative diseases: Nasopharyngeal and gut microbiota. J. Appl. Microbiol. 2016, 122, 306–320. [Google Scholar] [CrossRef] [Green Version]
  142. Braak, H.; Del Tredici, K.; Rüb, U.; Vos, R.A.I.; Jansen Steur, E.N.H.; Braak, E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging. 2003, 24, 197–211. [Google Scholar] [CrossRef]
  143. Doty, R.L. Handbook of Olfaction and Gustation, 3rd ed.; John Wiley & Sons: Hoboken, NJ, USA, 2015. [Google Scholar]
  144. Lema Tomé, C.M.; Tyson, T.; Rey, N.L.; Grathwohl, S.; Britschgi, M.; Brundin, P. Inflammation and alpha-synuclein’s prion-like behavior in Parkinson’s Disease—Is there a link? Mol. Neurobiol. 2013, 47, 561–574. [Google Scholar] [CrossRef] [Green Version]
  145. Pal, G.; Ramirez, V.; Engen, P.A.; Naqib, A.; Forsyth, C.B.; Green, S.J.; Mahdavinia, M.; Batra, P.S.; Tajudeen, B.A.; Keshavarzian, A. Deep nasal sinus cavity microbiota dysbiosis in Parkinson’s disease. NPJ Parkinsons Dis. 2021, 7, 111. [Google Scholar] [CrossRef]
  146. Diaz, H.R.; Wang, S.; Anuar, F.; Qian, Y.; Bjorkholm, B.; Samuelsson, A.; Hibberd, M.L.; Forssberg, H.; Pettersson, S. Normal gut microbiota modulates brain development and behavior. Proc. Natl. Acad. Sci. USA 2011, 108, 3047–3052. [Google Scholar]
  147. Lu, J.; Synowiec, S.; Lu, L.; Yu, Y.; Bretherick, T.; Takada, S.; Yarnykh, V.; Caplan, J.; Caplan, M.; Claud, E.C.; et al. Microbiota influence the development of the brain and behaviors in C57BL/6J mice. PLoS ONE 2018, 13, e0201829. [Google Scholar] [CrossRef]
  148. Wu, G.D.; Compher, C.; Chen, E.Z.; Smith, S.A.; Shah, R.D.; Bittinger, K.; Chehoud, C.; Albenberg, L.G.; Nessel, L.; Gilroy, E.; et al. Comparative metabolomics in vegans and omnivores reveal constraints on diet-dependent gut microbiota metabolite production. Gut 2016, 65, 63–72. [Google Scholar] [CrossRef] [PubMed]
  149. Park, W. Gut microbiomes and their metabolites shape human and animal health. J. Microbiol. 2018, 56, 151–153. [Google Scholar] [CrossRef] [Green Version]
  150. Rinninella, E.; Raoul, P.; Cintoni, M.; Franceschi, F.; Miggiano, G.A.D.; Gasbarrini, A.; Mele, M.C. What is the healthy gut microbiota composition? A changing ecosystem across age, environment, diet, and diseases. Microorganisms 2019, 7, 14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  151. Ley, R.E.; Peterson, D.A.; Gordon, J.I. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 2006, 124, 837–848. [Google Scholar] [CrossRef] [Green Version]
  152. Bassis, C.M.; Tang, A.L.; Young, V.B.; Pynnonen, M.A. The nasal cavity microbiota of healthy adults. Microbiome 2014, 2, 27. [Google Scholar] [CrossRef] [Green Version]
  153. Shilts, M.H.; Rosas-Salazar, C.; Tovchigrechko, A.; Larkin, E.K.; Toralba, M.; Akopov, A.; Halpin, R.; Peebles, R.S.; Moore, M.L.; Anderson, L.J.; et al. Minimally Invasive sampling method identifies differences in taxonomic richness of nasal microbiomes in young infants associated with mode of delivery. Microb. Ecol. 2016, 71, 233–242. [Google Scholar] [CrossRef] [Green Version]
  154. Branton, W.G.; Ellestad, K.K.; Maingat, F.; Wheatley, B.M.; Rud, E.; Warren, R.L.; Holt, R.A.; Surette, M.G.; Power, C. Brain microbial populations in HIV/AIDS: A-proteobacteria predominate independent of host immune status. PLoS ONE 2013, 8, e54673. [Google Scholar] [CrossRef] [Green Version]
