Microbiome and the Eye: What's the Connection?

By Jun Sun

Microbiome and the Eye: What’s the connection? highlights how alterations in the gut and eye microbiomes can lead to systemic immune alterations with subsequent effects on the eye. The book is divided into two sections, one highlighting how alterations in the gut microbiome impact various components of health outside the gut, with a focus on the immune system and inflammatory mediators, and the second focusing on studies on a variety of ocular diseases, including ocular surface diseases/dry eye, keratitis, uveitis, glaucoma, and retinopathy to gut dysbiosis. With its translational approach, the book is suitable for both researchers and clinicians.

The book will help readers understand the mechanisms in which gut and eye microbiome composition may influence health in multiple compartments, with a focus on eye diseases.

• Helps researchers understand the clinical eye diseases that have been linked to gut microbiome abnormalities
• Helps clinicians understand the mechanisms in which gut microbiome composition may influence health in multiple compartments
• Provides a foundation for future studies that consider gut microbiome manipulations as a treatment for specific eye diseases

• Language: English
• Publisher: Academic Press
• Release date: Jun 20, 2023
• ISBN: 9780323985376

Book preview

Microbiome and the Eye

Edited by

Anat Galor

Staff Physician, Miami Veterans Affairs Medical Center, Professor of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA

Jun Sun

Professor of Gastroenterology and Hepatology, University of Illinois Chicago College of Medicine, Chicago, Illinois, USA

Table of Contents

Cover image

Title page

Copyright

Contributors

Part 1. How does the microbiome influence human health

Chapter One. The normal gut microbiome and human health

1. Introduction

2. The definition of microbiome: Old concepts and new challenges

3. Concepts of gut microbiome health

4. Biological functions of a healthy microbiome: Quality not just quantity

5. Location matters: Eye, skin, brain, and gut microbiome

6. Mechanisms for better understanding modulation microbiome

7. Challenges, conclusion, and future work

Chapter Two. Structural and functional variation of human oral microbiome in health and disease

1. Introduction

2. Adult oral microbiome

3. Acquisition and maturation from birth, adolescence to adulthoods

4. Factors associated with structural and functional variation

5. Connection to gastrointestinal pathophysiology

6. Connection to systemic diseases

7. Concluding remarks

Chapter Three. The normal ocular microbiome and human eye health

1. Introduction

2. What components constitute the ocular surface?

3. What is the ocular surface microbiome?

4. Conclusion

Chapter Four. What is microbial dysbiosis and how does it impact human health?

1. What is the definition of dysbiosis?

2. Challenges in using the term ‘dysbiosis’

3. Examples of dysbiosis-disease associations at various body sites

4. What are the drivers of dysbiosis?

5. Current approaches and considerations for defining dysbiosis

6. Final thoughts

Chapter Five. Immune response to intestinal microbial dysbiosis

1. Healthy microbiota

2. Gut dysbiosis and the immune response in GI diseases

3. Perspectives

Part 2. Microbiome alterations and eye disease

Chapter Six. The impact of microbiome alterations on ocular surface diseases

1. Introduction

2. Gut microbiome and dry eye

3. Oral microbiome and dry eye

4. Ocular microbiome and dry eye

5. Conclusions

Chapter Seven. The microbiome and keratitis

Chapter EIGHT. Seven reasons for a uveitis specialist to understand the microbiome

1. The microbiome educates the immune response

2. Every immune-mediated disease is associated with dysbiosis

3. HLA associations with uveitis and other immune-mediated diseases might occur via the microbiome

4. Diet greatly affects the microbiome and so it must affect the immune response

5. The microbiome affects the efficacy of multiple medications

6. The microbiome has therapeutic potential

7. The microbiome could lead to the prevention of immune-mediated diseases

Chapter Nine. Influence of gut microbiome on primary open angle glaucoma

Chapter Ten. Microbiome abnormalities and retinal disease

1. The microbiome as a contributor to diabetic retinopathy

2. The gut-retina axis and age-related macular degeneration

3. Therapeutic considerations

Chapter Eleven. Microbiome manipulation as a target for eye diseases: Lessons from animal models

