Aquaporin5-Targeted Treatment for Dry Eye Through Bioactive Compounds and Gut Microbiota

Abstract

Dry eye and dry mouth are the principal sources of morbidity for patients with Sjögren's syndrome (SS). There are few effective treatments, particularly systemic ones. Targeting aquaprin-5 (AQP5)-mediated tear secretion has been tested as a novel ancillary strategy and has proved promising. Patients have a great interest in using complementary medicine, including nutraceuticals and bioactive compounds to alleviate their symptoms. Potential mechanisms by which phytocompounds and bioactive compounds may benefit SS ocular and mouth symptoms through modulation of AQP5 activity are presented within this review. Supplementation with prebiotics (such as polyphenols with high bioavailability) in SS patients with lower Firmicutes/Bacteroides (F/B) community ratio phenotype, through administration of butyrate-producing diets, is proposed as ancillary strategy for dry eye and mouth. The potential use of natural bioactive compounds to treat dry eye could also apply to dry mouth occurring in the context of aging and SS. This novel hypothesis could have implications with respect to planning a successful dietary regimen for achieving and maintaining a normal gut microbiota in SS patients. This regimen would include augmenting butyrate-producing foodstuffs and/or polyphenol-rich syrups, and high amounts of some specific probiotic-rich foodstuffs such as yogurt, soy yogurt, or as probiotic supplements. There are applications for pharmaceutical and nutraceutical products aiming to relieve dry eye and mouth.

Introduction

Dry eyes and dry mouth are clinical hallmarks of Sjögren's syndrome (SS), but also arise as a side effect of certain medications and other medical conditions.^1,2 The ocular tear film is comprised of an aqueous component secreted by the main and accessory lacrimal glands, mucin secreted by conjunctival goblet cells, and meibum lipids secreted by the Meibomian glands.³ Altogether, these components comprise the ocular secretory system.

The lacrimal and Meibomian glands are rich in aquaporin 5 (AQP5).^4–6 AQPs are a group of water channel proteins which mediate the passage of water molecules through membranes.⁷ Currently, treatment of dry eye relies on a multifaceted approach to supplement tears, prevent tear evaporation and drainage, augment tear secretion, and reduce ocular surface inflammation. Measures that specifically target AQP5-mediated tear secretion in the eye have been tested and have proved promising. AQP5-targeted therapy has been proposed before⁸ and has been tested as a topical therapy (ambroxol drops) for dry eye.⁹ The original work that led to the discovery of the importance of AQPs at the ocular surface tissues, mainly the conjunctiva, was published in 2015 by the same group.¹⁰ They then recognized the role of the conjunctiva, which occupies 95% of the ocular surface area in human, in the maintenance of ocular surface homeostasis,¹¹ and proposed targeting conjunctival AQP5 as dry eye therapy. They published several other articles in support of their hypothesis and proposal as well.^9–12

A selective defect in lacrimal gland AQP5 trafficking contributes to decreased lacrimation and dry eye in many medical conditions, including SS.¹³ It was recently shown that targeted AQP1 gene therapy of the submandibular glands in a murine model of SS not only improved salivary flow, but also lacrimal gland function.⁸ This latter effect occurred in the absence of any evidence of AQP1 expression in the lacrimal gland epithelium, suggesting for a systemic benefit possibly arising from decreased AQP1 antigen exposure and reduced inflammation in the treated salivary glands.

There are very few studies of improvement of the ocular secretory system through AQP5 activation. Other AQPs may be important to tear gland function, including AQP1,^8,14,15 AQP3,^14,16 and AQP4,^14,17,18 but the contribution of AQP5^{13–16,19–24} appears to be the most pronounced. In addition, there are few studies of AQP5 function in lacrimal glands. Thus, I rely on data obtained from studies of AQP5 in salivary secretion. There are no qualitative differences between the AQP5 of the salivary glands and that of the ocular secretory system.^25–27

In this communication, I provide a brief overview of bioactive compounds found in foods and medicinal herbs that could ameliorate dry eye based on AQP5 activation.

AQP Subfamilies, Autoimmunity, and SS

Abnormalities and dysregulation of AQPs have been implicated in a broad array of diseases including cancer, obesity, wound healing, edematous states, and several autoimmune diseases.²⁸ In recent years, the relationship between AQP subfamilies and SS has been the subject of multiple studies.

