Implementing PPPM for prevention and management of ocular diseases

Severe non-communicable disorders pose a significant social and economic burden on healthcare and society. This has prompted a shift towards implementing PPPM medicine, which focuses on preventative measures rather than reactive treatment [30]. Recently, PPPM provides a new approach to manage the ocular related diseases. One important example is the highlighting of protein profiles in tears and the exemplification of corresponding biomarkers for several relevant pathologies, such as dry eye disease and diabetic retinopathy. These biomarkers could predict disease development, target preventive measures, and facilitate the creation of treatment algorithms tailored to individual patient profiles [31]. Another prominent example is the strong recommendation to apply the “Flammer Syndrome Phenotype” questionnaire to select potential Sjögren’s syndrome patients, who can be detected early in life during the reversible phase of health adverse effects. This can lead to cost-effective targeted prevention [32]. In the context of PPPM, identifying reliable risk factors is crucial for effective disease management and control. In this direction, we can evaluate the risk factors and enforce effective interventions to suppress the disease initiation and progression. Previous researches have reported parental history of allergic disease, city residence at birth, regular meat, margarine consumption, and passive smoking are risk factors for allergic conjunctivitis [33, 34]. However, the current treatment of allergic conjunctivitis, which includes both non-pharmacological and pharmacological measures, is primarily reactive in nature and does not focus on preventative measures. Non-pharmacological measures for managing allergic conjunctivitis involve taking specific actions to reduce exposure to environmental allergens. Topical measures, such as non-steroidal anti-inflammatory agents and corticosteroids, as well as systemic pharmacological measures and immunotherapy, are also commonly used [2]. Therefore, it is need to seek special risk factors could also guide subsequent precise and individualized treatment for allergic conjunctivitis. In this study, the causal associations comprehensively and deeply between gut microbiota and allergic conjunctivitis based on publicly available genetic databases in multi-populations were investigated for the first time, and we established 5 distinct microbial genera are pivotal in the development of allergic conjunctivitis.

Allergic conjunctivitis reflects systemic impairments

The World Health Organization has reported that individuals with allergies often experience a suboptimal quality of life, which can lead to an adverse economic impact [35]. The World Allergy Organization has expressed concern over the increasing global burden of allergic diseases, especially in children and developing countries [36]. Allergic conjunctivitis refers to a group of heterogeneous ocular inflammatory conditions that are modulated by mast cells activation and can affect the conjunctiva, eyelids, and cornea. The most prevalent symptoms are ocular itching and blurred vision. Recently, the Ocular Allergy group of the European Academy of Allergy and Clinical Immunology revised the classification of allergic conjunctivitis, distinguishing between two types of ocular surface hypersensitivity disorders: ocular allergy and ocular non-allergic hypersensitivity. Ocular allergy is divided into IgE-mediated or non-IgE-mediated mechanisms. The IgE-mediated type includes seasonal allergic conjunctivitis (SAC), perennial allergic conjunctivitis (PAC), vernal keratoconjunctivitis (VKC), and atopic keratoconjunctivitis (AKC). The non-IgE-mediated forms include contact blepharoconjunctivitis, VKC, and AKC. Included in the category of ocular non-allergic hypersensitivity are various conditions such as giant papillary conjunctivitis, irritative conjunctivitis, irritative blepharitis, and other mixed or borderline forms. Currently, approximately 20% of the world population is affected by some form of allergy, with up to 40–60% of allergic patients experiencing ocular symptoms [37, 38]. Furthermore, allergic conjunctivitis is often associated with other allergic symptoms and diseases, such as asthma, rhinitis, and atopic dermatitis, indicating an abnormal immune system response to certain substances that leads to systemic inflammation and tissue damage [34]. For instance, SAC and PAC are the ocular forms of a systemic allergic disorder (a type 1 IgE-dependent hypersensitivity), which is typically manifested in the respiratory system as allergic rhinitis and/or asthma [39]. Additionally, VKC children have a higher prevalence of Ig deficiency and vitamin D deficiency, and 15–60% of affected children may also present with other atopic diseases [40, 41]. Moreover, AKC involves IgE-mediated, Th1-mediated allergy, and delayed-type hypersensitivity mechanisms, and can cause more severe ocular symptoms and signs, as well as a higher prevalence of atopic dermatitis and asthma [40]. Numerous studies have demonstrated that ocular disorders can indicate systemic impairments in the holistic PPPM approach [42, 43], such as diabetic retinopathy serving as an early event and a reliable predictor of severe complications associated with diabetes mellitus [44]. Therefore, allergic conjunctivitis may serve as an early indicator and reliable predictor of systemic dysfunction, making it crucial for predicting and preventing associated systemic pathologies.