1. Introduction

2. The intestinal microbiota influence on adaptive immunity

3. Alterations in the intestinal microbiota in noninfectious uveitis and other extraintestinal disease, lessons from rodents

4. Therapeutic targeting of the gut microbiome

5. Conclusions

Chapter Twelve. Microbiome manipulation as a target for eye diseases: lessons from humans

1. Introduction

2. What is a normal gut and the ocular surface microbiome?

3. Dysbiosis

4. Diet

5. Pre and probiotics

6. Fecal microbiota transplantation

7. Conclusion

Index

Copyright

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Contributors

Emma Allen-Vercoe,     Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada

Logan Charles Barr,     School of Medicine, Queen's University, Kingston, ON, Canada

Jason Betz

Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, United States

Miami Veterans Administration Medical Center, Miami, FL, United States

Kara Cavuoto,     Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, United States

Dong F. Chen,     Department of Ophthalmology, Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA, United States

Neda Dadgar,     Cole Eye Institute, Cleveland Clinic, Cleveland, OH, United States

Cintia S. de Paiva

Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, United States

Biochemistry and Cell Biology Graduate Program, Department of BioSciences, Rice University, Houston, TX, United States

Anat Galor

Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, United States

Miami Veterans Administration Medical Center, Miami, FL, United States

Tejpal Gill,     Department of Medicine, Oregon Health and Science University, Portland, OR, United States

David A. Good,     Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada

Hassan Hazari,     Department of Ophthalmology, Queen's University, Kingston, ON, Canada

Nobuhiko Kamada,     Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States

Ikuko Kato

Department of Oncology, Wayne State University School of Medicine, Detroit, MI, United States

Department of Pathology, Wayne State University School of Medicine, Detroit, MI, United States

Mohammed F. Khan,     Department of Physiology, Wayne State University School of Medicine, Detroit, MI, United States

Mohammed I. Khan,     Division of Hospital Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States

Sho Kitamoto,     Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States

Phoebe Lin,     Cole Eye Institute, Cleveland Clinic, Cleveland, OH, United States

Tammy M. Martin,     Departments of Ophthalmology and Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR, United States

Pasquale Napolitano,     Department of Medicine and Health Sciences V. Tiberio, University of Molise, Campobasso, Italy

Adwaita R. Parab,     Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, United States

Veshesh Patel,     Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, United States

James T. Rosenbaum,     Departments of Medicine, Ophthalmology, and Cell Biology, Oregon Health and Science University, Legacy Devers Eye Institute, Portland, OR, United States

Jacob Rullo

Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada

Department of Ophthalmology, Queen's University, Kingston, ON, Canada

Ritu R. Sampige,     Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, United States

Laura Schaefer,     Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, United States

Kaitlin K. Scholand

Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, United States

Biochemistry and Cell Biology Graduate Program, Department of BioSciences, Rice University, Houston, TX, United States

Anthony J. St. Leger,     Ophthalmology and Immunology, University of Pittsburgh, Pittsburgh, PA, United States

Jun Sun

Department of Medicine, College of Medicine, University of Illinois Chicago, Chicago, IL, United States

Department of Microbiology/Immunology, College of Medicine, University of Illinois Chicago, Chicago, IL, United States

Jesse Brown VA Medical Center, Chicago, IL, United States

Yinglin Xia,     Department of Medicine, College of Medicine, University of Illinois Chicago, Chicago, IL, United States

Part 1

How does the microbiome influence human health

Outline

Chapter One. The normal gut microbiome and human health

Chapter Two. Structural and functional variation of human oral microbiome in health and disease

Chapter Three. The normal ocular microbiome and human eye health

Chapter Four. What is microbial dysbiosis and how does it impact human health?