  155. Branton, W.G.; Lu, J.Q.; Surette, M.G.; Holt, R.A.; Lind, J.; Laman, J.D.; Power, C. Brain microbiota disruption within inflammatory demyelinating lesions in multiple sclerosis. Sci. Rep. 2016, 6, 37344. [Google Scholar] [CrossRef] [Green Version]
  156. Sarkar, S.R.; Banerjee, S. Gut microbiota in neurodegenerative disorders. J. Neuroimmunol. 2019, 328, 98–104. [Google Scholar] [CrossRef] [PubMed]
  157. Monnier, L.; Mas, E.; Ginet, C.; Michel, F.; Villon, L.; Cristol, J.P.; Colette, C. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA 2006, 295, 168–1687. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  158. Carlson, J.L.; Erickson, J.M.; Lloyd, B.B.; Slavin, J.L. Health effects and sources of prebiotic dietary fiber. Curr. Dev. Nutr. 2018, 2, nzy005. [Google Scholar] [CrossRef] [Green Version]
  159. Donohoe, D.R.; Garge, N.; Zhang, X.; Sun, W.; O’Connell, T.M.; Bunger, M.K.; Bultman, S.J. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab. 2011, 13, 517–526. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  160. Corrêa-Oliveira, R.; Fachi, J.; Vieira, A.; Sato, F.T.; Vinolo, M.A.R. Regulation of immune cell function by short-chain fatty acids. Clin. Transl. Immunol. 2016, 5, e73. [Google Scholar] [CrossRef]
  161. Rivière, A.; Selak, M.; Lantin, D.; Leroy, F.; De Vuyst, L. Bifidobacteria and butyrate-producing colon bacteria: Importance and strategies for their stimulation in the human gut. Front. Microbiol. 2016, 7, 979. [Google Scholar] [CrossRef] [Green Version]
  162. Louis, P.; Flint, H.J. Diversity, metabolism and microbial ecology of butyrate-producing bacteria from the human large intestine. FEMS Microbiol. Lett. 2009, 294, 1–8. [Google Scholar] [CrossRef] [Green Version]
  163. Louis, P.; Flint, H.J. Formation of propionate and butyrate by the human colonic microbiota. Environ. Microbiol. 2017, 19, 29–41. [Google Scholar] [CrossRef] [Green Version]
  164. Schwiertz, A.; Hold, G.L.; Duncan, S.H.; Gruhl, B.; Collins, M.D.; Lawson, P.A.; Flint, H.J.; Blaut, M. Anaerostipes caccae gen. nov., sp. nov., a new saccharolytic, acetate-utilising, butyrate-producing bacterium from human faeces. Syst. Appl. Microbiol. 2002, 25, 46–51. [Google Scholar] [CrossRef] [Green Version]
  165. Dupraz, L.; Magniez, A.; Rolhion, N.; Rolhion, N.; Richard, M.L.; Da Costa, G.; Touch, S.; Mayeur, C.; Planchais, J.; Agus, A.; et al. Gut microbiota-derived short-chain fatty acids regulate IL-17 production by mouse and human intestinal γδ T cells. Cell Rep. 2021, 36, 109332. [Google Scholar] [CrossRef]
  166. Requena, T.; Martínez-Cuesta, M.C.; Peláez, C. Diet and microbiota linked in health and disease. Food Func. 2018, 9, 688–704. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  167. Fernández-Quintela, A.; Milton-Laskibar, I.; Trepiana, J.; Gómez-Zorita, S.; Kajarabille, N.; Léniz, A.; González, M.; Portillo, M.P. Key Aspects in Nutritional Management of COVID-19 Patients. J. Clin. Med. 2020, 9, 2589. [Google Scholar] [CrossRef] [PubMed]
  168. Robinson, C.P.; Busl, K.M. Neurologic Manifestations of Severe Respiratory Viral Contagions. Crit. Care Explor. 2020, 2, e0107. [Google Scholar] [CrossRef] [PubMed]
  169. Einarsson, G.G.; Zhao, J.; LiPuma, J.J.; Downey, D.G.; Tunney, M.M.; Elborn, J.S. Community analysis and co-occurrence patterns in airway microbial communities during health and disease. ERJ Open Res. 2019, 5, 00128–02017. [Google Scholar] [CrossRef]