The systemic impact of gut microbiota

The gut microbiota is established before birth, and seven bacterial classes—Firmicutes, Bacteroidetes, Actinobacteria, Fusobacteria, Proteobacteria, Verrucomicrobia, and Cyanobacteria—tend to thrive in this environment [45]. Recent research has demonstrated that the mammalian gut microbiota positively impacts the host, including food provision, catabolism of indigestible chemicals, suppression of opportunistic pathogen colonization, and even participation in the growth and development of gut structures [13]. In addition, pattern recognition receptors—detection of pathogen-associated molecular patterns, antigen exposure and presentation, and epigenetic modification through metabolic by gut microbiota’s products such as short-chain fatty acids (SCFAs)—mediated interactions between gut commensal bacteria and the developing characteristics and functions of the human immune system [46]. It also contributes to the enhancement of the immune system, plays a vital role in digestion and metabolism, regulates epithelial cell proliferation and differentiation, modifies insulin resistance, and affects its secretion [47]. Furthermore, the gut microbiota influences brain-gut communication, impacting the mental and neurological functions of the host [48]. Therefore, the gut microbiota plays a significant role in maintaining normal gut physiology and overall health. Tachalov and colleagues recently demonstrated the crucial role of maintaining optimal oral hygiene practices for improving individual outcomes and reducing morbidity during the COVID-19 pandemic, within the context of PPPM. Their suggested pathomechanisms consider potential preferences in the interaction between the viral particles and the host microbiota including oral cavity, and the respiratory and gastrointestinal tracts [49]. It is known that alterations to the innate immune system, which may result from gut microbiota dysbiosis, have been linked to various illnesses, including allergies and autoimmune disorders [50]. Hence, from the perspective of PPPM, correcting gut microbiota imbalance should be taken into consideration when developing targeted interventions and preventative measures for immunity-related diseases, such as allergic conjunctivitis [51].

Link between gut microbiota and allergic disorders

Food allergy, atopic dermatitis, eczema, asthma, hay fever, allergic rhinitis, and allergic conjunctivitis are among the many types of allergic illnesses affecting an ever-increasing number of individuals throughout the globe. Strachan proposed the “hygiene hypothesis” in 1989, which states that the incidence of allergy diseases is correlated with decreasing exposure to environmental microbes [52]. Researchers back up this hypothesis with data from animal research and many epidemiological investigations [53]. An IgE-mediated Th2 immune response is significantly linked to allergic disorders. When allergens stimulate antigen-presenting cells, they deliver allergens to Th0 cells, which then develop into Th2 cells in response to cytokines like IL-4. Th2 cells, on the other hand, secrete cytokines, including interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13), which encourage B cells to make IgE and attach to the surface of sensitized effector cells like mast cells and basophils. Cell-mediated immunity, notably against intracellular bacterial and viral infections, autoimmunity, and tumor defense, were linked instead to Th1 responses. Furthermore, Th1-derived cytokines such as IFN-γ may stifle the differentiation of Th2 cells. As a bonus, IL-23 signaling may activate Th17, characterized by IL-17A production. So far, we have known the dynamic cross regulation between the mediators directing lymphocyte polarization exists, and dominant Th2 cell differentiation is one of the immunological bases of IgE-mediated allergic reactions [54]. Based on these evidences, it is not hard to conclude the factors that affect the immunity system homestasis, and enhanced IL4/IL13-driven response is the essential for allergy. Recently, genetic predisposition associated with a preponderance of type 2 immunity was confirmed contribute to the development of allergic disorders [55]. Further, the microbiota in one’s digestive tract may have a role in developing allergic disorders [56]. In light of these facts, we suggest that a hereditary predisposition to the effects of altered gut flora contributes to allergic disorders. In addition, Delday et al. [57] found fewer species of the genus Bacteroides and more species of the genus Firmicutes in infants with atopic dermatitis. Similarly, Stokholm et al. [11] found that children who developed asthma had reduced relative abundances of Lachnospiraceae (including Lachnospiraceae incertae sedis and Roseburia) and Ruminococcaceae (including Ruminococcus and Faecalibacterium). However, the mechanism connecting certain gut microbiota with allergic conjunctivitis has not been explored till now and warrants more study.