Chapter Five. Immune response to intestinal microbial dysbiosis

Chapter One: The normal gut microbiome and human health

Yinglin Xia ¹ , and Jun Sun ¹ , ² , ³       ¹ Department of Medicine, College of Medicine, University of Illinois Chicago, Chicago, IL, United States      ² Department of Microbiology/Immunology, College of Medicine, University of Illinois Chicago, Chicago, IL, United States      ³ Jesse Brown VA Medical Center, Chicago, IL, United States

Abstract

Our body sites are colonized by microbes that have different types of interactions with our organs. In the past decades, the complex interactions between the host and the microbiome are being deciphered, due to the development of molecular tools and techniques, such as metagenomics, metabolomics, lipidomics, and metatranscriptomics. Microbiome, as an invisible organ that inhabits a particular environment and especially the collection of microorganisms living in or on the human body. Normal microbiome is described as a microbial community with high diversity, good balance, and normal functions in host-microbial interactions for immunity, barriers, nutrients, and metabolism. In this chapter, we discuss the definition of normal microbiome, methods to study/quantify microbiome, and potential strategies to restore its healthy status in human diseases. The contribution of the microbiome to homeostatic regulation extends beyond the gut to almost all organs, e.g., eyes, in the human body. Thus, microbiome definition and functions have location and organ specificity. We also outline the challenges in the field and future directions for functional studies, physiological relevance, host-microbial interactions, and metabolites. Insights into healthy microbiomes will help us to develop new strategies to maintain healthy status and prevent/treat diseases.

Keywords

Dysbiosis; FMT; Health; Microbiome; Microbiota; Probiotics

1. Introduction

The gut microbiota is now considered as one of the essential elements in health and disease. Its functions are involved in immunity, barrier, nutrients, energy, and metabolism. Thus, gut microbiota deviations are linked with various human diseases not only in the gastrointestinal tract but also in other organs. These diseases include intestinal bowel diseases, hepatic steatosis, cancers, infectious diseases, allergy, obesity, type 2 diabetes, and ocular diseases [1,2].

In this chapter, we discuss the concept/definition of normal/healthy microbiome and its functions in health and disease. We then outline the normal biological functions of microbiome, methods to study microbiome, and current understanding of mechanisms by which microbiome interacts with the host. A healthy microbiome leads to healthy metabolites, which are critical for a healthy body/host. We consider the potential to restore the healthy status of the microbiome in diseases. We also discuss the challenges in the field and future directions for functional studies, physiological relevance, host-microbial interactions, and metabolites. A better understanding of the microbiome will help us to develop novel strategies for disease prevention, diagnosis, and treatment.

2. The definition of microbiome: Old concepts and new challenges

The microbiome research emerged from the ecology area. An ecological definition of microbiome is described by Whipps et al. [3] as: a convenient ecological framework of microbiome in biocontrol systems. They [3] defined the microbiome as a characteristic microbial community occupying a reasonably well defined habitat which has distinct physio-chemical properties. This definition emphasizes the microbiome's distinct physio-chemical properties and functions and its interactions with environment. A narrower definition proposed in 1952 used the whole microbiome to define The protozoan fauna that is in species and individuals [4].

The traditional microbiological studies largely rely on cultured methods. However, the majority of bacteria cannot be cultured using the simplified experimental condition in the lab. Traditional microbiology focuses on single microbial species but not the community with dynamic microbial-microbial interactions, and many efforts have been spent on fighting the pathogens, but not on promoting the beneficial microbes. In the past 20 years, the exciting progress of microbiome research is due to the advanced modern molecular biology methods and omics data analysis. The old terms microflora and gut flora have been replaced with better-defined terms microbiome and microbiota. Several variant definitions of the microbiome have been described from the perspective of multiple disciplines. One narrowly defined microbiome refers to the collection of genes and genomes of members of a microbiota [5] or all the microbes of a community [6]. The genomic definition considers the microbiome as a collective genome of microorganisms inhabiting a particular environment and especially the human body [7,8].

The most cited definition of microbiome is a narrower definition proposed in 2001 [9], which describes microbiome as an ecological community of commensal, symbiotic and pathogenic microorganisms within a body space or other environment [9]. The Human Microbiome Project [10] defined the human microbiome from the perspective of microbial-host organism's interaction as the collection of all the microorganisms living in or on the human body, including eukaryotes, archaea, bacteria, and viruses [11].

In the literature, the two terms microbiota and microbiome have been mis-used or used interchangeablely [5,12]. Actually, microbiome contains both the microbiota (community of microorganisms) and their theater of activity (structural elements, metabolites/signaling molecules, and the surrounding environmental conditions) [3,11,12] (Fig. 1.1). Consensus has been reached in the research community that does not use the old term flora.