  170. Baig, A.M.; Khaleeq, A.; Ali, U.; Syeda, H. Evidence of the COVID-19 virus targeting the CNS: Tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS Chem. Neurosci. 2020, 11, 995–998. [Google Scholar] [CrossRef] [Green Version]
  171. Zhu, N.; Zhang, D.; Wang, W.; Li, X.; Yang, B.; Song, J.; Zhao, X.; Huang, B.; Shi, W.; Lu, R.; et al. China Novel Coronavirus Investigating and Research Team. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N. Engl. J. Med. 2020, 382, 727–733. [Google Scholar] [CrossRef]
  172. Yavarpour-Bali, H.; Ghasemi-Kasman, M. Update on neurological manifestations of COVID-19. Life Sci. 2020, 257, 118063. [Google Scholar] [CrossRef]
  173. Arbour, N.; Day, R.; Newcombe, J.; Talbot, P.J. Neuro invasion by human respiratory coronaviruses. J. Virol. 2000, 74, 8913–8921. [Google Scholar] [CrossRef] [Green Version]
  174. Lau, K.K.; Yu, W.C.; Chu, C.M.; Lau, S.T.; Sheng, B.; Yuen, K.Y. Possible central nervous system infection by SARS coronavirus. Emerg. Infect. Dis. 2004, 10, 342–344. [Google Scholar] [CrossRef]
  175. Yeh, E.A.; Collins, A.; Cohen, M.E.; Duffner, P.K.; Faden, H. Detection of coronavirus in the central nervous system of a child with acute disseminated encephalomyelitis. Pediatrics 2004, 113, e73–e76. [Google Scholar]
  176. Wu, Y.; Xu, X.; Chen, Z.; Duan, J.; Hashimoto, K.; Yang, L.; Liu, C.; Yang, C. Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain Behav. Immun. 2020, 87, 18–22. [Google Scholar] [CrossRef]
  177. Keni, R.; Alexander, A.; Nayak, P.G.; Mudgal, J.; Nandakumar, K. COVID-19: Emergence, spread, possible treatments, and global burden. Front. Public Health 2020, 8, 216. [Google Scholar] [CrossRef]
  178. Murta, V.; Villarreal, A.; Ramos, A.J. Severe acute respiratory syndrome coronavirus 2 impact on the Central nervous system: Are astrocytes and microglia Main players or merely bystanders? ASN Neuro 2020, 12, 1759091420954960. [Google Scholar] [CrossRef]
  179. Zhou, Z.; Kang, H.; Li, S.; Zhao, X. Understanding the neurotropic characteristics of SARS-CoV-2: From neurological manifestations of COVID-19 to potential neurotropic mechanisms. J. Neurol. 2020, 267, 2179–2184. [Google Scholar] [CrossRef]
  180. De Maio, F.; Posteraro, B.; Ponziani, F.R.; Cattani, P.; Gasbarrini, A.; Sanguinetti, M. Nasopharyngeal Microbiota Profiling of SARS-CoV-2 Infected Patients. Biol. Proced. Online 2020, 22, 18. [Google Scholar] [CrossRef]
  181. Ventero, M.P.; Cuadrat, R.; Vidal, I.; Andrade, B.; Molina-Pardines, C.; Haro-Moreno, J.M.; Coutinho, F.H.; Merino, E.; Regitano, L.; Silveira, C.B.; et al. Nasopharyngeal Microbial Communities of Patients Infected With SARS-CoV-2 That Developed COVID-19. Front. Microbiol. 2021, 12, 637430. [Google Scholar] [CrossRef]
  182. Larsen, J.M. The immune response to Prevotella bacteria in chronic inflammatory disease. Immunology 2017, 151, 363–374. [Google Scholar] [CrossRef] [Green Version]
  183. Wu, D.; Yang, X.O. TH17 responses in cytokine storm of COVID-19: An emerging target of JAK2 inhibitor Fedratinib. J. Microbiol. Immunol. Infect. 2020, 53, 368–370. [Google Scholar] [CrossRef]
