Gut Microbiome

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Introduction

The gut microbiome refers to the commensal bacteria, fungi, and viruses seen in the gut that are important for nutritional, developmental, defensive, and physiologic processes.[1][2] Bacteria that are commonly seen in the gut microbiome have important roles in extracting nutrients from food, synthesizing vitamins and amino acids, maintaining homeostasis, and protecting against pathogens.[1][2] The gut microbiome is enormous in number and diversity of species, outnumbering human cells 10:1 and contributing approximately 8 million genes.[1][2] In contrast, the human genome carries only about 20,000 genes.[2]

Composition of the Gut Microbiome

Factors that Affect the Diversity of the Microbiome

The diversity of the gut microbiome can vary between individuals depending on age, gender, ethnicity, genetics, and pathology.[1] Lifestyle factors have a strong association with the diversity of the bacteria seen in the gut microbiome. For example, there is a strong association between both the frequency and duration of physical activity and diversity of the bacteria seen in the microbiome.[3] Healthy diets consisting of fruits, vegetables, omega-3 fatty acids, and cruciferous vegetables are positively correlated with increased diversity of bacteria that constitute the microbiome.[3]

Table 1: Composition of the Gut Microbiome[1][4][5][6][7][8][9]
Microbes of the Gut Most Commonly Seen Microbes
Bacteria Phylum Level:
  • Bacteroidetes
  • Firmicutes
  • Actinobacteria
  • Proteobacteria
  • Fusobacteria
Viruses
  • Bacteriophages
Fungi Phylum Level:
  • Ascomycota
  • Basidiomycota

Genus Level:

  • Saccharomyces
  • Candida
  • Cladosporium
  • Malassezia

Bacteria

The most commonly seen phyla in a typical gut microbiome include Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria, and Fusobacteria which constitute >90% of the gut microbiota.[1][4][5]

Viruses

Viruses in the gut microbiome consist primarily of bacteriophages.[6] The most prevalent and persistent bacteriophages present in the microbiome infect Bacteroides, Faecalibacterium, Eubacterium, Prevotella, and Parabacteroides.[6]

Fungi

On a phylum level, the fungi most commonly seen in the microbiome include Ascomycota and Basidiomycota, and the fungi most commonly seen in the microbiome on the genus level include Saccharomyces, Candida, Cladosporium, and Malassezia.[7][8][9]

Disease Entity

Gut Microbiome and Negative Associations with Human Health

Dysbiosis of the gut microbiome can manifest in a variety of ways, including diarrhea, nausea, and acid reflux.[3] In addition, BMI, weight, and blood pressure have also been shown to have a significant negative correlation with diversity.[3] A dysbiotic microbiome has been associated with a variety of diseases. For example, those with lung cancer show reduced levels of Actinobacteria.[10] There is increasing evidence that dysbiosis of the gut microbiome also plays a role in different forms of inflammatory bowel conditions such as Crohn’s disease and ulcerative colitis.[11] However, to date it is still unclear whether dysbiosis is a direct cause for inflammatory bowel syndrome or if dysbiosis occurs secondarily.[11] Dysbiosis has been linked to celiac disease, multiple sclerosis, rheumatoid arthritis, type 1 diabetes, colorectal cancer, and systemic lupus erythematosus.[11][12][13] Studies have also shown that dysbiosis is associated with a variety of ocular manifestations.

Ocular Pathologies Associated with Gut Microbiome Dysbiosis

Table 2: Ocular Pathologies Associated with Gut Microbiome Dysbiosis[9][14][15][16][17][18][19][20][21][22] [23][24]
Ocular Manifestations Relative Abundance Increase Relative Abundance Decrease
Age-Related Macular Degeneration Bacterial
  • Prevotella (Bacteroidetes)
  • Anaerotruncus (Firmicutes)
  • Oscillibacter (Firmicutes)
Bacterial
  • Ruminococcaceae (Firmicutes)
Uveitis Bacterial
  • Prevotella (Bacteroidetes)
  • Streptococcus (Firmicutes)