AQP5 in animal models of SS

AQP5 is abnormally distributed in the salivary glands of nonobese diabetic (NOD) mice, a strain susceptible to the spontaneous development of SS.²³ There is a direct link between AQP5 distribution and inflammation in submandibular glands from 3 SS murine models, namely IQI/JIC, r1ΔT/r2n,. and NOD. An altered AQP5 distribution in submandibular acinar cells from r1ΔT/r2n, IQI/JIC, and NOD mice correlated with the presence of inflammatory infiltrates and acinar destruction.²¹ In these animal models, Zeng Ye decoction (ZYE), a traditional Chinese medicinal agent extracted from figwort, Ophiopogon japonicus and Rehmannia glutinosa Libosch, upregulates AQP1 and AQP5 expression levels and thus might have a therapeutic benefit in man. ZYE showed a significant protective effect on SS through upregulation of the expression levels of AQP1 and/or AQP5.¹⁵

Similar improvement in tear and salivary gland function was seen following intragastric administration of the traditional Chinese medicine agent Shaoyao-Gancao Decoction (SGD) in the SS murine model. SGD mediated these effects by regulating the cAMP-PKA signaling pathway and increasing M3R and AQP5 levels.²⁰ Cevimeline improved saliva secretion and AQP5 localization in SS mice.¹⁴ Another Chinese medicine, total glucosides of peony, has been shown to improve the histopathology of submandibular glands of NOD mouse with SS by upregulating AQP5 and AQP5 mRNA expression in submandibular glands.¹⁹ These studies^14,15,19,20 suggest that enhancement of AQP5 expression could alleviate dry eye and dry mouth and that AQP may be a therapeutic target in SS.

AQP5 in patients with SS

In healthy controls and patients with non-SS dry eye, AQP5 had the expected apical distribution in lacrimal acinar cells. In contrast, patients with SS had a cytoplasmic distribution of AQP5.¹³ In a histologic study of labial minor salivary gland tissues, Ichiyama et al.¹⁶ showed that staining intensity for AQP3 in the apical membrane was significantly stronger in SS, and that for AQP5 was significantly weaker in biopsies from non-SS patients with dry mouth. This study suggests that expression of AQP3 and AQP5 may help distinguish dry mouth patients with and without SS. In human studies, anti-AQP5 autoantibodies act as mediators of glandular hypofunction and are proposed as a potential therapeutic target in SS.^29,30 In one cohort study, screening anti-AQP5 autoantibodies was helpful in identifying subgroups of SS for targeted therapy.²⁴

In another study, treatment of ductal cells with 5-aza-2'-deoxycytidine (5-Aza-CdR), a DNA demethylating agent, resulted in the expression of the AQP5 gene, thereby leading to increased fluid secretion from ductal cells in SS salivary glands.²²

These studies support the concept that lower expression of AQP5 is important to the pathophysiology of SS. I will shortly discuss MicroRNAs and their potential for regulation of AQP-based disorders in the Discussion section.

Gut Microbiota

A healthy microbiome plays a critical role in the homeostasis of the immune system and its alteration has been correlated with systemic autoimmune diseases.^31,32

The relative proportion of Firmicutes to Bacteroidetes is decreased in SS patients in most studies (see table 1 of reference³³ for a good review). Also, stool from SS patients has a greater relative proportion of Pseudobutyrivibrio, Escherichia/Shigella, Streptococcus, and Blautia, while the relative proportion of Bacteroides, Parabacteroides, Faecalibacterium, and Prevotella was reduced compared with healthy controls. The severity of SS ocular and systemic disease is negatively correlated with gut microbial diversity.³⁴

In a recent study, it was revealed that primary SS (pSS) patients have less commensal butyrate-producing bacteria and a higher proportion of opportunistic pathogens with proinflammatory properties.³⁵ This means that dietary habits which promote growth of such beneficial bacteria, or antibiotics which hinder/suppress them, may influence symptoms of SS accordingly.

