Núria Mach
email: nuria.mach@inrae.fr

The forecasting power of the mucin-microbiome axis in livestock respiratory diseases

Keywords: livestock, mucin, microbiome, ncRNAs, respiratory diseases

Complex respiratory diseases are a significant challenge for the livestock industry worldwide. These diseases cause severe economic losses but also have a considerable impact on animal health and welfare. One of the first lines of pathogen defense combines the respiratory tract mucus, a highly viscous material primarily formed by mucin, and a thriving multi-kingdom microbial ecosystem, referred to herein as the mucin-microbiome axis. This axis can be considered a mighty two-edged sword, as its usual function is to protect from unwanted substances and organisms at one arm's length, while its dysfunction may be a clue for pathogen infection and respiratory disease onset. We further learned that the structure and function of this axis might be modulated by noncoding regulatory RNAs (e.g., microRNAs, long RNAs). This opinion paper unearths the current understanding of the triangular relationship of mucins, holobiont, and noncoding RNAs and the wide range of functions exhibited by the mucinmicrobiome axis under respiratory infection settings. There is a need to look at these molecular underpinnings that dictate distinct health and disease outcomes to implement effective prevention, surveillance, and timely intervention strategies tailored to the different epidemiological contexts.

Introduction

Complex respiratory diseases are a significant problem in livestock production, particularly in intensive systems. These diseases can cause significant economic losses due to reduced productivity, increased morbidity, premature mortality, treatment costs, and severe consequences for public health and the environment [START_REF] Bond | Upper and lower respiratory tract microbiota in horses: Bacterial communities associated with health and mild asthma (inflammatory airway disease) and effects of dexamethasone[END_REF][START_REF] Oladunni | EHV-1: A constant threat to the horse industry[END_REF][START_REF] Ericsson | Respiratory dysbiosis and population-wide temporal dynamics in canine chronic bronchitis and non-inflammatory respiratory disease[END_REF][START_REF] Ericsson | Composition and predicted metabolic capacity of upper and lower airway microbiota of healthy dogs in relation to the fecal microbiota[END_REF][START_REF] Mach | The Airway Pathobiome in Complex Respiratory Diseases: A Perspective in Domestic Animals[END_REF] . In livestock physiopathology, there is a growing awareness that infectious agents frequently do not operate alone, and their virulence can be affected by multispecies synergic interactions [START_REF] Bond | Upper and lower respiratory tract microbiota in horses: Bacterial communities associated with health and mild asthma (inflammatory airway disease) and effects of dexamethasone[END_REF][START_REF] Oladunni | EHV-1: A constant threat to the horse industry[END_REF][START_REF] Ericsson | Respiratory dysbiosis and population-wide temporal dynamics in canine chronic bronchitis and non-inflammatory respiratory disease[END_REF][START_REF] Ericsson | Composition and predicted metabolic capacity of upper and lower airway microbiota of healthy dogs in relation to the fecal microbiota[END_REF][START_REF] Kuiken | Pathogen surveillance in animals[END_REF][START_REF] Blakebrough-Hall | An evaluation of the economic effects of bovine respiratory disease on animal performance, carcass traits, and economic outcomes in feedlot cattle defined using four BRD diagnosis methods[END_REF][START_REF] Holt | BPEX Pig Health Scheme: A useful monitoring system for respiratory disease control in pig farms?[END_REF] . Consequently, a central finding of disease complexes involves interactions among holobionts (the host and the many other microorganisms living in or around it [START_REF] Simon | Host-microbiota interactions: From holobiont theory to analysis[END_REF] ) and multiple etiological agents [START_REF] Mach | The Airway Pathobiome in Complex Respiratory Diseases: A Perspective in Domestic Animals[END_REF] .

Undoubtedly, complex respiratory diseases entail multifactorial processes whose mechanisms are still not fully understood. New evidence has shown that the airway microbiota, defined as the complex community of microorganisms living in the respiratory tract, including bacteria, eukaryotes (especially yeast and protists), and archaea [START_REF] Zeineldin | Contribution of the Mucosal Microbiota to Bovine Respiratory Health[END_REF] , might act as a gatekeeper that provides resistance to infection on the mucosal surface [START_REF] Li | The commensal microbiota and viral infection: A comprehensive review[END_REF][START_REF] Man | The microbiota of the respiratory tract: Gatekeeper to respiratory health[END_REF] . Under normal physiological conditions, the diverse community of commensal microorganisms maintains a mutualistic relationship with the host, acting as the prime educator and maintainer of the airway's innate and adaptive immune functions [START_REF] Mach | The Airway Pathobiome in Complex Respiratory Diseases: A Perspective in Domestic Animals[END_REF][START_REF] Zeineldin | Contribution of the Mucosal Microbiota to Bovine Respiratory Health[END_REF] . Classifying healthy versus diseased individuals based on their airway microbiome has been done successfully for ruminants [START_REF] Zeineldin | Meta-analysis of bovine respiratory microbiota: Link between respiratory microbiota and bovine respiratory health[END_REF][START_REF] Mcmullen | Topography of the respiratory tract bacterial microbiota in cattle[END_REF][START_REF] Zeineldin | Contribution of the Mucosal Microbiota to Bovine Respiratory Health[END_REF][START_REF] Gaeta | Deciphering upper respiratory tract microbiota complexity in healthy calves and calves that develop respiratory disease using shotgun metagenomics[END_REF][START_REF] Chai | Bovine respiratory microbiota of feedlot cattle and its association with disease[END_REF][START_REF] Holman | The nasopharyngeal microbiota of feedlot cattle that develop bovine respiratory disease[END_REF][START_REF] Nicola | Characterization of the upper and lower respiratory tract microbiota in Piedmontese calves[END_REF][START_REF] Zeineldin | Disparity in the nasopharyngeal microbiota between healthy cattle on feed, at entry processing and with respiratory disease[END_REF][START_REF] Mcmullen | Comparison of the nasopharyngeal bacterial microbiota of beef calves raised without the use of antimicrobials between healthy calves and those diagnosed with bovine respiratory disease[END_REF][START_REF] Timsit | Effects of nasal instillation of a nitric oxide-releasing solution or parenteral administration of tilmicosin on the nasopharyngeal microbiota of beef feedlot cattle at high-risk of developing respiratory tract disease[END_REF] , pigs [START_REF] Wang | Comparison of Oropharyngeal Microbiota in Healthy Piglets and Piglets With Respiratory Disease[END_REF][START_REF] Correa-Fiz | Antimicrobial removal on piglets promotes health and higher bacterial diversity in the nasal microbiota[END_REF][START_REF] Correa-Fiz | Piglet nasal microbiota at weaning may influence the development of Glässer's disease during the rearing period[END_REF][START_REF] Mahmmod | Variations in association of nasal microbiota with virulent and non-virulent strains of Glaesserella (Haemophilus) parasuis in weaning piglets[END_REF] , horses [START_REF] Bond | Effects of nebulized dexamethasone on the respiratory microbiota and mycobiota and relative equine herpesvirus-1, 2, 4, 5 in an equine model of asthma[END_REF] , and chickens [START_REF] Ngunjiri | Farm stage, bird age, and body site dominantly affect the quantity, taxonomic composition, and dynamics of respiratory and gut microbiota of commercial layer chickens[END_REF][START_REF] Yitbarek | Commensal gut microbiota can modulate adaptive immune responses in chickens vaccinated with whole inactivated avian influenza virus subtype H9N2[END_REF][START_REF] Yitbarek | Gut microbiota-mediated protection against influenza virus subtype H9N2 in chickens is associated with modulation of the innate responses[END_REF] . However, we can take one step further and broaden our view of the dynamics of respiratory diseases in livestock to include an additional aspect of the complex system: the respiratory mucus.