Fungal

  • Candida glabrata (Ascomycota)
  • Malassezia globosa (Basidiomycota)
  • Malassezia restricta (Basidiomycota).
Bacterial
  • Faecalibacterium (Firmicutes)
  • Ruminococcus (Firmicutes)
  • Lachnospiraceae (Firmicutes)
  • Bacteroides (Bacteroidetes)
Glaucoma Bacterial
  • Prevotellaceae (Bacteroidetes)
  • Enterobacteriaceae (Proteobacteria)
  • Escherichia coli.(Proteobacteria)
Bacterial
  • Megamonas (Firmicutes)
  • Bacteroides plebeius (Bacteroidetes)
Retinopathy of Prematurity Bacterial
  • Enterobacteriaceae (Proteobacteria)
N/A
Retinal Artery Occlusion Bacterial
  • Bifidobacterium spp. (Actinobacteria)
  • Bacteroides stercoris (Bacteroidetes)
  • Faecalibacterium prausnitzii (Firmicute)
Bacterial
  • Odoribacter (Bacteroidetes),
  • Parasutterella (Proteobacteria)
  • Lachnospiraceae (Firmicute)
Fungal Keratitis Bacterial
  • Treponema (Spirochaetes)
  • Bacteroides fragilis (Bacteroidetes).
Bacterial
  • Faecalibacterium prausnitzii (Firmicute),
  • Bifidobacterium adolescentis (Actinobacteria),
  • Lachnospira (Firmicute),
  • Mitsuokella multacida (Firmicute)
  • Bacteroides plebeius (Bacteroidetes),
  • Megasphaera (Firmicute)
  • Lachnospiraceae (Firmicute)
Bacterial Keratitis Fungal
  • Aspergillus (Ascomycota)
  • Malassezia (Basidiomycota)
Bacterial
  • Dialister (Firmicute)
  • Megasphaera (Firmicute)
  • Faecalibacterium (Firmicute)
  • Lachnospira (Firmicute)
  • Ruminococcus (Firmicute)
  • Veillonellaceae (Firmicute)
  • Ruminococcaceae (Firmicute)
  • Lachnospiraceae (Firmicute)

Fungal

  • Mortierella (Mucoromycota)
  • Rhizopus (Mucoromycota)
  • Kluyveromyces (Ascomycota)
  • Embellisia (Ascomycota)
Sjogren’s Syndrome and Dry Eye Bacterial
  • Proteobacteria  
  • Actinobacteria
  • Bacteroidetes
  • Faecalibacterium (Firmicutes)
N/A

Age-Related Macular Degeneration

Dysbiosis of the gut microbiome has been associated with the onset and progression of age-related macular degeneration (AMD).[14] Lin et al. found that patients with advanced AMD had higher abundance of Prevotella (Bacteroidetes) and lower abundance of Ruminococcaceae (Firmicutes) compared to controls.[14][15] Zinkernagel et al. found that patients with neovascular AMD had a greater proportion of Anaerotruncus (Firmicutes) and Oscillibacter (Firmicutes) compared to controls.[14][16] Zysset-Burri et al. also found that Firmicutes were more prevalent in patients with neovascular AMD and may even be a potential biomarker for for the disease.[14][25] Bacteroides species may even be protective for neovascular AMD, as they were more abundant in control patients.[14][15][16]

Uveitis

Patients with uveitis show reduced diversity of various anti-inflammatory Firmicutes such as Faecalibacterium, Ruminococcus, and Lachnospiraceae and reduced diversity of Bacteroides, which is a genus of Bacteroidetes.[17] A greater proportion of pro-inflammatory Bacteroidetes and pathogenic Firmicutes, such as Prevotella and Streptococcus, respectively, are seen in cases of uveitis when compared to healthy controls.[17]

Dysbiosis of the fungal microbiome has also been seen in patients with uveitis.[9] Uveitis patients may see enrichment of various opportunistic pathogens such as Candida glabrata (Ascomycota), Malassezia globosa (Basidiomycota), and Malassezia restricta (Basidiomycota).[9] Furthermore, healthy patients may have a greater abundance of yeast genera that are anti-inflammatory and antipathogenic.[9]

Glaucoma

Patients with primary open-angle glaucoma have gut microbiota that are different compared to healthy subjects.[18] Patients with primary open-angle glaucoma show increased abundance in Bacteroidetes such as Prevotellaceae and Proteobacteria such as Enterobacteriaceae and Escherichia coli.[18] On the other hand, healthy subjects have significantly fewer Megamonas, which is a genus of Firmicutes, and Bacteroides plebeius.[18]

Retinal Manifestations

Diabetes Mellitus and Diabetic Retinopathy

Major phyla, such as Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria, do not vary significantly between healthy patients and those with type-2 diabetes mellitus (T2DM) who do not develop diabetic retinopathy.[26] Minor phyla between these groups vary, such as Synergistetes, Lentisphaerae, Spirochaetes, Crenarchaeota, Saccharibacteria, Fusobacteria, Euryarchaeota, and Elusimicrobia.[26] However, those who have T2DM and diabetic retinopathy have significantly fewer Bacteroidetes and Actinobacteria compared to healthy patients, and these patients also show a significant reduction in Actinobacteria compared to those who have T2DM but do not develop diabetic retinopathy.[26] There is no significant difference in microbiome composition between varying severities of diabetic retinopathy.[26]