The imbalance of intestinal gut microbiota in SS patients could be improved through administration of (i) Gram-positive bacteria, (ii) probiotics, and (iii) fecal microbiota transplantation. These measures serve to engraft a healthy gut microbiota into patients, with the goal of re-establishing or reintroducing a stable intestinal environment that affects both the host and the endogenous microbes. See De Luca and Shoenfeld.³²

Briefly, SS patients have significant gut dysbiosis when compared with healthy controls and patients with environmental dry eye syndrome, manifest compositional changes of their gut microbiome somewhere in between SS and controls.³⁶ Recently, Moon et al. postulated pathways that might underlie the “gut dysbiosis/ocular surface/lacrimal gland axis”. According to their extensive review, a decrease in both the F/B ratio and genus Faecalibacterium is commonly seen in SS subjects.³³ This finding raises the possibility that modification of gut microbiota may ameliorate dry eye syndrome in SS patients. Based on the empirical data and clinical trials mentioned above,^37–42 herbal extracts and probiotics may benefit SS patients through possible alterations of the intestinal microbiota.

Direct evidence from gut dysbiosis and dry eye

It is not known whether aquaporin5-targeted treatment would involve pathophysiologic pathways related to gut dysbiosis. However, there is direct and indirect evidence that this may be the case, at least in some SS patients.

Furthermore, there are numerous evidences that support the hypothesis that gut dysbiosis may deteriorate dry eye through AQP5 dysfunction: (i)

There is significant relationship between oral and gut microbiota.⁴³

(ii)

Salivary dysbiosis in SS may be an immunomodulatory commensal bacterium in pSS.⁴⁴

(iii)

There is a potential role of oral microbiota and autoantibodies against either AQP5 or AQP1 in the pathogenesis of SS.⁴⁵

(iv)

There is strong association between aging-dependent gut microbiome dysbiosis and dry eye severity (in male mouse model).⁴⁶

(v)

Gut dysbiosis is prevailing in SS^36,47 and is related to dry eye severity^34,36,46 and is associated with systemic disease activity.⁴⁷

(vi)

Dry eye severity is related to AQP5 dysfunction.^13,16

(vii)

In other SS-like diseases (like ocular autoimmune diseases, such as autoimmune uveitis with similar underlying pathology), gut dysbiosis has an established pathologic role, where autoreactive humoral and T cell-mediated immunity against AQP4 drives neuromyelitis optica pathogenesis.⁴⁸

Collectively, it might be conjectured that gut dysbiosis may exert its effects through AQP5 dysfunction by its immunomodulatory effects and contribute to severity of dry eye.

Yoon et al. just recently provided the first empirical evidence showing a strong association between aging-dependent gut microbiome dysbiosis (phylum Firmicutes, Proteobacteria, and Cyanobacteria, F/B ratio, and genus Alistipes, Bacteroides, Prevotella, Paraprevotella, and Helicobacter) and dry eye severity in C57BL/6 male mouse model. After adjustment for age, the phylum Proteobacteria, F/B ratio, and genus Lactobacillus, Alistipes, Prevotella, Paraprevotella, and Helicobacter were significantly associated with dry eye severity. They did not measure AQP5 levels or its expression; however, considering the prominent role of AQP5 role in lacrimal gland secretion, it is most likely that a genuine correlation exists between gut dysbiosis and AQP5. In this study, there might be a role for oral dysbiosis and an association between oral and gut dysbiosis, since oral and gut microbiota are associated with each other.⁴³ Oral dysbiosis⁴⁹ and gut dysbiosis^33,36 take part in the pathogenetic mechanisms involved, however, it is also possible that these conditions are corollary result of the reduced saliva and lacrimal gland secretion and function.

Figure 1 shows the schematic diagram showing the paths by which bioactive compounds may benefit dry eye.

FIG. 1.

Schematic diagram showing the paths by which bioactive compounds may benefit dry eye.