  184. Khan, A.A.; Khan, Z. COVID-2019-associated overexpressed Prevotella proteins mediated host-pathogen interactions and their role in coronavirus outbreak. Bioinformatics 2020, 36, 4065–4069. [Google Scholar] [CrossRef]
  185. Gu, S.; Chen, Y.; Wu, Z.; Chen, Y.; Gao, H.; Lv, L.; Guo, F.; Zhang, X.; Luo, R.; Huang, C.; et al. Alterations of the Gut Microbiota in Patients with COVID-19 or H1N1 Influenza. Clin. Infect. Dis. 2020, 71, 2669–2678. [Google Scholar] [CrossRef]
  186. Shen, Z.; Xiao, Y.; Kang, L.; Ma, W.; Shi, L.; Zhang, L.; Zhou, Z.; Yang, J.; Zhong, J.; Yang, D.; et al. Genomic Diversity of Severe Acute Respiratory Syndrome-Coronavirus 2 in Patients with Coronavirus Disease 2019. Clin. Infect. Dis. 2020, 71, 713–720. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  187. Khatiwada, S.; Subedi, A. Lung microbiome and coronavirus disease 2019 (COVID-19): Possible link and implications. Hum. Microbiome J. 2020, 17, 100073. [Google Scholar] [CrossRef] [PubMed]
  188. Rabaan, A.A.; Al-Ahmed, S.H.; Haque, S.; Sah, R.; Tiwari, R.; Malik, Y.S.; Dhama, K.; Yatoo, M.I.; Bonilla-Aldana, D.K.; Rodriguez-Morales, A.J. SARS-CoV-2, SARS-CoV, and MERS-CoV: A comparative overview. Infez. Med. 2020, 28, 174–184. [Google Scholar]
  189. Fotuhi, M.; Mian, A.; Meysami, S.; Raji, C.A. Neurobiology of COVID-19. J. Alzheimers Dis. 2020, 76, 3–19. [Google Scholar] [CrossRef] [PubMed]
  190. Spence, J.D.; de Freitas, G.R.; Pettigrew, L.C.; Ay, H.; Liebeskind, D.S.; Kase, C.S.; Del Brutto, O.H.; Hankey, J.; Venketasubramanian, N. Mechanisms of stroke in COVID-19. Cerebrovasc. Dis. 2020, 49, 451–458. [Google Scholar] [CrossRef]
  191. Brown, E.E.; Kumar, S.; Rajji, T.K.; Pollock, B.G.; Mulsant, B.H. Anticipating and mitigating the impact of the COVID-19 pandemic on Alzheimer’s disease and related dementias. Am. J. Geriatr. Psychiatry 2020, 28, 712–721. [Google Scholar] [CrossRef]
  192. Zhang, Q.; Schultz, J.L.; Aldridge, G.M.; Simmering, E.; Narayanan, N.S. Coronavirus disease 2019 case fatality and Parkinson’s disease. Mov. Disord. 2020, 35, 1914–1915. [Google Scholar] [CrossRef]
  193. Van der Heide, A.; Meinders, M.J.; Bloem, B.R.; Helmich, R.C. The impact of the COVID-19 pandemic on psychological distress, physical activity, and symptom severity in parkinson’s disease. J. Parkinsons Dis. 2020, 10, 1355–1364. [Google Scholar] [CrossRef]
  194. Guo, D.; Han, B.; Lu, Y.; Lv, C.; Fang, X.; Zhang, Z.; Liu, Z.; Wang, X. Influence of the COVID-19 pandemic on quality of life of patients with parkinson’s disease. Parkinsons Dis. 2020, 2020, 1216568. [Google Scholar] [CrossRef]
  195. Besnard, S.; Nardin, C.; Lyon, E.; Debroucker, T.; Arjmand, R.; Moretti, R.; Pochat, H. Electroencephalographic abnormalites in SARS-CoV-2 patients. Front. Neurol. 2020, 11, 582794. [Google Scholar] [CrossRef]
  196. Antony, A.R.; Haneef, Z. Systematic review of EEG findings in 617 patients diagnosed with COVID-19. Seizure 2020, 83, 234–241. [Google Scholar] [CrossRef] [PubMed]
  197. Mazza, M.G.; De Lorenzo, R.; Conte, C.; Poletti, S.; Vai, B.; Bollettini, I.; Melloni, E.M.T.; Furlan, R.; Ciceri, F.; Rovere-Querini, P.; et al. Anxiety and depression in COVID-19 survivors: Role of inflammatory and clinical predictors. Brain Behav. Immun. 2020, 89, 594–600. [Google Scholar] [CrossRef]
Microorganisms 10 01405 g001 550