The take-home messages are that microbiomes have distinct physiological and chemical properties, functions, and interactions with their environments, while the host-microbial interactions and microbe-microbe interactions are dynamic, substantially changing over time, and depending on host and environmental factors.

3. Concepts of gut microbiome health

The reborn interest in microbes is due to their novel and potential roles in disease pathogenesis and treatment. The definition related to gut microbiome health must reflect the physiological status and functions in health. Thus, we will discuss the Gut Health first. In a 2021 Lancet paper [14], Gut Health is defined by the absence of gastrointestinal symptoms (e.g., abdominal pain, diarrhea) and disease (e.g., IBD, colon cancer), as well as an absence of other unfavorable local conditions, such as increased intestinal permeability, mucosal inflammation, or deficiency (or even excess) of short-chain fatty acids (SCFAs) [14]. Interestingly, this definition emphasizes diet and includes SCFAs, bacterial metabolites, as a readout. Actually, the gut microbiome is a key driver of the individuality of diet–health relationships. A 2010 review [15] also provided a summary of biomarkers for gut and microbiome health, highlighting the gastrointestinal microbiome as a critical contributor to achieve gut health. In 2012, Backhed et al. discussed the importance to elucidate the properties of healthy microbiota, which will provide a target for interventions and/or microbial modifications aimed at sustaining health in generally healthy populations and improving the health of individuals exhibiting disrupted microbiota in various diseases [16].

Figure 1.1  The microbiome includes the microbiota and several other elements. This schematic highlights how the term microbiome encompasses both the microbiota (community of microorganisms) and their theater of activity (structural elements, metabolites/signaling molecules, and the surrounding environmental conditions) [13]. Modified from G. Berg, et al., Microbiome definition re-visited: old concepts and new challenges, Microbiome 8 (1) (December 2020) 103. https://doi.org/10.1186/s40168-020-00875-0.CCBY4.0.

It is well accepted that in a healthy situation, gut microbiome contributes to maintain intestinal barrier, to improve insulin secretion and insulin sensitivity, to reduce food intake, to lower plasma lipids, and to avoid hepatic steatosis and metabolic endotoxemia, thus lowering inflammation. Conversely, opposite effects have been observed in pathological situations of various diseases [17].

We then visit the concept of healthy microbiome, which is related to its functions and diversity [18]. In general, normal microbiome is described as a microbial community with high diversity, good balance, and normal functions in host-microbial interactions for immunity, barriers, nutrients, and metabolism. Microbiome diversity is often used as a proxy for health status. However, reduced microbiome diversity in the infant intestine does not always have adverse effects on the community or host health [19]. The germ-free mice with genetic defects, e.g., IL-10 knockout, were able to avoid the development diseases, such as IBD. The diverse microbiome does not reflect the functional microbiome. Therefore, concepts as modularity or interconnectedness, of the microbiome may be useful for describing microbiome community structure and associated impacts on host [20]. Additionally, identifying keystone microbial taxa or functions that promote emergent community function can provide critical insights into host health [21].

The normal/healthy gut microbiome needs to maintain in the gastrointestinal epithelium underpins, metabolic and immune functions as its central role in gut health, as well as to maintain the functioning interactions with organs beyond GI. However, it is not yet possible to define the optimal gut microbiome, and therefore make recommendations as to how to achieve its healthy status [18]. Among the unknowns include the dynamic and interactive functions of specific microbial species and strains, particularly under different host conditions, including the host's recent and long-term dietary intake. A wide range of microbiome profiles could be considered normal or healthy [18].

In the literature, the unhealthy or abnormal microbiome is usually described as dysbiosis. Dysbiosis refers to an imbalance between the types of organisms present in a person's natural microbiome, contributing to a range of illness. Dysbiosis in the gut microbiota has been linked to multiple GI disorders, such as IBD, irritable bowel syndrome (IBS), and celiac disease, colon cancer [17,22,23]. A much broader stimulatory/regulatory role of the gut microbiota in disorders involves organ systems other than the digestive tract, such as the eyes, lungs, breast, and brain [17,24–27].