While mucus has historically been viewed as a simple physical barrier, recent work has suggested that mucins, the major gel-forming components of mucus, have many structural and functional roles in the respiratory system [START_REF] Ridley | Mucins: the frontline defence of the lung[END_REF][START_REF] Atanasova | Strategies for measuring airway mucus and mucins[END_REF][START_REF] Rose | Respiratory Tract Mucin Genes and Mucin Glycoproteins in Health and Disease[END_REF][START_REF] Thornton | Structure and Function of the Polymeric Mucins in Airways Mucus[END_REF][START_REF] Hansson | Mucus and mucins in diseases of the intestinal and respiratory tracts[END_REF][START_REF] Thai | Regulation of Airway Mucin Gene Expression[END_REF] . Mucins are high-molecular-weight glycosylated proteins with hundreds of branching chain sugar (O-linked glycans), representing up to 80% of mucin weight. Through this rich biochemistry, O-linked glycans on mucins (collectively termed glycome) confer a wealth of physical and functional properties in the respiratory tract [START_REF] Shipunov | Glycome assessment in patients with respiratory diseases[END_REF] . First, the glycans on mucins provide a physical barrier that traps and clears inhaled particles and a chemical barrier that neutralizes toxins, allergens, pollutants, and pathogens [START_REF] Atanasova | Strategies for measuring airway mucus and mucins[END_REF][START_REF] Rose | Respiratory Tract Mucin Genes and Mucin Glycoproteins in Health and Disease[END_REF][START_REF] Reily | Glycosylation in health and disease[END_REF][START_REF] Qin | The host glycomic response to pathogens[END_REF][START_REF] Schnaar | Glycans and glycan-binding proteins in immune regulation: A concise introduction to glycobiology for the allergist[END_REF][START_REF] Brazil | Finding the sweet spot: glycosylation mediated regulation of intestinal inflammation[END_REF] . This limits the growth and colonization of pathogens and their adhesion and invasion of the respiratory epithelium. Thus, in addition to their role as a physical and chemical barrier, glycans on mucins have also been shown to have immune-modulating properties and may regulate inflammation [START_REF] Hansson | Mucus and mucins in diseases of the intestinal and respiratory tracts[END_REF] . However, mucins' glycans are considered a double-edged sword, as they can aid invading pathogens to subvert host immune machinery. On top of these protective properties, mucin glycome affects the respiratory microbiota composition and functionality while serving as an environmental niche and a carbon and nitrogen source [START_REF] Bergstrom | Core 1-and 3-derived Oglycans collectively maintain the colonic mucus barrier and protect against spontaneous colitis in mice[END_REF][START_REF] Rose | Respiratory Tract Mucin Genes and Mucin Glycoproteins in Health and Disease[END_REF][START_REF] Chatterjee | Defensive Properties of Mucin Glycoproteins during Respiratory Infections-Relevance for SARS-CoV-2. Garsin DA[END_REF] . Reciprocally, the respiratory tract microbiota's composition and activity can influence mucins' production and quality while stimulating the immune system and protecting against pathogen infection [START_REF] Pérez-Cobas | Ecology of the respiratory tract microbiome[END_REF] . Any disruption in the display or function of mucins and the glycosylation pattern of their glycans can lead to dysbiosis and respiratory diseases and potentially increase the risk of respiratory infections in livestock.

The next complexity is that mucin production, secretion, and glycosylation are highly regulated by noncoding ncRNAs (ncRNAs) at the genomic level. The glycans on mucins are products of multiple glycosyltransferases and glycosidases working in a coordinated manner to synthesize structures appended to proteins [START_REF] Thu | Sweet Control: MicroRNA Regulation of the Glycome[END_REF] . Increasing evidence shows that ncRNAs are critical regulators of cellular and biological processes in living organisms, including mucin modifications [START_REF] Thu | Sweet Control: MicroRNA Regulation of the Glycome[END_REF][START_REF] Agrawal | Mapping posttranscriptional regulation of the human glycome uncovers microRNA defining the glycocode[END_REF] . The research community has classified the ncRNAs based on their length: small ncRNAs (sncRNAs) and long ncRNAs (lncRNAs) [START_REF] Weber | The MicroRNA Spectrum in 12 Body Fluids[END_REF] . One type of ncRNA implicated in mucin glycome regulation is microRNAs (miRNAs) [START_REF] Thu | Sweet Control: MicroRNA Regulation of the Glycome[END_REF][START_REF] Agrawal | Mapping posttranscriptional regulation of the human glycome uncovers microRNA defining the glycocode[END_REF][START_REF] Ng | High-Throughput Analysis Reveals miRNA Upregulating α-2,6-Sialic Acid through Direct miRNA-mRNA Interactions[END_REF] . miRNAs are small (~22 nucleotides) RNA molecules that bind to messenger RNAs (mRNAs) and regulate their translation and stability into proteins. Several miRNAs have been identified to fine-tune the glycan biosynthetic enzymes and regulate the expression of mucin genes in the respiratory tract of humans, including miR-34b/c 50 , miR-146a [START_REF] Zhong | MiR-146a negatively regulates neutrophil elastase-induced MUC5AC secretion from 16HBE human bronchial epithelial cells[END_REF] , miR-378 [START_REF] Skrzypek | Interplay Between Heme Oxygenase-1 and miR-378 Affects Non-Small Cell Lung Carcinoma Growth, Vascularization, and Metastasis[END_REF] , and miR-141 [START_REF] Siddiqui | Epithelial miR-141 regulates IL-13-induced airway mucus production[END_REF] .