Supporting Evidences

Evidence supporting improvement of F/B ratio

In a randomized, crossover, controlled trial, a possible effect of prebiotics was evaluated, both with respect to the modulation of the gut microbiota composition following moderate intake of red wine polyphenols and the improvement in the risk factors for the metabolic syndrome in obese patients. The dominant bacterial composition did not change significantly between the study groups after the 2 red wine intake periods. In patients with metabolic syndrome, polyphenols significantly increased the total number of fecal bifidobacteria and Lactobacillus (protectors of the intestinal barrier) and butyrate-producing bacteria (Roseburia and Faecalibacterium prausnitzii) at the expense of less desirable groups of bacteria, such as lipopolysaccharide producers,⁵⁰ which belong to B community. It is noteworthy that Lactobacillus, Roseburia, and F. prausnitzii belong to F family. In another open-label, randomized clinical trial, the impact of Helicobacter pylori infection (ie, B family), eradication therapy, and probiotic supplementation on gut microenvironment homeostasis were evaluated. It was found that after eradication therapy colony counts of most butyrate-producing bacteria decreased significantly, while those of several detrimental bacteria increased. Supplementation with probiotics was associated with an improved F/B ratio.⁵¹ In a randomized placebo-controlled intervention study, the relative abundance of Roseburia hominis, a major butyrate producer belonging to F family, was significantly increased in the group supplemented with prebiotic UG1601. The abundances of the phylum Firmicutes and the family Lachnospiraceae (phylum Firmicutes) were significantly decreased in the responders within the prebiotic group.⁵² Finally, Acarbose significantly augmented colonic butyrate production by several mechanisms.⁵³

Evidence for beneficial effects of bioactive compounds on AQP5

Nomura et al. first reported that all-trans retinoic acid increases AQP5 mRNA and protein expression, and AQP5 promoter activity in murine lung epithelial (MLE-12) cells.⁴⁰ In a recent article, it was shown that extract of the herbal medicine, Ixeris dentate (IXD), regulates salivary secretion through the activation of AQP5 and prevents diabetes-induced xerostomia in diabetic rats.³⁷ Interestingly, the same finding was replicated with age-induced dry mouth in diabetic rats 1 year later.³⁸ In another study with a similar design, the combination of extracts from IXD and Lactobacillus gasseri could improve salivary function in a diabetes-associated dry mouth rat model.³⁹ The most relevant and direct evidence for beneficial effects of bioactive compounds on AQP5 function was provided by a mechanistic study aimed to investigate the effect of Dendrobium candidum extracted liquid (DCEL) in promoting expression of AQP5 for treatment of SS. Sixteen patients with SS and dry mouth symptoms were enrolled. After 1 week of oral administration of DCEL, saliva and salivary gland biopsies were collected and examined. As compared with the control group, salivary secretion increased by 65% in patients treated with DCEL. In SS patients who had taken DCEL, immunoreactivity for AQP5 was higher in the acinar cells of the salivary glands compared with controls, when studied with immunohistochemical staining. These results thus showed that D. candidum can increase AQP5 expression in labial salivary glands and thereby promote salivary secretion to improve dry mouth symptoms.⁴¹ For a comprehensive review on bioactive phytocompounds that modulate AQPs, see Portincasa and Calamita.⁵⁴

Evidence for beneficial effects of bioactive compounds on inflammation

The beneficial effects of phytocompounds or plant-derived bioactive compounds on markers of inflammation have been extensively reviewed before. I refer readers to high-quality reviews and meta-analysis.^55,56

Potential Mechanisms

It seems that bioactive compounds may improve the pathogenesis of SS mainly by altering the effects of intestinal immunity and improving the composition of gut microbiota. Other potential mechanisms by which phytocompounds and bioactive compounds, as ancillary treatments, may benefit SS ocular and mouth symptoms may include, but are not limited to, regulation of the cAMP-PKA signaling pathway and increasing M3R and AQP5 levels,²⁰ decreasing the production of proinflammatory cytokines and increasing the release of the anti-inflammatory cytokine IL-10 and the peripheral Forkhead box protein P3 (FOXP3) mRNA expression,³⁵ TNF-alpha-mediated inhibition of AQP5 expression through histone H4 acetylation suppression,⁴² generation of autoreactive CD4⁺T cells with greater pathogenicity,⁵⁷ improvement of F/B ratio,^50–53 and inhibition of the NF-κB pathway in case of Capsaicin (trans-8-methyl-N-vanilyl-6-nonenamide, which is an alkaloid isolated from hot chili peppers of the capsicum family) and flavone Cardamonin.^58,59

Furthermore, the gut microbiota acts as an orchestrator of xenobiotic metabolism,⁶⁰ such as aldehydes, which are highly reactive molecules. Genetic errors⁶¹ and polymorphisms⁶² in their metabolism are the molecular bases of several diseases, including SS.⁶¹ It is noteworthy that SS is basically caused by mutations in the aldehyde dehydrogenase 3 A2 gene that encodes fatty aldehyde dehydrogenase 3, an enzyme that catalyzes the oxidation of fatty aldehyde to fatty acid.⁶³ Mechanism behind the association between aldehyde dehydrogenase 3 A2 gene and AQPs expression is not fully explained, however, based on some recent studies^64–66 it might be hypothesized that this association may be partly mediated by vasopressin hormone and arginine vasopressin receptor 2.