Altered functions of microbiome would be more critical than the diversity or imbalanced. The take-home message for defining normal/healthy microbiome should be related to its biological functions, not just the changes in diversity or profile. Gut microbiome is a determiner of gut health and human health.

4. Biological functions of a healthy microbiome: Quality not just quantity

Human Microbiome Project [10] is designed to understand the microbial components of our genetic and metabolic landscape, and how they contribute to our normal physiology and disease predisposition [28]. The definition of the normal gut microbiome, a concept of core microbiome was proposed [10]. The first metagenomic study of human gut microbiome was reported in 2006 [29]. Researchers have then used and developed many molecular tools and techniques (e.g., metagenomics, metabolomics, metatranscriptomics, and lipidomics) for microbiome research. Thus, we are able to decipher the complex interactions between the host and the microorganisms. As reviewed in many previous papers [22,28,30–32], the human microbiota is an acquired and essential organ of the body. The gut microbiota provides the host with beneficial functions for the myriad aspects of host biology. It confers protection from pathogens through colonization resistance, influences host nutrition and metabolism, trains and modulates immune function, and contributes to patterns of brain development and behavior.

An important update in the microbiome research is the ratio of bacteria to human cells. Old literature cited that the ratio of bacteria to human cells is 10:1. The ratio of bacteria to human cells was updated from 10:1 to closer to 1:1 based on the 2016 Cell paper [33]. However, this updated ratio does not take away from the biological importance of the microbiota.

The development of the microbiome field has opened the doors to apply computational and mathematical models to characterize community structure and dynamics, to predict responses to perturbations, and to explore general dynamical properties such as stability, alternative stable state, and periodicity.

The dynamic microbiome can be analyzed through a regression-based time series model [34]. This kind of time series model treats the relative abundances of taxa or ecological diversity of the gut microbiota over time as dependent variables (a series of observations) and uses a function of time and other covariates as independent variables.

We can categorize the time series model for measuring dynamic microbiome into four groups: (1) time-series clustering method (TSCM); (2) dynamical systems theory model (DSTM); (3) time-dependent generalized additive models (TDGAM), and (4) nonautoregressive microbial time series model (NAMTSM). TSCM first groups together OTUs based on the similarity of their temporal profiles and then performs statistical hypothetic testing of OTUs rather than average the OTUs [35,36]. For example, MC-TIMME (Microbiome Counts Trajectories Infinite Mixture Engine) uses a time-series clustering algorithm [35] and nonparametric Bayesian techniques to automatically infer the temporal patterns from microbiome data and then assign OTUs in a dataset to the inferred temporal patterns [37].

DSTM has been proposed on microbial time series, which belongs to autoregressive models. DSTM has been used in the exploration of microbial communities. The Lotka–Volterra model is one of the most used models [38–41], with a special emphasis on the generalized Lotka–Volterra (gLV) nonlinear differential equations [20,40]. This model assumes the growth of species in an ecosystem is density-bounded and modulated by other species in the system either positively or negatively. One example of using the gLV equations to analyze the dynamics of relative abundances of OTUs from 16S rRNA was reported from Ref. [42].

TDGAM is another dynamical systems theory model, which uses the framework of generalized additive models (GAMs). It is nonparametric and often preferable using in cases with litter a priori information on a system [43]. TDGAM has been extensively used for the analysis of ecological time series [44–46]. It has been adopted to analyze microbiota time-series data [47,48] to capture the dynamics of the human infant gut microbiota.

NAMTSM assumes that the human gut microbiome is driven by two dynamic regimes: external environmental fluctuations and internal processes [49]. The external environmental fluctuations are nonautoregressive, driven by external factors (e.g., diet), and denominate the dynamics of the human gut microbiome, i.e., most organisms are stable, carrying fixed capacities and abundant taxa across individuals. The autoregressive dynamics happen occasionally when the system recovers from larger shocks.

Unlike autoregressive models (e.g., Lotka–Volterra), NAMTSM analyzes gut microbial time series via a nonautoregressive approach [49]. The vector autoregressive models (VARs) are used to separately model autoregressive and nonautoregressive components [50,51]. VARs assume the time series process with autocorrelation, cross-correlations, and serially uncorrelated or independent noise. Additionally, in these models, within-host dynamics characterized by continuous methods instead of taking community state-clustering approach [49].