Determining the underlying causes of complex respiratory disease in farm animals is complicated. Species of veterinary interest are subjected to different host variables, environments, and pathogens, which could all play a role in disease, alone or in concert. From a One-Health-One Welfare perspective, this opinion paper aims to give insights into the potential avenues of complex respiratory disease, building on the surge of recent primary research to debate different aspects of the complex and intricate relationships between pathogens, the holobiont, mucins, and their genetic regulation. Underpinning these mechanisms will be crucial to determine how these can be harnessed to develop novel interventions to prevent disease infection and improve animal health and welfare.

Food-producing animal complexes: holobionts in a polymicrobial environment

Respiratory complex diseases constitute a significant cause of morbidity and mortality in livestock, in which prevention and prompt diagnosis, and targeted treatments are essential [START_REF] Bond | Upper and lower respiratory tract microbiota in horses: Bacterial communities associated with health and mild asthma (inflammatory airway disease) and effects of dexamethasone[END_REF][START_REF] Oladunni | EHV-1: A constant threat to the horse industry[END_REF][START_REF] Ericsson | Respiratory dysbiosis and population-wide temporal dynamics in canine chronic bronchitis and non-inflammatory respiratory disease[END_REF][START_REF] Ericsson | Composition and predicted metabolic capacity of upper and lower airway microbiota of healthy dogs in relation to the fecal microbiota[END_REF][START_REF] Mach | The Airway Pathobiome in Complex Respiratory Diseases: A Perspective in Domestic Animals[END_REF] . For example, the bovine respiratory disease complex (BRDC) is a leading cause of morbidity and economic losses in wealthy countries, especially for newly feedlot calves, ranging from 30% in Belgium, [START_REF] Van Leenen | Comparison of bronchoalveolar lavage fluid bacteriology and cytology in calves classified based on combined clinical scoring and lung ultrasonography[END_REF] to 49% in Switzerland, and up to 90% in the U.S.A. [START_REF] Hilton | BRD in 2014: Where have we been, where are we now, and where do we want to go?[END_REF] . Similarly, sheep respiratory disease affects many animals [START_REF] Lacasta | Preface: Special issue on sheep respiratory diseases[END_REF] , leading to significant indirect losses, such as carcass condemnations, treatments, and decreased production [START_REF] Lacasta | Preface: Special issue on sheep respiratory diseases[END_REF] . Analogously, the prevalence of the porcine respiratory disease complex (PRDC) in finishing pigs continues to grow [START_REF] Qin | Viral communities associated with porcine respiratory disease complex in intensive commercial farms in Sichuan province, China[END_REF] , with a morbidity rate ranging from 10% in Denmark [START_REF] Hansen | An investigation of the pathology and pathogens associated with porcine respiratory disease complex in Denmark[END_REF] to 40% in the U.S.A [START_REF] Harms | Three cases of porcine respiratory disease complex associated with porcine circovirus type 2 infection[END_REF] . As for common livestock animals, the respiratory disease complex in commercial birds remains widespread [START_REF] Guinat | Spatio-temporal patterns of highly pathogenic avian influenza virus subtype H5N8 spread, France, 2016 to 2017[END_REF][START_REF] Filaire | Highly Pathogenic Avian Influenza A(H5N8) Clade 2.3.4.4b Virus in Dust Samples from Poultry Farms, France, 2021[END_REF] . It has become endemic in different countries, causing subclinical infections, mild respiratory symptoms, and high production losses in birds raised for meat or eggs [START_REF] Samy | Avian respiratory coinfection and impact on avian influenza pathogenicity in domestic poultry: Field and experimental findings[END_REF][START_REF] Guabiraba | Avian colibacillosis: Still many black holes[END_REF][START_REF] Awad | An overview of infectious bronchitis virus in chickens[END_REF][START_REF] Patel | Metagenomic of clinically diseased and healthy broiler affected with respiratory disease complex[END_REF] .

