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  • Ophthalmology news: the microbiota and the ocular microbiome

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    What is the microbiota?

    The concept of microbiota in the human body in recent years has gathered great interest in the scientific world, which focused on studying its characteristics in the intestine, the oral cavity and the skin. In 2008 the National Institutes of Health launched The Human Microbiome Project, which highlighted an abundant and diverse amount of microbial species that inhabit the human body (specifically bacteria, but also viruses and fungi) and form the human microbiota. Understanding the role of trillions of microorganisms that populate various regions of our body can be crucial to improve the knowledge of many diseases and develop new therapeutic solutions.

    Microbiota and microbiome

    Microbiota and microbiome are two terms often used as synonyms, though they do not mean the same thing. Microbiota refers to the microorganisms that colonise a specific region of the body at a given time; the microbiome indicates the whole genetic heritage expressed by the microbiota. Therefore, although there is a distinct difference between the two terms, their ‘interchangeable’ use does not affect the understanding of information.

    The ocular microbiome

    The light reaching the human eye is divided into a visible spectrum (between 380 nm and 780 nm) and a non-visible spectrum (which includes UV rays and INFRARED rays). UV rays are absorbed by the cornea and crystalline lens, while blue light penetrates the crystalline lens and reaches the retina. Over time, both can cause damage, even permanently, to the eyes.

    The ocular microbiome

    The ocular surface, like any other lining and cutaneous surface, has a microbial flora, consisting of Gram+ and Gram- microorganisms present on the skin and that colonise the ocular surface immediately after birth. Furthermore, throughout our entire life the ocular surface is continuously exposed to the external environment and therefore to contact with different types of micro-organisms. Recent advances in the knowledge of the human microbiome, its importance in maintaining the homeostasis that characterises healthy mucous and cutaneous regions and its potential role in multiple pathologies, have led to study the ocular surface under a new light and in particular the microbial population permanently residing on it and its potential link to infectious and inflammatory (or ‘idiopathic’) eye diseases.
    The first studies, based solely on bacterial cultures sown in different grounds, showed poor bacterial colonisation of the human ocular surface in physiological conditions. Culture studies have shown that the most frequently cultivable bacteria obtained from swabs of the ocular surface are coagulase-negative staphylococci (20-80% of positive cultures from conjunctival samples and 30-100% from eyelid samples), Propionibacterium sp. and Corynebacterium sp. However, cultivable bacteria represent only a fraction of the microbes that can colonise humans and recent metagenomic studies have shown that the number of microbial cells present on or in a human being is much higher and is approximately 10 times higher than the number of human cells in our body. The application of these techniques to the study of the ocular surface microbiome has allowed for the identification of a wide variety of bacteria, viruses and fungi that cannot be cultivated by using traditional techniques.
    The various studies have led to the identification of 12 bacterial types that can be considered as a ‘core’ microbiome of the ocular surface, i.e. types that exist and can be found even in different subjects. This core consists mainly of bacteria and also, to a very limited extent, viruses and fungi and among the types identified and recognised as present on the ocular surface there are also types that are generally known as ‘pathogens’ responsible for the main ocular surface diseases (Fig. 1)

    Role of the microbiome on ocular surface immunity

    Some studies conducted on patients with Dry Eyes, associated or not with autoimmune diseases, showing alterations in the ocular surface microbiome, support the existence of a link between microbiome and health of the ocular surface. Moreover, an interesting experimental model developed at Harvard University using ‘germ-free’ mice and mice subjected to topical or systemic antibiotic therapies, recently showed that depletion of the ocular surface microbiome increases susceptibility to keratitis from Pseudomonas aeruginosa.
    The role of the microbiome on the ocular surface can therefore be the same as that in other regions of the body (e.g. skin, intestine), meaning that commensal bacterial flora interacts with epithelial and immune system cells and coordinates various functions aimed at maintaining homeostasis and local well-being such as preserving the epithelial barrier, inhibiting apoptosis and inflammation, accelerating wound healing, competitive exclusion of potential pathogens, maintaining the homeostasis of the immune system’s response. Recent experimental evidence has increased the knowledge of how the ocular microbiome and the intestinal microbiome – through different mechanisms and pathways – contribute to regulating the immunity of the ocular surface, intervening on the production of IgA, on innate immunity and on autoimmunity.