Figure 1. (A) Nasal microbiota interactions with the olfactory system that influence olfactory functions. Microorganisms enter through respiratory airways and interact with olfactory receptor cells (Orc) of the neuroepithelium (NE) that protrude through the perforations in the cribriform plate (CP) and extend its connections with olfactory neurons (ON) in the olfactory bulb (OB). The tuft of ONs forms the olfactory tract (OT), which connects to other olfactory cortices (OC); (B) Interactions of olfactory neurons within the brain. The tuft of olfactory nerve fibers from OT receives connections from the neurotransmitter system and OC. ON interacts with OC, hippocampus (HC), amygdala (AG), entorhinal cortex (EC), hypothalamus (HT), and locus coeruleus and reaches the reticular formation system (RFS), where the visceral responses of smell can be produced.
Figure 1. (A) Nasal microbiota interactions with the olfactory system that influence olfactory functions. Microorganisms enter through respiratory airways and interact with olfactory receptor cells (Orc) of the neuroepithelium (NE) that protrude through the perforations in the cribriform plate (CP) and extend its connections with olfactory neurons (ON) in the olfactory bulb (OB). The tuft of ONs forms the olfactory tract (OT), which connects to other olfactory cortices (OC); (B) Interactions of olfactory neurons within the brain. The tuft of olfactory nerve fibers from OT receives connections from the neurotransmitter system and OC. ON interacts with OC, hippocampus (HC), amygdala (AG), entorhinal cortex (EC), hypothalamus (HT), and locus coeruleus and reaches the reticular formation system (RFS), where the visceral responses of smell can be produced.
Microorganisms 10 01405 g001
Microorganisms 10 01405 g002 550
Figure 2. Barriers of the central nervous system. (A) The blood–brain barrier (BBB) is lined with tightly packed endothelial cells; (B) The blood–cerebrospinal fluid (CSF) barrier (BCSFB) is lined with a layer of endothelial cells and choroid plexus epithelial cells comprising CSF in between the choroid plexus epithelial cell layers. The possible means of bacterial entries, such as (C) transcellular transportation; (D) paracellular transportation; and (E) Trojan-horse mechanism. The illustration was created with BioRender.com.
Figure 2. Barriers of the central nervous system. (A) The blood–brain barrier (BBB) is lined with tightly packed endothelial cells; (B) The blood–cerebrospinal fluid (CSF) barrier (BCSFB) is lined with a layer of endothelial cells and choroid plexus epithelial cells comprising CSF in between the choroid plexus epithelial cell layers. The possible means of bacterial entries, such as (C) transcellular transportation; (D) paracellular transportation; and (E) Trojan-horse mechanism. The illustration was created with BioRender.com.
Microorganisms 10 01405 g002
Microorganisms 10 01405 g003 550
Figure 3. Illustration representing the correlation between nasal microbial dysbiosis and chronic rhinosinusitis (CRS), Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS). C. pneumonia (Chlamydia pneumoniae); P. acnes (Propionibacterium acnes); C. diphtheria (Corynebacterium diphtheriae); B. wexlerae (Blautia wexlerae); L. pectinoschiza (Lachnospira pectinoschiza); P. humerusii (Propionibacterium humerusii); S. aureus (Staphylococcus aureus).