Complex respiratory diseases involve interactions among holobionts and multispecies synergistic etiological agents [START_REF] Mach | The Airway Pathobiome in Complex Respiratory Diseases: A Perspective in Domestic Animals[END_REF] . More than one pathogen-one disease paradigm is needed to explain complex respiratory disorders [START_REF] Vayssier-Taussat | Emerging horizons for tick-borne pathogens: From the "one pathogen-one disease" vision to the pathobiome paradigm[END_REF] . Synergistic interactions between pathogens often occur through mechanisms such as chemical signaling influencing gene expression or metabolic exchange/complementarity to avoid competition for nutrients and improve the metabolic ability of microbial consortium (Mach and Clark 2017b; Mazel-Sanchez et al. 2019). A plethora of examples in ruminants and swine illustrates the framework for co-infection between pathogens (Gaudino et al. 2023), especially under intensive production, where animal density and stressing conditions are increased, and breeding programs are overly focused on enhancing traits related to production instead of robustness and disease resistance. In this context, multiple viral agents can contribute to the development of BRDC [START_REF] Zeineldin | Meta-analysis of bovine respiratory microbiota: Link between respiratory microbiota and bovine respiratory health[END_REF][START_REF] Zeineldin | Contribution of the Mucosal Microbiota to Bovine Respiratory Health[END_REF][START_REF] Chai | Bovine respiratory microbiota of feedlot cattle and its association with disease[END_REF][START_REF] Holman | The nasopharyngeal microbiota of feedlot cattle that develop bovine respiratory disease[END_REF][START_REF] Alexander | The role of the bovine respiratory bacterial microbiota in health and disease[END_REF] , including bovine viral diarrhea virus (BVDV), bovine respiratory syncytial virus (BRSV), bovine herpes virus 1 (BHV-1), influenza D virus (IDV) (Oliva et al. 2019; Lion et al. 2021), bovine coronavirus (BCoV) [START_REF] Salem | Global Transmission, Spatial Segregation, and Recombination Determine the Long-Term Evolution and Epidemiology of Bovine Coronaviruses[END_REF] and parainfluenza three virus (PI3V) [START_REF] Klima | Pathogens of Bovine Respiratory Disease in North American Feedlots Conferring Multidrug Resistance via Integrative Conjugative Elements. Onderdonk AB[END_REF] . In particular, IDV increases the susceptibility to the respiratory pathogen Mycoplasma bovis (Lion et al. 2021; Gaudino et al. 2023). Mannheimia haemolytica is the primary causative pathogen leading to lung damage in sheep [START_REF] Gupta | The trehalose glycolipid C18Brar promotes antibody and T-cell immune responses to Mannheimia haemolytica and Mycoplasma ovipneumoniae whole cell antigens in sheep[END_REF] . Yet, Mycoplasma ovipneumoniae and PI3V combined with adverse physical and physiological effects of stress predispose Mannheimia haemolytica infection [START_REF] Sharp | Ovine pneumonia[END_REF][START_REF] Gupta | The trehalose glycolipid C18Brar promotes antibody and T-cell immune responses to Mannheimia haemolytica and Mycoplasma ovipneumoniae whole cell antigens in sheep[END_REF] . The swine influenza virus also compensates for the lack of suilysin (cytotoxic protein secreted by Streptococcus suis) in the adherence and invasion process of suilysin-negative Streptococcus suis [START_REF] Meng | Viral coinfection replaces effects of suilysin on streptococcus suis adherence to and invasion of respiratory epithelial cells grown under air-liquid interface conditions[END_REF] . A synergism between nasal Staphylococcus aureus and pathobionts such as Pasteurella multocida and Klebsiella spp. has also been reported in pigs [START_REF] Espinosa-Gongora | Differential analysis of the nasal microbiome of pig carriers or non-carriers of staphylococcus aureus[END_REF] . Co-occurrence between the porcine reproductive and respiratory syndrome virus (PRRSV), Haemophilus parasuis, and Mycoplasma hyorhinis in pig lungs is repeatedly observed [START_REF] Jiang | Illumina MiSeq Sequencing investigation of microbiota in bronchoalveolar lavage fluid and cecum of the swine infected with PRRSV[END_REF] . The swine influenza virus enhances the morbidity of Streptococcus suis infection by decreasing mucociliary clearance, damaging epithelial cells, and facilitating its adherence, colonization, and invasion in the lungs [START_REF] Meng | Efficient suilysin-mediated invasion and apoptosis in porcine respiratory epithelial cells after streptococcal infection under air-liquid interface conditions[END_REF] . Another case in point is the low pathogenic avian influenza viruses (LPAIV) that, during outbreaks, are coupled with coinfections by Mycoplasma gallisepticum, Mycoplasma synoviae, Ornithobacterium rhinotracheale, avian pathogenic Escherichia coli (APEC) and Staphylococcus aureus, increasing the mortality rate (Much et al. 2002; Umar et al. 2020; Filaire et al. 2022) and a marked reduction in egg production of laying hens (Umar et al. 2016). Frequently, these polymicrobial infections significantly hamper therapy, prognosis, and overall disease management. Under such circumstances, prevention is essential.

The untapped potential of airway mucins: the frontline defense of the respiratory tract

The respiratory tract is resistant to environmental injury, despite continuous exposure to pathogens, particles, and toxic chemicals in inhaled air [START_REF] Fahy | Airway Mucus Function and Dysfunction[END_REF] . Such resistance primarily depends on a highly effective defense provided by mucus [START_REF] Fahy | Airway Mucus Function and Dysfunction[END_REF] , a discontinuous, thin, and viscoelastic complex biological fluid that shields the lungs from environmental insults through a process known as mucociliary clearance [START_REF] Song | MUC5B mobilizes and MUC5AC spatially aligns mucociliary transport on human airway epithelium[END_REF] .

The mucus is mostly water (usually > 97%), mucins, non-mucin proteins, ions, lipids, and immunological factors [START_REF] Fahy | Airway Mucus Function and Dysfunction[END_REF][START_REF] Bansil | The biology of mucus: Composition, synthesis and organization[END_REF][START_REF] Nason | Display of the human mucinome with defined O-glycans by gene engineered cells[END_REF] . The major macromolecular mucus components are the mucin Olinked glycoproteins [START_REF] Ridley | Mucins: the frontline defence of the lung[END_REF] . Mucins have a unique structure that distinguishes them from other proteins. First, they have a central protein core rich in Ser, Pro, or Thr-repetitive and nonrepetitive sequences [START_REF] Ridley | Mucins: the frontline defence of the lung[END_REF][START_REF] Hansson | Mucus and mucins in diseases of the intestinal and respiratory tracts[END_REF] . Second, these repeated sequences allow for extensive post-translational modifications, including adding glycans and their glycosylation [START_REF] Reily | Glycosylation in health and disease[END_REF] . The glycans attached to mucins are highly O-glycosylated [START_REF] Ridley | Mucins: the frontline defence of the lung[END_REF] . O-glycosylation is increasingly revealed as a sophisticated informational system that underlies essential biological functions at the cellular and organismal levels [START_REF] Varki | Glycan-based interactions involving vertebrate sialic-acid-recognizing proteins[END_REF] . Glycomics, one of the latest omics system science fields, evaluate the structures and function of glycoproteins in a biological system [START_REF] Kunej | Rise of Systems Glycobiology and Personalized Glycomedicine: Why and How to Integrate Glycomics with Multiomics Science?[END_REF] . The study of the glycome is metaphorically akin to forestry; each glycoprotein comprises glycans (leaves) conjugated to a protein (tree trunk) [START_REF] Critcher | Seeing the forest through the trees: characterizing the glycoproteome[END_REF] . These O-glycans are primarily built from five O-linked monosaccharide components: galactose, N-acetylglucosamine (GlcNAc), and N-acetylgalactosamine (GalNAc), fucose, and sialic acid [START_REF] Ridley | Mucins: the frontline defence of the lung[END_REF][START_REF] Hansson | Mucus and mucins in diseases of the intestinal and respiratory tracts[END_REF] attached to the protein backbone through an oxygen atom. The process of Oglycosylation leads to remarkable O-linked glycan heterogeneity and diversity, with over 200 distinct forms identified on mucins, representing a wealth of biochemical information in a minimum of space. The mucin glycome is analogous to the genome, transcriptome, and proteome but even more dynamic, and it has higher structural complexity that has yet to be fully defined. The human and mouse airway mucin glycome has started to be determined through different omic technologies [START_REF] Shipunov | Glycome assessment in patients with respiratory diseases[END_REF][START_REF] Jia | The Human Lung Glycome Reveals Novel Glycan Ligands for Influenza A Virus[END_REF]100 . However, information needs to be created for livestock. Only two studies have described the N-glycan patterns in pig 101 or chicken 102 lungs, with no information about the O-glycome.