Retinopathy of Prematurity

There is a possible association between gut microbiome profile and retinopathy of prematurity pathogenesis.[19] Skondra et al. found that infants with type 1 retinopathy of prematurity had marked enrichment of Enterobacteriaceae (Proteobacteria) at 28 weeks compared to infants who were high-risk preterm neonates with similar baseline comorbidities but no retinopathy.[19] In addition, several amino acid metabolism pathways were enriched in the gut microbiota of those who did not develop retinopathy of prematurity.[19]

Retinal Artery Occlusion

Patients with non-arteritic retinal artery occlusion show a decreased abundance of Bacteroidetes but an increased abundance of Proteobacteria when to compared to age- and sex-matched controls.[20] On the genus level, patients with retinal artery occlusion see enriched Bifidobacterium spp. (Actinobacteria), Bacteroides stercoris (Bacteroidetes), Faecalibacterium prausnitzii (Firmicute) but decreased levels of Odoribacter (Bacteroidetes), Parasutterella (Proteobacteria), or Lachnospiraceae (Firmicute).[20] In fact, patients with retinal artery occlusions have gut microbiomes that are enriched in genes of the cholesterol metabolism pathways such as pro-atherogenic metabolite trimethylamine-N-oxide.[20]

Keratitis

Fungal Keratitis

Patients with fungal keratitis are commonly seen with dysbiosis of the gut microbiome. These patients typically have fewer symbiotic bacteria and more abundant pro-inflammatory bacteria.[21] Patients with fungal keratitis see a significant reduction in bacterial diversity in their gut microbiota compared to healthy patients.[21] For example, healthy patients compared to fungal keratitis patients typically have enriched Faecalibacterium prausnitzii (Firmicutes), Bifidobacterium adolescentis (Actinobacteria), Lachnospira (Firmicutes), Mitsuokella multacida (Firmicutes), Bacteroides plebeius (Bacteroidetes), Megasphaera (Firmicutes), and Lachnospiraceae (Firmicutes).[21] Fungal keratitis patients see an increase in pathogenic pro-inflammatory bacteria such as Treponema (Spirochaetes) and Bacteroides fragilis (Bacteroidetes).[21] Patients with fungal keratitis do not show any significant dysbiosis of the fungal gut microbiota compared to controls.[21]

Bacterial Keratitis

Patients with bacterial keratitis show dysbiosis in both the fungal and bacterial gut microbiota.[22] Compared to patients with bacterial keratitis, healthy patients show an increase in abundance of anti-inflammatory Firmicutes such as Dialister, Megasphaera, Faecalibacterium, Lachnospira, Ruminococcus, Veillonellaceae, Ruminococcaceae, and Lachnospiraceae compared to bacterial keratitis patients.[22] Bacterial keratitis patients also show dysbiosis of the fungal microbiome with decreased Mortierella (Mucoromycota), Rhizopus (Mucoromycota), Kluyveromyces (Ascomycota), and Embellisia (Ascomycota) and elevated amounts of pathogenic fungi such as Aspergillus (Ascomycota) and Malassezia (Basidiomycota).[22]

Sjogren’s Syndrome and Dry Eye

Patients with Sjogren’s syndrome with or without dry eye show changes in composition in the gut microbiome compared to healthy patients. However, the reported changes in composition vary across studies. Patients with Sjogren’s syndrome with or without dry eye may show increased abundance of Proteobacteria (3.0-fold), Actinobacteria (1.7-fold) and Bacteroidetes (1.3-fold) compared to healthy patients.[23] There are no compositional differences between Sjogren’s syndrome patients with or without dry eye.[23] Patients with Sjogren’s syndrome may also show a greater abundance of Faecalibacterium (Firmicutes).[24]

Management and Treatment

The management and treatment of gut dysbiosis has not been studied extensively. However, it is recommended that patients maintain diets that include high fiber diets and short-chain fatty acids, which can promote the health of the gut microbiome and reduce the potential for ocular inflammation and manifestations such as AMD.[27]

Probiotics could also play a role in treating a patient with gut dysbiosis and associated ocular manifestations. However, given that certain diseases are associated with a few specific changes in the gut microbiome, while others are associated with many changes, there is great difficulty in determining which probiotics are best in treating particular diseases.[27] Treatment could potentially involve “resetting” the gut microbiome with antibiotic and subsequent probiotic treatment.[27]

Fecal transplants may also be a promising avenue for treating gut dysbiosis and associated ocular manifestations. A study conducted by Wang et al. found that mice that were germ free showed greater corneal barrier disruption, greater goblet cell loss , and greater inflammatory cell infiltration within the lacrimal gland. Fecal microbiota transplant from healthy mice into these germ-free mice alleviated ocular manifestations.[28]

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