Figure 3. Illustration representing the correlation between nasal microbial dysbiosis and chronic rhinosinusitis (CRS), Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS). C. pneumonia (Chlamydia pneumoniae); P. acnes (Propionibacterium acnes); C. diphtheria (Corynebacterium diphtheriae); B. wexlerae (Blautia wexlerae); L. pectinoschiza (Lachnospira pectinoschiza); P. humerusii (Propionibacterium humerusii); S. aureus (Staphylococcus aureus).
Microorganisms 10 01405 g003
Table
Table 1. Representing different microbial communities residing in the respiratory tract across the ages.
Table 1. Representing different microbial communities residing in the respiratory tract across the ages.
S. No.SamplesExperimental SubjectsStudy MethodologyCommensal MicrobiotaReference
1Anterior nares and OropharynxElderly participants (age 68 to 96 years)16S rRNA gene sequencingPropionibacterium spp., Corynebacterium spp., Staphylococcus spp., Veillonella spp., Streptococcus spp.[16]
2Nasal and OropharynxElderly participants (age ≥ 65 years); 152 controls and 152 patients with RTIs.16S rRNA gene sequencing, quantitative real-time PCR, and culture.In the nasal passage: Corynebacterium, Staphylococcus, Moraxella, Dolosigranulum, Streptococcus, Haemophilus, Peptoniphilus, Cutibacterium, Anaerococcus, and Enterobacteriaceae. Less abundantly: Pseudomonas and Neisseria.
In the oropharynx: Prevotella, Veillonella, Streptococcus, Neisseria, Fusobacterium, Leptotrichia, Haemophilus, Rothia, Porphyromonas, Actinobacillus, Lactobacillus, Staphylococcus.		[19]
3URT, NasopharynxHealthy children (n = 60); Age 1.5, 6, 12, and 24 months.16S rRNA-based pyrosequencingAt 1.5 months of age: Staphylococcus sp., Corynebacterium sp., Moraxella sp.
At 1.5 to 6 months of age: M. catarrhalis, Dolosigranulum sp., Corynebacterium sp.
At 6 months of age: Staphylococcus aureus
In the first 2 years of age: Moraxella sp., Dolosigranulum sp., Corynebacterium sp., Haemophilus sp., Streptococcus sp.		[20]
4URT, NasopharynxInfants exclusively breastfed (n = 101) and exclusively fed formula (n = 101); Age 6 weeks to 6 months.16S-based GS-FLX-titanium-pyrosequencingBreastfed infants: Abundance of Dolosigranulum sp., Corynebacterium, pseudodiphteriticum, C. propinquum, C. accolens, C. fastidiosum, or C. segmentosum, Decreased abundance of Staphylococcus spp., Prevotella sp., Veilonella sp.
Formula-fed infants: Dolosigranulum sp., Corynebacterium sp.		[39]
5URT, NasopharynxA cohort of 234 children, including healthy infants and infants who had experienced acute respiratory infections once.Microbial profiling using 16S rRNA gene deep sequencingStaphylococcus sp., Corynebacterium sp., Alloiococcus sp., Moraxella sp., Haemophilus sp.[41]
6URT-anterior nares (left and right)Healthy adults and hospitalized patients. S. aureus carriers (n = 26) and non-carriers (n = 16).Culture-independent analysis of 16S rRNA sequencingActinobacteria (Propionibacterium sp., Corynebacterium sp.)
Firmicutes (Staphylococcus spp.), Proteobacteria (Enterobacter sp.)		[58]
7URT-anterior naresA healthy cohort of 236 subjects from the Human Microbiome Project.16S rRNA gene sequencingMoraxella sp., Corynebacterium sp., Propionibacterium sp., Staphylococcus sp.[59]
8URT-anterior and posterior vestibule, inferior and middle meatuses of the nasal passageA cohort of CR and CR-free individuals (n = 79).Illumina paired-end sequencing of the V1-V2 variable regions of the 16S rRNA gene.Staphylococcusaureus, Moraxella sp., Finegoldia magna, Prevotella sp., Staphylococcus epidermidis, Haemophilus influenzae.[60]
9URT, NasopharynxThe unselected birth cohort of healthy children born by Cesarean (n = 40) and vaginal birth (n = 62); Age (birth to 6 months).Constructing the phylogenetic library by amplifying hypervariable v4 region of 6s rRNA geneStaphylococcus aureus, Streptococcus viridans, S. pneumoniae, Corynebacterium pseudodiphteriticum, C. propinquum, Dolosigranulum pigrum, Moraxella catarrhalis, M. nonliquefaciens, Haemophilus influenzae[61]
10The right and left nasopharynx and oropharynxSmoking (n = 29) and non-smoking (n = 33) healthy asymptomatic adults16S rRNA-based pyrosequencingThe nasopharynx is dominated by Firmicutes, Proteobacteria, Bacteroidetes, Actinobacteria, and Campylobacter sp. Streptococcus, Shigella, Acinetobacter, and Corynebacterium sp.