Immunomodulatory functions of Ruminococcaceae_UCG_002, Holdemanella, Catenibacterium, and Oscillospira genera

Changes in Firmicutes and Bacteroidetes are particularly significant in many pathological states since these two constitute the vast majority of the bacterial population. Trans-differentiation of Th17 cells into regulatory T cells (Tregs) is connected with the ratio of Firmicutes to Bacteroidetes, which could be used as a disease predictor [58]. Our investigation revealed that the genera Ruminococcaceae_UCG_002, Holdemanella, Catenibacterium, and Oscillospira, all of the phylum Firmicutes, are associated with the onset of allergic conjunctivitis. Ruminococcaceae_UCG_002 can convert certain primary bile acids into secondary bile acids since it is a member of the bile salt hydrolase and 7-dehydroxylase-active family Ruminococcaceae [59]. As we know, bile acids exert hormone-like functions by activating FXR and TGR5 and the dysregulated bile acid pool may lead to perturbations in multiple pathological processes, such as immune regulation and lipid and glucose homeostasis. In addition, prior research has linked the Ruminococcaceae_UCG_002 genera to immune regulation and shown an inverse association between their level and C-reactive protein [59, 60]. Holdemanella biformis is inversely correlated with C-reactive protein levels [61]. Several researchers discovered that Holdemanella could create a high quantity of C18-3OH, and mice treated orally with C18-3OH were less likely to develop colitis after being given dextran sulfate sodium [62]. Thus, it was hypothesized that Holdemanella, through C18-3OH, may influence the host’s immunological and neuroendocrine communication pathways. Recurrent oral and vaginal ulcers, skin lesions, and uveitis are classic symptoms of Behçet’s illness, a Th1 paradigm disease. Behçet’s disease patients have significantly greater levels of Catenibacterium than the general population [63]. Due to its prevalence, Catenibacterium was likely linked to Th1 trans-differentiation, which IL-6 controls. These results suggest that the bacterial genera Ruminococcaceae_UCG_002, Holdemanella, and Catenibacterium are all engaged in immunomodulation via regulating lymphocyte polarization and affecting the dynamic cross-regulation of immune cells.

Comparatively, the functions of the three other genera of gut microbes that demonstrate pathogenic potential are consistent except for the Oscillospira genus. Consistent with our findings, Canani et al. [64] reported that after treatment with Lactobacillus rhamnosus GG, the only species substantially different between tolerant and allergic babies with cow’s milk allergy was Oscillospira and that there was a large quantity of Oscillospira in the allergic samples. Oscillospira overabundance was also positively correlated with the onset of diabetes and inflammation in animals with obesity, type 2 diabetes mellitus, and dextran sulfate sodium-induced ulcerative colitis [65]. Recent research has shown that Oscillospira may create a wide variety of SCFAs, with butyrate being the most abundant and strongly correlated to inflammatory disorders [66]. As described previously, early intestinal dysbiosis activates pro-allergic processes and increases the risk of allergy by the mechanisms disrupting the balance between Th1 and Th2 cells. Taken together, suppressing Th17 cells, enhancing IL-10 production, and activating the Treg/Th2 are the essential factors which induce the immune system balance, and might be the pathology mechanics of enriched Oscillospira and impoverished Ruminococcaceae_UCG_002, Holdemanella, and Catenibacterium in allergic conjunctivitis. Future molecular and clinical studies are needed to understand the underlying processes better.

Study limitations

Although large-scale GWAS studies allow for more solid inferences, they are not without flaws. For one, the majority of participants in the GWAS were of European ancestry, the causal relationship between gut microbiota alteration and allergic conjunctivitis might be limited in others ethnic group. Secondly, we selected the GWAS data of exposure (gut microbiota) and outcome (allergic conjunctivitis) from publicly available summary data; however, it is impossible to establish whether overlapping subjects were engaged in the two samples’ MR analyses. Third, due to the limitation of the database, we could not distinguish different forms of allergic conjunctivitis. Further research is needed to test the gut microbiota alteration in different types of allergic conjunctivitis, aiming to promote a PPPM in patients with allergic conjunctivitis. Fourth, we did not account for multiple testing because a rigorous multiple testing correction may neglect potential strains that are causally related to allergic conjunctivitis.