4. DISCUSSION
Ocular allergy represents one of the most common ocular surface diseases. Despite an emerging picture of immunologic mechanisms underlying AC, the etiology is not fully understood especially for severe forms like VKC. In this study, we characterized the associations of conjunctival microbiome dysbiosis with AC and identified the species involved in the dysbiosis. Though it is unclear which aspects of the microbial dysbiosis are causes or consequences of the onset of diseases, these findings captured novel characteristics of AC. Future studies are needed to clarify the roles of the discovered associated species in the development and exacerbation of ocular allergy. Current treatment regimens of AC mainly focus on suppressing inflammation, and combining these first-line treatments with therapies targeting the ocular surface microbiome may be beneficial.
The age distribution of the AC participants was older than epidemiologically expected. This might be owing to temporal interval between the first onset of AC and the time when they came to our hospital. Although the age of healthy and AC participants were not exactly matched, the age-associated species were absent from the species identified in this study.10 This implies that age is not the driver of microbiome differences between healthy and AC participants in our study. In addition, it is unknown if the colonization of these species predates the onset of AC (especially in early life), highlighting the need for longitudinal studies to investigate the transition to microbial dysbiosis in AC.
We did not find significant differences in species composition between SAC and PAC, which is consistent with their similarity in signs and symptoms. Most of the species with different abundance between SAC/PAC and VKC were enriched in VKC. The involvement of type IV hypersensitivity might be related to the overgrowth of these species. In clinical practice, the allergens of SAC and PAC are often clear, whereas the triggers of VKC are generally difficult to find. This highlights the value of investigating the roles of microorganisms in VKC.
The incidence of allergic diseases is influenced by multiple factors. For instance, personal life experiences lead to distinct allergen profiles across individuals. Despite enrichment in AC, some species were also present in healthy individuals, suggesting that other factors might contribute to the pathogenicity of these species. Moreover, some individuals with AC harbored one or a few prominent species unlike other patients. For example, a sample from an eight-year-old boy with VKC contained a non-negligible abundance (>10%) of human beta herpesvirus 6A. This reflects the complexity and individuality of microbial mechanisms in AC.
It is of particular interest that some species enriched in AC have been previously shown to contribute to other allergic diseases like atopic dermatitis and asthma. This suggests that various allergic disorders might have some microbial mechanisms in common. Specifically, the ocular surface is connected with the nasopharynx through the nasolacrimal canal. This connection may facilitate the exchange of pathogenic species. Further studies are required to provide evidence for the similar roles of these species on conjunctiva as on other mucosal surfaces. Apart from local airways microbiome, gut microbiome also plays a part in asthma. Likewise, the association of gut microbiome and AC is worth investigating.
Of note, many of the species involved in AC overlapped the most niche-associated (showing great phylogenetic separation between body sites) species identified by the Human Microbiome Project,33 such as Haemophilus parainfluenzae ,Rothia dentocariosa , and Streptococcus sanguinis . It is very likely that ocular surface harbors unique strains of these species emphasizing the need for further efforts to characterize the genomes of species living on the ocular surface. These efforts may include whole genome sequencing on the isolates cultured from ocular surface samples, as well as large-scaled metagenome assembly. Further investigation will lead to a better understanding of how specific strains of these microorganisms are associated with AC.
Besides small sample size, a limitation of this study is that AKC was not included. AKC is least common and its pathologic mechanism is considered similar with that of VKC. In addition, we only sampled from inferior bulbar conjunctiva while other parts of the ocular surface (lid, cornea, and other regions of conjunctiva) could also be affected in AC.
In summary, our study characterizes and contextualizes the conjunctival microbiome dysbiosis in AC. The microbiome signatures identified here represent potential targets for follow-up studies on the microbial mechanisms that underlie AC and other non-infectious ocular surface inflammations.