Broadly, there are two classes of mucins, those that remain tethered to cell membranes and those secreted, usually by the goblet cells. The cell-tethered mucins form the basis of a gel-like layer surrounding the cilia (periciliary layer) essential for regular ciliary action to move mucus out of the airways [START_REF] Ridley | Mucins: the frontline defence of the lung[END_REF] and help control the mucus hydration 103 . In contrast, the secreted mucins constitute the mobile mucus layer 103 . Currently, 22 mucins (from MUC1 to MUC21) are identified in humans (denoted with capital letters), and 16 are found in the respiratory tract 104 . The major mucins produced in the airways are the secreted polymeric mucins MUC5AC and MUC5B 105 and the cell-tethered mucins MUC1, MUC4, MUC16, and MUC20 106 . MUC5AC and MUC5B are large (5-50 Mda) polymeric mucins and underpin the structure and organization of the airway's mucus gel [START_REF] Ridley | Mucins: the frontline defence of the lung[END_REF] . MUC5AC is mainly produced in epithelial surface goblet cells in the upper airways, whereas MUC5B is primarily secreted from mucous cells in submucosal glands 105 . Similar conformation is observed in pigs 107,108 .

Most of the physical properties and functions of MUC5B and MUC5AC are governed by the glycosylation patterns of their O-linked glycan structures [START_REF] Ridley | Mucins: the frontline defence of the lung[END_REF] . Indeed, mucin glycosylation patterns are partially responsible for mucus's ability to set protective physical barriers against mechanical and chemical damage from the external environment (Goto et al. 2016) and harmful microorganisms 109 . They also prevent opportunistic microbes' virulence 110,111 , aggregation, and biofilm formation, interfering with pathogen adhesion and cell receptor binding 111 . Glycans on mucins also possess antimicrobial properties and modulate and maintain immune homeostasis 38- 41 . Most of these actions in health are regulated by MUC5B, the major gel-forming mucin in the lung 105 . Conversely, MUC5AC production is much lower in healthy airways but is upregulated, for example, in response to viral infections [START_REF] Ridley | Mucins: the frontline defence of the lung[END_REF] . It acts as a decoy for viral receptors and is essential for an allergic inflammatory challenge [START_REF] Ridley | Mucins: the frontline defence of the lung[END_REF][START_REF] Ridley | Mucins: the frontline defence of the lung[END_REF]108 .

Despite mucins' various defensive and tolerative properties, some pathogens have developed strategies to exploit or manipulate mucins while enhancing their survival and evasion of the immune system. Certain viruses have evolved surfaces that do not adhere to mucins 112 . Other pathogens can degrade the mucus layer and penetrate, release toxins that disrupt the epithelial barrier or modify mucus pH, influencing its viscosity. This is possible thanks to mucin-degrading proteases, chemotaxis, and flagella, which allow pathogens to move inside the mucus, adhere to and produce infection 113 . Once secreted mucus barrier is surpassed, pathogens recognize and target particular classes of cell receptors, such as sialylated glycans, glycosaminoglycans, and cell adhesion molecules, to mediate cellular attachment and entry [START_REF] Varki | Glycan-based interactions involving vertebrate sialic-acid-recognizing proteins[END_REF]114 . Several RNA and DNA viruses use sialylated glycans, e.g., sialic acids (Sia), to access the host cells as initial anchors 115 . In particular, influenza and coronaviruses, two of the most critical zoonotic threats, use sialic acids as cellular entry receptors 116 . More than 60 different Sias are known, which differ in sugar structural modifications [117][118][119] . The presence or absence of an appropriate Sia receptor is a significant determinant of the host tropism of a pathogen. Indeed, studying the glycan structures in the chicken trachea and lung, Suzuki et col 102,120 reported that IAVs bind preferentially to terminal Sia on glycans that possess Sia α2-3Gal, with or without fucosylation and 6-sulfation but not to α2,6-Sia. At the same time, horses' Sia α2,3-Gal is predominantly expressed on the surface of ciliated epithelial cells of the nasal mucosa, trachea, and bronchus 120 . In contrast, the trachea of cows is deficient in both Sia α2,6-Gal and SA α2,3-Gal receptors 121 . All influenza viruses tested in pigs interacted with one or more sialylated N-glycans but not O-glycans or glycolipid-derived glycans 101 . In addition to serving as receptors for viral attachment, sialic acids can also play a role in viral evasion of the host immune system. Pathogens can mimic or mask their surface glycans to resemble those of host cells, making it difficult for the immune system to recognize and target them, otherwise called molecular mimicry. Other pathogens often carry glycan structures on their surface, e.g., sialic acid-specific glycans, to decorate their cell surfaces, aid in host cell attachment, and assist in evading host immunity [START_REF] Schnaar | Glycans and glycan-binding proteins in immune regulation: A concise introduction to glycobiology for the allergist[END_REF]117,[122][123][124][125] . In summary, pathogens exploit their own and host mucin glycans to establish infection and survival.

Airway mucins: sweet and well-coated partners for microbiota

Interestingly, mucins also contain, feed, and dictate the airway microbiome ecosystem [START_REF] Varki | Glycan-based interactions involving vertebrate sialic-acid-recognizing proteins[END_REF] while tolerating their enormous diversity [START_REF] Bergstrom | Core 1-and 3-derived Oglycans collectively maintain the colonic mucus barrier and protect against spontaneous colitis in mice[END_REF]126 and dictating their relationship (Varki 2007a. The respiratory tract microbiome is less diverse than the gut, with Bacteroidetes and Firmicutes as the dominant phyla in mammals [START_REF] Mach | The Airway Pathobiome in Complex Respiratory Diseases: A Perspective in Domestic Animals[END_REF] . High microbial biomass colonizes the mammal upper respiratory tract [START_REF] Zeineldin | Contribution of the Mucosal Microbiota to Bovine Respiratory Health[END_REF] . Conversely, the lower respiratory tract exhibits low biomass, with a significant role in lower airway mucosal immunology 127 . The colonization of the airways occurs shortly after birth, with the maturation of the microbiome occurring fast [START_REF] Mach | The Airway Pathobiome in Complex Respiratory Diseases: A Perspective in Domestic Animals[END_REF] . The airway microbiota composition is mediated mainly by microbial immigration, microbial elimination, and the proliferation rate of bacteria [START_REF] Mach | The Airway Pathobiome in Complex Respiratory Diseases: A Perspective in Domestic Animals[END_REF] . The airway microbiota has been shown to have essential roles in lung development 128 and maintaining homeostasis [START_REF] Zeineldin | Contribution of the Mucosal Microbiota to Bovine Respiratory Health[END_REF]129 . The significance of microbial research, especially when the world is trying to combat deadly infectious viral diseases and microbial resistance, has opened possibilities to explore diseased individuals based on their airway microbiome with much ease. Progress in this branch of science has helped elucidate the holobiont dynamics under respiratory infections in ruminants [START_REF] Zeineldin | Meta-analysis of bovine respiratory microbiota: Link between respiratory microbiota and bovine respiratory health[END_REF][START_REF] Mcmullen | Topography of the respiratory tract bacterial microbiota in cattle[END_REF][START_REF] Zeineldin | Contribution of the Mucosal Microbiota to Bovine Respiratory Health[END_REF][START_REF] Gaeta | Deciphering upper respiratory tract microbiota complexity in healthy calves and calves that develop respiratory disease using shotgun metagenomics[END_REF][START_REF] Chai | Bovine respiratory microbiota of feedlot cattle and its association with disease[END_REF][START_REF] Holman | The nasopharyngeal microbiota of feedlot cattle that develop bovine respiratory disease[END_REF][START_REF] Nicola | Characterization of the upper and lower respiratory tract microbiota in Piedmontese calves[END_REF][START_REF] Zeineldin | Disparity in the nasopharyngeal microbiota between healthy cattle on feed, at entry processing and with respiratory disease[END_REF][START_REF] Mcmullen | Comparison of the nasopharyngeal bacterial microbiota of beef calves raised without the use of antimicrobials between healthy calves and those diagnosed with bovine respiratory disease[END_REF][START_REF] Timsit | Effects of nasal instillation of a nitric oxide-releasing solution or parenteral administration of tilmicosin on the nasopharyngeal microbiota of beef feedlot cattle at high-risk of developing respiratory tract disease[END_REF] , pigs [START_REF] Wang | Comparison of Oropharyngeal Microbiota in Healthy Piglets and Piglets With Respiratory Disease[END_REF][START_REF] Correa-Fiz | Antimicrobial removal on piglets promotes health and higher bacterial diversity in the nasal microbiota[END_REF][START_REF] Correa-Fiz | Piglet nasal microbiota at weaning may influence the development of Glässer's disease during the rearing period[END_REF][START_REF] Mahmmod | Variations in association of nasal microbiota with virulent and non-virulent strains of Glaesserella (Haemophilus) parasuis in weaning piglets[END_REF] , horses [START_REF] Bond | Effects of nebulized dexamethasone on the respiratory microbiota and mycobiota and relative equine herpesvirus-1, 2, 4, 5 in an equine model of asthma[END_REF] , and chickens [START_REF] Ngunjiri | Farm stage, bird age, and body site dominantly affect the quantity, taxonomic composition, and dynamics of respiratory and gut microbiota of commercial layer chickens[END_REF][START_REF] Yitbarek | Commensal gut microbiota can modulate adaptive immune responses in chickens vaccinated with whole inactivated avian influenza virus subtype H9N2[END_REF]130 .

Being both an environmental niche and a food source 131 , respiratory mucins are essential drivers of microbiota composition, diversity, stability, and functionality, which can, in turn, influence microbial behavior and community structure under respiratory infection. Mucins create ecosystem heterogeneity by binding certain nutrients, leading to gradient formation and spatial niche partitioning. This is especially true for the airway microbiota, which primarily extracts nutrients from the respiratory mucins because nutrients are scarce 131 . Many Bacteroides spp and Akkermansia muciniphila encode an extensive repertoire of carbohydrate-active enzymes (CAZymes) that sequentially cooperate in metabolizing the host mucins 132,133 . The first targets for CAZymes are the terminal residues on the O-glycans, such as sialic acid, fucose, and glycosulfate 134 . The complete degradation of mucin polysaccharides can be done by combining enzymes that a diverse range of microbes can express. Insight into the enzymatic capacity of the microbiota is essential to predict how glycans on mucin landscapes contribute to the microbiota assembly and to host-microbiome symbiosis in eubiosis 135 and how we can use them to prevent complex diseases. Notably, the first insights into the respiratory mucin-microbiome axis in the livestock show how microbiota modifications (due to different levels of ammonia concentrations) in growing pigs impacted the thickness and viscosity of the mucus layer and increased the colonization of harmful bacteria 136 . Enriching the upper respiratory tract with the probiotic Bacillus amyloliquefaciens in chicken increased the sIgA levels, the count of goblet cells, and the expression of the MUC2 gene in the tracheal epithelium and the overall respiratory mucosal barrier function 137 .

Yet, the relationship between the microbiome and the mucins in the respiratory tract is mutualistic and implies a two-way traffic. Thus, reciprocally, airway microbiotas have a pervasive impact on the composition and functionality of mucins. Microbiota is required to synthesize large gel-forming mucins completely, including encapsulation, glycosylation, changes in fucosylation and sialidation patterns, and thickness 134,138,139 . Looking deeper at the sheer amount of data we have gathered from the mucin-microbiome axis in the gut, we know that microbiota metabolites regulate gut mucin synthesis at the transcriptional and epigenetic levels. Indeed, butyrate and propionate epigenetically regulate MUC2 gene expression in the human goblet cell-like LS174T cells 140 and help maintain intestinal barrier function. In line with these findings, an elegant study by Bergstrom and Xia 141 showed that the SCFAs resulting from Oglycan fermentation regulated intestinal mucin barrier function. Bioactive SCFA administration (primary butyrate) also promotes MUC2 and MUC5AC gene expression and increases epithelial cell integrity after damage 142 . A study in piglets concluded that gastric infusions of SCFAs maintained intestinal barrier function by increasing the expression of intestinal tight junction proteins occludin and claudin-1 genes and decreasing the gene and protein abundances of IL-1 in the colon, coupled with reduced intestinal epithelial cell apoptosis 143 . Interestingly, co-culturing experiments of A. muciniphila with non-mucus-degrading butyrate-producing bacteria 144 indirectly stimulated intestinal butyrate levels near the intestinal epithelial cells with potential health benefits to the host. The mucin-microbiome axis study undoubtedly opens possibilities to explore terra incognita in health and disease contexts for animals of veterinary interest.

The mucin-microbiome axis in respiratory infections

The importance and problems mucus and mucins encounter are evident for the general public during upper respiratory tract colds [START_REF] Hansson | Mucus and mucins in diseases of the intestinal and respiratory tracts[END_REF] . Persistent mucus accumulation and plugging of the airways pervasively impair microbial clearance, enhance the transition from the microbiome to the pathobiome [START_REF] Ridley | Mucins: the frontline defence of the lung[END_REF][START_REF] Fahy | Airway Mucus Function and Dysfunction[END_REF] , and inflammation [START_REF] Rose | Respiratory Tract Mucin Genes and Mucin Glycoproteins in Health and Disease[END_REF]145 . Thus, excessive mucin production can no longer attenuate microbial virulence and pacify opportunistic pathogens 146 . The conversion from healthy to pathologic mucus occurs through multiple mechanisms [START_REF] Fahy | Airway Mucus Function and Dysfunction[END_REF] , including abnormal secretion of salt and water, increased submucosal gland mucus secretion 147 , mucus infiltration with inflammatory cells, and heightened broncho-vascular permeability with respiratory distress [START_REF] Fahy | Airway Mucus Function and Dysfunction[END_REF] .

In line with this, a first study in pigs indicates that infections primarily drive changes in the quantity and physicochemical properties of airway mucins and may enhance pathogen biofilm formation and promote survival in nutrient-limited conditions, as reported for Streptococcus mutans in pigs 148 . Similarly, the expression of MUC5AC has been induced in cells exposed to a wide variety of Gram-negative and Gram-positive bacteria, including P. aeruginosa and Staphylococcus aureus, evoking that mucin secretion is a host defense response to infection 149,150 . Viruses can prominently stimulate MUC5AC expression in vitro or in vivo on airway epithelial cells [START_REF] Thai | Regulation of Airway Mucin Gene Expression[END_REF] .

Beyond mucin expression alterations, glycan glycosylation patterns have also been linked to respiratory physiopathology [START_REF] Shipunov | Glycome assessment in patients with respiratory diseases[END_REF]151 . For instance, mucin glycans exhibit reduced chain length, sulfation, fucosylation, and increased sialylation during inflammation 146 . It is important to note that seemingly minor differences in glycan structures may result in significant pathophysiological outcomes. As an illustration, a shift in the nine-carbon backbone monosaccharides of the sialic acid might enhance the virus binding and infection of cells or can act as decoy receptors that bind virions and block viruses 152 or bacteria, facilitating increased colonization and the development of lung disease 153,154 . The specific roles of mucins and the glycome during infections can vary depending on the pathogen, tissue, and host factors involved 155 . Yet, these early results give states good reason to continue investigating how respiratory pathogens shift host mucins and their associated glycome and the microbiome.

Given the intertwined relationship between pathogens, the airway microbiota, and mucins, and the considerable malleability of the microbiota relative to host genomes, the possibility of influencing respiratory tract health via microbiota manipulation seems possible 151 . Today, controlling pathogens' access to glycans on mucins via microbiome modifications has proven to be a promising method to prevent infection 151 . Elegantly, Pereira et al. 156 demonstrated that the administration of a synthetic bacterial consortium could decrease the availability of sialic acid from mucins by cross-feeding microbes and, thereby, protect against an infection caused by microbial pathogens that use these sugar groups as binding sites, e.g., Clostridiodes difficile 156 or viruses such as influenza virus, reovirus, adenovirus, and rotavirus 114 . Therefore, synthetic microbial communities expressing sialidase activity might improve mucosal health and prevent complex respiratory diseases 157 . Complementary to this approach, nebulizing heparan sulfateconsuming commensal bacteria consistently contained SARS-CoV-2 attachment in higher-risk individuals 158 . At the same time, nebulized fucose has been shown to reduce bacterial adhesion and improve lung function in animal models of respiratory infections 159 . Determining the ideal microbial composition for optimal respiratory health and immune function in livestock is still a topic of ongoing research [START_REF] Mcmullen | Topography of the respiratory tract bacterial microbiota in cattle[END_REF][START_REF] Chai | Bovine respiratory microbiota of feedlot cattle and its association with disease[END_REF][START_REF] Holman | The nasopharyngeal microbiota of feedlot cattle that develop bovine respiratory disease[END_REF][START_REF] Mahmmod | Variations in association of nasal microbiota with virulent and non-virulent strains of Glaesserella (Haemophilus) parasuis in weaning piglets[END_REF][START_REF] Alexander | The role of the bovine respiratory bacterial microbiota in health and disease[END_REF][160][161][162][163][164][165][166] . The nature and the mechanisms behind respiratory microbiome and its interactions with the mucins and glycome profiles in livestock are not understood. Yet, it seems likely that there is a substantial amount of untapped potential concerning the airway microbiome-mucin axis in livestock and how external factors, such as the administration of nebulized synthetic bacterial consortium or the use of food containing synthetic and natural dietary glycans designed to target microbial activity at the mucosa. In the gut, such approaches have shed light on how alterations to the biochemistry of mucins and mucus impact their protective capacity and restore healthy mucosal function 135,167,168 .

The non-coding RNAs: an engaged control of the mucin production and glycome patterns

Next to the use of microbial consortia or dietary glycans to control mucins glycome, understanding the genetic regulation of mucin production and glycosylation patterns offers a way to modulate mucin levels, affecting specific signaling pathways or transcription factors involved in mucin synthesis, glycosylation inhibitors, and glycosyltransferases, among others. However, transmembrane and secreted mucins have a complex glycosylated nature and extreme size 169 . They are products of an orchestrated collection of enzymes working in a coordinated manner to synthesize structures appended to proteins and lipids [START_REF] Reily | Glycosylation in health and disease[END_REF]170 .

As conserved regulatory agents, ncRNAs have started to gain attention as crucial regulators of mucin and glycome regulators at the transcriptional, post-transcriptional, and translational levels. The ncRNAs are RNA molecules that do not encode proteins but have regulatory or structural functions within cells 171 . ncRNAs are mainly divided into small ncRNAs and long non-coding RNAs. microRNAs, circular RNAs, and their precursor pri-miRNAs are sncRNAs ranging from ~22 bp in their mature form to ~70 bp in their premature stem-loop form. LncRNAs are noncoding RNAs transcribed by RNA polymerase II (RNA Pol II) and are longer than 200 nucleotides. Like miRNAs, lncRNAs have emerged as new regulators of gene expression and have become a focal point of biomedical and veterinary research 172 . MiRNAs regulate gene expression at the post-transcriptional level by binding (usually with imperfect complementarity) to the 3-UTR of a target mRNA, resulting in translation degradation or inhibition. A single miRNA can have hundreds of target genes, and multiple miRNAs can converge on a single mRNA. Unlike transcriptional regulators, the role of miRs is not to turn a gene on or off but instead to tune protein expression [START_REF] Thu | Sweet Control: MicroRNA Regulation of the Glycome[END_REF] . The lncRNAs regulate the genomic output at many levels, from transcription to translation 173 . The effect of lncRNAs is mainly achieved by interfering with the expression of downstream genes, supplementing or interfering with the mRNA splicing process, and regulating protein activity 174 . Besides, a growing body of research has found that lncRNAs can regulate gene transcription through the function of competing endogenous RNAs (ceRNAs) 174 . An individual transcriptome contains more lncRNAs than mRNA molecules 175 . For livestock, the most significant number of identified lncRNA transcripts is available for pigs and cattle 175 . Poultry is represented by less than half of the records. Genomic annotation of lncRNAs showed that most are assigned to introns (pig, poultry) or intergenic (cattle) 176 . The number of detected miRNAs in farm animal species is lower than lncRNs, from 1064 in cattle to 267 in goats and 406 in pigs (miRbase release 22 (http://www.mirbase.org/).

Given the emerging importance of ncRNAs in conditions and their potential to identify genes that underlie specific biological processes, it is clear that more attention should be paid to ncRNA and mucins interactions. To this point, data on the roles of ncRNAs in mucin regulation has been mainly generated by well-controlled murine models and humans. For instance, several miRNAs have been identified that regulate the expression of mucin genes in the respiratory tract of humans, namely miR-34b/c 50 , miR-146a 51 , miR-378 [START_REF] Skrzypek | Interplay Between Heme Oxygenase-1 and miR-378 Affects Non-Small Cell Lung Carcinoma Growth, Vascularization, and Metastasis[END_REF] , and miR-141 [START_REF] Siddiqui | Epithelial miR-141 regulates IL-13-induced airway mucus production[END_REF] . Additionally, modifications of miRNA expression can result in significant alterations of glycosyltransferases and glycome [START_REF] Agrawal | Mapping posttranscriptional regulation of the human glycome uncovers microRNA defining the glycocode[END_REF]170 . Jame-Chenarboo et al. (2022) established that miRNAs are substantial regulators of cell glycosylation. Therefore, changes to mucin glycosylation patterns, such as increased sialylation, will likely alter mucin's binding properties with pathogens and their protective functions. miRNAs also play a crucial role in regulating mucin barrier functions, which has mainly been studied in the gut and the context of inflammatory bowel diseases [177][178][179] . Although these studies have elegantly displayed the impact of the regulatory ncRNAs on mucin structure and function, much work is needed to see whether these outcomes directly reflect livestock's complexity (genetic, environmental, comorbidities). The proposed mechanisms and results based on laboratory animals have yet to be validated in animals of veterinary interest due to the limitations regarding obtaining samples and the complexity of production systems, hosts, biotic and abiotic stressors, and infectious etiology. This complicates the application of human and laboratory animal-based findings to livestock. Therefore, the role of ncRNA on mucin glycome remains an open question in livestock. Coupled with this heterogeneity, the disease is known to change ncRNA behavior in livestock. For instance, PRRSV, one of the most important viral pathogens in the swine industry, affects host homeostasis through changes in miRNA expression 180-182 183 (reviewed elsewhere 184 ). Profiles of lncRNA expression in disease were also affected by porcine circovirus-associated disease 185,186 .

An extra difficulty lies in the fact that the presence and activity of microbiota might also regulate the host ncRNAs 187,188 . Indeed, the microbiomes and microbial metabolites such as secondary bile acids and SCFAs have been shown to regulate the expression of miRNAs 189 and lncRNAs in the intestine epithelial cells 190 , macrophages 191 , and other metabolic organs 190 in adult mice or in vitro 192 , evoking that the gut microbiome regulates the expression of both coding RNAs and ncRNAs regionally and systemically 193 , especially during pathogen infection 194 . For instance, a study investigating early rumen development in neonatal dairy calves revealed that nearly 46% of miRNAs expressed in the rumen are responsive to SCFA 195 . Analouglsy, another study focused on rumen microbiota 196 suggested that the microbiota influences the host's miRNA expression pattern and that the host potentially helps shape the gut bacterial profile by producing specific miRNAs. Minimal knowledge exists about the ncRNA regulatory mechanisms behind mucin-microbiome interactions. Still, these emerging nuances illustrate that microbiome interacts with the host directly (direct modulation of transcriptome) and indirectly via the expression of ncRNA 173 .

Concluding remarks

In livestock pathology, there is a growing awareness that infectious agents frequently do not operate alone, and their virulence can be likely affected by their interaction with the microbiomemucin axis. Therefore, the microbiome-mucin axis is a significant player in the health of the respiratory tract. As such, they contain signals that can be used to forecast airway pathophysiology. There are fundamental gaps for species of veterinary interest, yet, these signals can be harnessed by combining microbial and glycomics omics, two fields that have tremendously developed in recent years. Based on the emerging evidence evaluated in this opinion paper, ncRNAs may play a vital role in the microbiota-mucin crosstalk via modifying the holobiont. The next phase in the livestock research area should focus on understanding whether particular microbiome-mucin glycome structures confer resistance and resilience to microbial infection and which are the critical factors controlling the mucin-microbiome axis, including the role of ncRNA. It is now time to harness the forecasting power of the microbiomemucin axis.

Figures Figure 1. The microbiome-mucin axis in the respiratory tract: mucin damage matters

Upper panel: The mutualistic relationship between the airway mucins and the microbiota and derived metabolites under eubiosis. On the one hand, the microbiota and their metabolism induce the synthesis of large gel-forming mucins, including encapsulation, glycosylation, changes in fucosylation and sialidation patterns, and thickness. On the other hand, the mucin layer serves as an environmental niche and a food source for the microbiota. The high diversity of gut mucins impacts the gut microbiota composition, diversity, and stability but also influences immune homeostasis.

Bottom panel: The mutualistic relationship between the mucin glycome and the microbiota under a disrupted airway ecosystem and environment. The deterioration of the respiratory mucosal barrier enables virus binding to the cells, and the translocation of bacteria and lipopolysaccharides (LPS) outside the respiratory tract, triggering immune and inflammatory responses, often resulting in increased permeability and, eventually, endotoxemia. Changes in

Declaration of interest

The author declares no competing interests. the respiratory barrier integrity involve changes in the abundance, expression, and glycosylation of mucins, and thus immune dysregulation, dysbiosis, and risk of disease onset. This figure has been created with BioRender.com.