This indicates that ancillary strategies that focus the mentioned pathways may ameliorate dry eye and mouth and maybe some other symptoms of SS.

Discussion

There are some flaws in methodology of published articles that should be mentioned and addressed in future experiments and trials. It is already known that bioactive compounds such as probiotics,^67,68 functional foods,^69,70 and curcumin^71,72 ameliorate SS severity and dry eye through suppression of inflammatory mediators. It is not known however whether improvement of dry eye and mouth and increase in AQP5 expression following administration of these bioactive compounds correlates with suppression of inflammatory mediators and/or an improvement in the F/B ratio or is a genuine independent and direct effect. This is especially important both in terms of designing novel drugs and indication/contraindication of concomitant treatments, medications (such as antibiotics), and dietary supplements in these patients. In addition, different biological pathways are operative in patients with pSS with different clinical phenotypes. A better understanding of these specific processes may be instrumental in tailoring more effective target therapies.⁷³

Murine models are widely utilized for SS translational research; however, this model must be used with caution. Mouse salivary glands are similar in different aspects to human salivary glands (for instance their anatomy, histology, and physiology). It should be reminded that there are some important differences between the 2 organisms, and by extension, the salivary glands derived from them that should be considered in translational studies.⁷⁴ I propose that future experiments and clinical trials include all necessary variables including the AQP5 expression (as well as AQP3 and AQP4), muscarinic receptor 3 levels and inflammatory mediators concomitantly in their study design to attempt to find out any direct, indirect and causal relation between AQP5 expression, inflammatory mediators, gut microbiota and severity of dry eye in SS.

AQPs are currently under extensive attention as targets for therapeutic intervention with potential broad applications. However, efficient AQP modulating agents have been difficult to find, mostly due to either lack of stability and selectivity, or accompanied toxicity issues that limit in vivo studies. MicroRNAs are naturally occurring short endogenous noncoding RNAs that regulate posttranscriptional gene expression and are involved in several diseases,⁷⁵ including SS.⁷⁶ For a comprehensive list of MicroRNAs in ocular surface and dry eye diseases, see Rassi et al.⁷⁷ and Reale et al.⁷⁸ Just very recently, Pilson et al. identified MicroRNA-744-5p as the mediating ocular inflammation through Pellino3 expression in pSS patients,⁷⁶ which can be used by other researchers. Future clinical trials may include MicroRNA expression profile of lacrimal and salivary glands in their study design as most accurate futuristic biomarkers of salivary and lacrimation dysfunction, to obtain the most precise results and also calculate risk/benefit ratios following their interventions.

Conclusion

It is possible to adjust the diversity of intestinal gut microbiota and the abundance and the composition of intestinal microbiota and thereby improve the disease activity through novel drugs and bioactive compounds, similar to that of gene therapy targeted to enhance AQP5 expression. A supplementation with prebiotics (such as polyphenols with high bioavailability) in SS patients with lower F/B community ratio phenotype, through administration of butyrate-producing diets, is proposed as ancillary strategy for dry eye and mouth. It can be predicted that in the near future, investigators may replace AQP expression with more accurate markers, that is, MicroRNA expression profile in SS investigations.

The potential use of natural bioactive compounds to treat dry eye could also apply to dry mouth occurring in the context of aging and SS. This hypothesis could have relevant implication in planning a successful dietary regimen for achieving and maintaining a normal gut microbiota in SS patients, especially including much more use of polyphenol-rich foodstuffs and/or polyphenol-rich syrups and including high amounts of probiotic-rich foodstuffs like yogurt, soy yogurt, or as probiotic supplements. There are applications for pharmaceutical and nutraceutical products aiming to relieve dry eye and mouth.

Footnotes

Acknowledgment

The author extends his sincere gratitude to Alan N. Baer (The Johns Hopkins University Medical School, Baltimore, MD; Division of Rheumatology, The Johns Hopkins University Medical School, Baltimore, MD) for critical appraisal and invaluable comments.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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