The Role of the Intestinal Microbiome in Ocular Inflammatory Disease

Phoebe Lin

Disclosures

Curr Opin Ophthalmol. 2018;29(3):261-266. 

In This Article

Abstract and Introduction

Abstract

Purpose of review: The intestinal commensal microbiota are important in shaping immune cell repertoire and are influenced by host genetics. Because of this intricate interaction, an intestinal dysbiosis has been associated with multiple immune-mediated polygenic diseases. This review summarizes the literature on how alterations in the intestinal microbiota contribute to immune-mediated ocular disease, and how to potentially target the gut microbiome for therapeutic benefit.

Recent findings: Several groups have demonstrated the importance of the intestinal microbiome in uveitis pathogenesis. Two groups showed that altering the microbiota with oral antibiotics results in reduced uveitis severity, and another group demonstrated that a commensal bacterial antigen activates retina-specific autoreactive T cells, potentially indicating a commensal trigger for uveitis. We have found that commensal bacterial metabolites, short chain fatty acids, can suppress autoimmune uveitis. Age-related macular degeneration is associated with an intestinal dysbiosis, which can be influenced by genetic risk alleles and age-related eye disease study (AREDS) supplementation. Strategies that might be effective for targeting the intestinal microbiota might involve several approaches, including the use of antibiotics, drugs that supplement beneficial bacterial components or target inflammatory bacterial strains, dietary strategies or microbial transplantation.

Summary: The intestinal microbiota are potentially crucial in propagating inflammatory diseases of the eye, and can be targeted for therapeutic benefit.

Introduction

The microbiome refers to a community of micro-organisms and all of its genetic material. The Human Microbiome Project was initiated by the National Institutes of Health in 2007 to identify the microorganisms that reside normally on the healthy human body, as well as to ultimately characterize changes associated with disease states. The importance of this endeavour becomes evident when one considers that commensal microbes outnumber our mammalian cells by approximately 10 to 1.[1] If we consider this in terms of genetic information of the human body, a single human comprises 23 000 host genes, but the microbes that live on our body make up more than 3 000 000 genes, a greater than 100-fold difference.[2] A large proportion of the human microbiome is found in the gastrointestinal tract, which is also where a large portion of the human body's immune system is located. It is therefore not surprising that there appears to be strong associations with an intestinal dysbiosis (imbalance of commensal organisms) and various disease states that involve immune system derangement, including but not limited to, multiple sclerosis (MS), spondyloarthropathies such as ankylosing spondylitis (AS) and rheumatoid arthritis (RA).[3–6] The development of the early microbiota in the human body influences immune system development, and in the absence of normal colonization of the gastrointestinal tract in infants, such as occurs in C-section delivery rather than vaginal delivery, for instance, there is a predilection for immune-mediated diseases later in life according to large registry studies.[7,8]

The pathogenesis of immune-mediated (or noninfectious) uveitis is not completely understood. Although uveitis represents a heterogeneous group of conditions with differing causes, many uveitic conditions converge on certain inflammatory cytokine pathways. Elevated levels of interleukin-6 (IL-6), IL-17, IL-23 or tumour necrosis factor-alpha have been discovered in the serum or ocular fluids of immune-mediated uveitis patients of many causes. In fact, the vast majority of therapeutic targets over the past decade have involved these inflammatory cytokine pathways, have had varied degrees of success, but still require ongoing investigation for efficacy. However, clinicians often have difficulty studying what triggers uveitis, and what mechanisms lead to the above inflammatory cytokines being elevated in the eye or serum of uveitis patients. In addition, treatments aimed at re-establishing immune homeostasis are somewhat understudied. Recently, it has been discovered that the commensal microbiota plays a significant role in immune-mediated diseases in that it can either promote or inhibit (i.e. regulate) inflammation. Manipulating the microbiome can thus potentially aid in identifying novel mechanisms of disease pathogenesis, as well as new avenues of therapeutic targeting.

We now understand that there exists a complex interaction between the human microbiome, particularly that found in the gastrointestinal tract, and the body's immune system. This occurs even at the level of strain-specific alterations of immune cell repertoire. For instance, certain bacterial strains, segmented filamentous bacteria found in rodents[9] and analogous bacterial strains found in humans[10] can promote differentiation of T helper 17 cells (Th17) in the gut. Remember that Th17 cells, when they become pathogenic, are highly associated with autoimmune diseases such as uveitis. On the contrary, other bacterial species such as certain types of Clostridia, and the bacterial species, Bacteroides Fragilis, a commonly found intestinal commensal, can enhance differentiation of colonic regulatory T cells (Tregs) thus contributing to immune homeostasis.[11,12] One can imagine that the balance of the microbiota found in the body can thus affect immune-mediated disease significantly. On the flip side, several groups have found that host genetics, even HLA (human leukocyte antigen)-type can influence the microbial composition of the gut.[13,14] Other niches of the human microbiome, including the oral microbiome, the pulmonary microbiome, the skin microbiome and even the ocular microbiome, may indeed be large influencers of disease, but will not be covered in this review.

In this review, we aim to summarize the current literature on how alterations in the intestinal microbiota contribute to immune-mediated ocular diseases, and how to potentially target the gut microbiome for therapeutic benefit.

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