    Microbiome, probiotics, paraprobiotics

    In recent years, scientific literature reported large evidence supporting a role of the intestinal and cutaneous microbiome in regulating type 2 immune responses and in the development of allergies, from atopic dermatitis to food and respiratory allergies.
    This evidence has led to numerous studies aimed at improving the microbiome (mainly intestinal) of allergic patients or those at risk of developing allergies through food supplementation with probiotics and prebiotics. For example, the World Allergy Organisation recommends dietary supplementation with probiotics, defined as “live microorganisms administered in adequate amounts that confer a beneficial health effect on the host”, in children at high risk of developing allergies and in their mothers during pregnancy and lactation. However, recent research showed that cell lysates and no longer viable microbial cells can also have a ‘probiotic’ effect in regulating local immunity. This led to formulating the definition of paraprobiotics as “inactivated microbial cells or cellular fractions capable of having a beneficial effect on the health of the subject to which they are administered”, showing they act on specific cell receptors and induce the expression of cytokines, such as interleukins, tumour necrosis factors, interferons and natural killer cells. Bacterial cell fragments therefore interact with various components of the innate and adaptive immune responses of the various regions of the body that are intimately connected to each other by shaping the various molecules involved in the two processes.
    Generally, probiotics and paraprobiotics have a regulating and modulating effect of the 2-mediated T helper response, shifting the Th-2 mediated responses to Th-1 or Th-reg, which play a key role in managing allergic phenomena.

    Note: the main players of the immune response are the Thelper lymphocytes that regulate the adaptive and inflammatory immune response. After activation by the cells with the antigen, the various types of Thelper are developed and specialise in the production of specific cytokines. For example, Th1 lymphocytes regulate cell-mediated responses through IFN-γ and IL-12 production; Th2 lymphocytes regulate the humoral immune response and allergic responses by producing IL-4 which in turn activates IgE; Th-17 lymphocytes are involved in defence against pathogens; Regulatory T lymphocytes (Treg) are a subpopulation of T lymphocytes specialised in suppressing the activation of the immune system towards self-antigens.

    Alternative adjuvant therapeutic approaches to dietary supplementation have been attempted with interesting results, especially in the topical use of different types of Lactobacillus-based probiotics. Lactobacilli are non-pathogenic microorganisms, gram+, the main components of the commensal microbial flora that in various clinical studies have shown effectiveness in the adjuvant treatment of various allergic forms and evidence also regarding their use in ophthalmology. A pilot study in 2008 carried out on 7 paediatric patients with mild to moderate vernal keratoconjunctivitis, demonstrated the effectiveness in reducing the signs and symptoms of a galenic preparation for ophthalmic use based on heat-inactivated Lactobacillus acidophilus, in a saline solution, and given to patients 4 times a day for 4 weeks. The assessment of signs and symptoms in relation to the baseline, after 2 and 4 weeks of administration of the preparation, showed a reduction in the parameters examined. Furthermore, the cytological evaluation on 3 patients also demonstrated a down regulation of ICAM1 and TLR4, showing that lactobacilli are able to counterbalance the Th2 mediated immune responses typical of an allergic disease.

    Lactobacillus sakei

    Among the various lactobacilli, the strain of Lactobacillus sakei, isolated from Kimchi, a typical Korean dish, has shown an effective anti-Staphylococcus aureus activity and a high immunomodulatory capacity both in vivo and in cell cultures. This is supported by various studies such as a study published in 2013, which evaluated the effect of L. sakei on an animal model of DNCB-induced atopic dermatitis (chlorodinitrobenzene). The L. sakei strain was administered to mice for 2 weeks in the form of viable cells and lysate and a positive effect was seen both in vivo, by evaluating the injuries and itching, and in vitro, by assessing the IgE, chemokines and IL4 and IL6 serum levels. The results indicate that lysate reduces the concentration of IgE and inhibits IL4 and IL6, increased after the allergic phenomenon has occurred. This effect is demonstrated by other studies as a randomised clinical trial on 28 patients with atopic dermatitis treated in one part of the body with an emollient containing L. sakei and the other part with only the emollient (control), which showed a significant improvement of the clinical picture in the body area treated with the paraprobiotic based on L. sakei.
    In short, the link between microbiome, paraprobiotic probiotics and ocular surface pathologies is a fascinating topic, subject to increasing attention from scientific research and with many potential physiopathological, clinical and therapeutic implications. The availability of a topical paraprobiotic formulation for ophthalmic use represents an interesting new resource, able to introduce a series of new therapeutic options. The potential benefits of this approach in the exclusive or ancillary treatment of many ‘idiopathic’ irritations and inflammations of the ocular surface are still largely unknown.

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