Because microbiome has diverse biological effects on the host, alerted microbiome during early life and adulthood are recognized as leading to dysregulation of immune, metabolic, and neuroendocrine processes [17,52]. Although causality can be difficult to establish, evidence for a causal role of an altered microbiome is growing. Microbes can be passed from parents to offspring [19], thus, the health status of the microbiome also influences health in an intergenerational fashion and many pathological states resulting from an altered microbiome in mothers could have adverse effects on the gestational environment for the next generation [19].

In summary, biological functions of gut microbiome include: (1) secreting antimicrobial products to negatively select against pathogens; (2) gleaning indigestible ingredients from foods for energy storage, and nutrition synthesis; (3) detoxifying the deleterious xenobiotics and affecting the host metabotypes; (4) training and developing robust intestinal and immune system; and (5) providing signals for epithelial renewal and maintaining intestinal integrity and barrier [31,32]. When we discuss the normal microbiome, we need to refer to its normal biological functions in the host.

5. Location matters: Eye, skin, brain, and gut microbiome

Our body sites are colonized by microbes which have different types of crosstalk with our organs. The complex interactions occurring between the host and the different microorganisms are also related to location and organ specificity. The abundance of bacteria varies according to the different body sites [17]. The key members of bacteria are also different depending on locations and time.

Microbiota in the gastrointestinal tract is known for its spatial heterogeneity [53]. In the colon, the microbiota can reach 10¹⁰–10¹² CFU/mL with Firmicutes, Bacteroidetes, Lachnospiraceae, Bacteroidaceae, and Prevotellaceae, as well as strict colonic anaerobes, e.g., Clostridium, Eubacteria, and Roseburia [54,55]. The diversity of the gut microbiota in the proximal colon is normally higher than that in the distal colon [53] because of microenvironmental conditions, such as pH, bile acids, oxygen levels), mucus, nutrients, and immune factors, as well as microbial community dynamics.

The keystone taxa could be drivers of microbiome structure and functioning [21]. For example, in the human gut microbiome, keystone taxa, such as Bacteroides thetaiotaomicron [56], Bacteroides fragilis, and Ruminococcus bromii [57], exert considerable control on microbiome structure and functioning [21]. In the oral microbiome, Porphyromonas gingivalis causes inflammatory tissue destruction and initiates imbalance or dysbiosis of the microbial community that favors further growth of this keystone taxon [58].

Host site factors (e.g., the pH and oxygen levels) are further refined by interactions with the environmental factors (e.g., diet and antibiotic use) [59]. Despite the overall low number of bacteria on the ocular surface microbiome (OSM: eye microbiome), studies have demonstrated the existence of an OSM in healthy individuals with the three dominant phyla: Proteobacteria, Firmicutes, and Actinobacteria [60], although the precise distribution of each phylum varies by individual. This is supported by several studies despite different geographic locations and patient populations [61]. In contrast, the gut microbiome has Firmicutes, Bacteroidetes, and Proteobacteria predominate at the phyla level. At the genus level, the most consistent contributions on the ocular surface as detected by culture-independent methods are from Propionibacterium, Corynebacteria, Staphylococcus, and Streptococcus, with small contributions from Acinetobacter, Brevundomonas, Pseudomonas sp., Aquabacterium, and Sphingomonas [62].

Many eye microbiome research [1,2] focuses on microbiome on host immunity and metabolism. There are significant associations between the altered gut microbiome and specific ocular diseases and pathological processes, including Behcet's syndrome, autoimmune uveitis, age-related macular degeneration, choroidal neovascularization, bacterial keratitis, and Sjogren-like lacrimal keratoconjunctivitis. Alerted gut microbiome resulted in quantifiable changes in the host immune response, suggesting immunopathogenesis as the basic link between intestinal dysbiosis and ocular disease [2]. Furthermore, there are also studies on the local changes in the eye microbiome in the disease development [1]. With enhanced understanding of the microbiome in ophthalmic diseases, the stage is set for further studies on the underlying