The oropharynx is dominated by Streptococcus Bacteroidetes, Firmicutes, Proteobacteria, and Fusobacteria.
Prevotella, Fusobacterium, Neisseria, Leptotrichia, and Veillonella sp.		[62]
11Nasal cavity and dust samplesA cohort of healthy volunteers (n = 50) without a history of respiratory system diseases.Standard mycological techniques based on gross cultural and microscopic morphologyAspergillus, Penicillium, Yeast, Alternaria and Rhizopus[63]
12NasopharynxChildren (Age < 6 years; n = 135) with and without severe acute respiratory infections (SARI)Metagenomic analysis based on Next-Generation SequencingIn children with SARI: Members of the Paramyxoviridae, Coronaviridae, Parvoviridae, Orthomyxoviridae, Picornaviridae, Anelloviridae and Adenoviridae
In children without SARI: Members of Anelloviridae		[64]
13Oropharynx
Nasopharynx Bronchoalveolar		Children with or without lung infection (n = 78)16S rRNA gene sequencingMoraxella, Haemophilus, Staphylococcus, Streptococcus, Neisseria, Prevotella and Corynebacterium spp.[65]
14BronchoalveolarAsymptomatic subjects. Never-smokers (n = 9), former-smokers (n = 14), and current-smokers (n = 6).16S rRNA gene sequencingPropionibacterium, Staphylococcus, Corynebacterium, Stenotrophomonas, Pseudomonas, Prevotella, Veillonella,
Streptococcus, Fusobacterium,
Porphyromonas, Sphingomonas,
Tropheryma, Acidovorax, and Asticcacaulis		[66]
15oropharynx and nasopharynxHealthy children (Age 1 to 4.5 years; n =51) and accompanying parents (n = 19).Molecular profiling of the bacterial 16S rRNA geneOropharynx of both children and adults: Streptococcus sp., Rothia sp., Prevotella sp. Gemella sp., Veillonella sp., Fusobacteria sp., Haemophilus spp., Neisseria sp.
Nasopharynx of adults: Firmicutes sp., Staphylococcus sp., Streptococcus sp., Bacteriodetes sp., Prevotella sp., Actinobacteria sp., Corynebacterium sp., Rothia sp., and Propionibacterium sp.,
Nasopharynx of children: Moraxella spp., Enterobacteriaceae sp., Haemophilus sp., Enterococcus sp.		[67]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Thangaleela, S.; Sivamaruthi, B.S.; Kesika, P.; Bharathi, M.; Chaiyasut, C. Nasal Microbiota, Olfactory Health, Neurological Disorders and Aging—A Review. Microorganisms 2022, 10, 1405. https://doi.org/10.3390/microorganisms10071405

AMA Style

Thangaleela S, Sivamaruthi BS, Kesika P, Bharathi M, Chaiyasut C. Nasal Microbiota, Olfactory Health, Neurological Disorders and Aging—A Review. Microorganisms. 2022; 10(7):1405. https://doi.org/10.3390/microorganisms10071405

Chicago/Turabian Style

Thangaleela, Subramanian, Bhagavathi Sundaram Sivamaruthi, Periyanaina Kesika, Muruganantham Bharathi, and Chaiyavat Chaiyasut. 2022. "Nasal Microbiota, Olfactory Health, Neurological Disorders and Aging—A Review" Microorganisms 10, no. 7: 1405. https://doi.org/10.3390/microorganisms10071405

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop