Niche- and Gender-Dependent Immune Reactions in Relation to the Microbiota Profile in Pediatric Patients with Otitis Media with Effusion

Abstract

Otitis media with effusion (OME) is a common inflammatory disease, primarily affecting children. OME is defined as a chronic low-grade inflammation of the middle ear (ME), without any signs of infection and with effusion persisting in the ME for more than three months. The precise pathogenesis is, however, not fully understood. Here, we comprehensively characterized and compared the host immune responses (inflammatory cells and mediators) and the overall microbial community composition (microbiota) present in matched middle ear effusion samples (MEE), external ear canal lavages, and nasopharynx (NPH) samples from children with OME. Female patients had significantly increased percentages of T lymphocytes and higher levels of a wide array of inflammatory mediators in their MEEs compared to male patients, which was unrelated to microbiota composition. The relative abundances of identified microorganisms were strongly associated with their niche of origin. Furthermore, specific inflammatory mediators were highly correlated with certain bacterial species. Interestingly, some organisms displayed a niche-driven inflammation pattern, where presence of Haemophilus spp and Corynebacterium propinquum in MEEs was accompanied by pro-inflammatory mediators, whereas their presence in NPH was accompanied by anti-inflammatory mediators. For Turicella and Alloiococcus we found exactly the opposite results, i.e., an anti-inflammatory profile when present in MEEs, whereas their presence in the NPH was accompanied by a pro-inflammatory profile. Altogether, our results indicate that immune responses in children with OME are highly niche- and microbiota-driven, but gender-based differences were also observed, providing novel insight into potential pathogenic mechanisms behind OME.

Nasopharyngeal microbiome composition associated with Streptococcus pneumoniae colonization suggests a protective role of Corynebacterium in young children

“…In contrast, C . propinquum was reported to correlate with anti-flammatory mediators in human nasopharynx [ 61 ]. Whether and what type of immune responses the Corynebacterium species may elicit in vivo to imped Spn colonization thus await future investigation.…”

Case-Control Microbiome Study of Chronic Otitis Media with Effusion in Children Points at Streptococcus salivarius as a Pathobiont-Inhibiting Species

“…In addition to these classic otopathogens, multiple 16S rRNA gene sequencing studies of OME middle ear effusion also reported high levels of Alloiococcus otitis, Corynebacterium otitidis (formerly Turicella otitidis [4]), Pseudomonas spp., and Staphylococcus spp. (Staphylococcus aureus, Staphylococcus auricularis, and Staphylococcus epidermidis) (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). It is, however, still uncertain if these taxa, many of which are residents of the ear canal (17,18) or the healthy URT (19), contribute to middle ear disease.…”

Innate Immunity in the Middle Ear Mucosa

“…The mechanisms by which the middle ear microbiome, in concert with that of the nasopharyngeal microbiome, may impact on the development and pathogenesis of OM remain largely unknown. This is a growing area of investigation (Schenck et al, 2016;Enoksson et al, 2020;Marsh et al, 2020), as the presence of a healthy middle ear microbiome is controversial (Johnston et al, 2019) with one key study in adults finding no evidence of bacterial colonisation of the middle ear using microscopy and culture techniques (Jervis-Bardy et al, 2019). The inflammation that defines OM, however, is induced by invading respiratory viral pathogens and dysregulated commensal bacterial populations within the nasopharynx, which then migrate through the upper respiratory tract via the eustachian tubes to infect the middle ear.…”

“…The healthy middle ear of both humans and animal models of OM is host to immunocompetent cell types, although not in significantly high numbers until infiltration occurs during AOM (Jecker et al, 1996;Jecker et al, 2001;Suenaga et al, 2001) or COME (Enoksson et al, 2020). Mast cells and macrophages are the predominant cell types in non-inflamed middle ear, with dendritic cells and macrophages present in the tympanic membrane (Ichimiya et al, 1990;Mittal et al, 2014b) These antigen-presenting cell phenotypes provide a mechanism for interconnection of the local innate mucosal immune response with the more specific adaptive immune system (Ichimiya et al, 1997).…”

“…Upregulation of the innate immune response, as evidenced by immunocompetent cell infiltration, has long been demonstrated in COM patients (Palva et al, 1981;Enoksson et al, 2020), whilst mouse models of NTHi infection of the middle ear have also demonstrated leukocyte infiltration (Hernandez et al, 2008;Hernandez et al, 2015;Trune et al, 2015). Furthermore, the acute inflammatory response during AOM in the rat model shows time-dependent increases in identification of macrophages, dendritic cells, polymorphs and natural killer cells (Jecker et al, 1996;Forseni et al, 1999), with T-cells present 3 days after perforation of the tympanic membrane (Tahar Aissa and Hultcrantz, 2009).…”