Table 2.

Ocular clinical studies examining gut dysbiosis.

General								Measurement of microbiome	Intervention if applicable	Outcomes
Author, Date	Title	Study type	Participants (# pts with which disease)	Age of cohorts	Gender (% female)	Racial information	Disease category			Primary Ocular Outcome	GI outcomes?	Microbiome Notes	Bacteria specific notes
Watane et al. [44]	Fecal Microbial Transplant in Individuals With Immune-Mediated Dry Eye.	Nonrandomized clinical trial	10 patients diagnoses with Dry Eye due to Sjogren Syndrome	60.4 years old	70%	50% white, 50% hispanic	Sjogren Syndrome	Fecal DNA sequencing	Fecal microbiota transplant	Reduction in self reported Dry Eye symptoms 5/10 patients 3 month FU	No side effects noted of FMT	SS: decreased abundance of genera Faecalibacterium, Prevotella, and Ruminococcus and an increased abundance of genera Alistipes, Streptococcus, and Blautia relative to healthy donor biome.	Faecalibacterium noted to be decreased in prior Dry Eye study
McPherson et al. [25]	Irritable bowel syndrome and risk of glaucoma: An analysis of two independent population-based cohort studies.	Analysis of two prospective cohort studies	71362 IBS patients, 625410 age matched controls	n/a	51.50%	97.9 % white	Glaucoma	none	none	Increased odds of developing glaucoma if IBS present (OR = 5.84)	none	none	none
Das et al. [18]	Alterations in the gut bacterial microbiome in people with type 2 diabetes mellitus and diabetic retinopathy.	Cross sectional study	25 patients with diabetes 28 patiens with DR 30 healthy controls	57.3 55.07 52.2	44% 25% 43%	n/a	Diabetes and Diabetic Retinopathy	16s RNA sequencing	none	none	Dysbiosis most pronounced in patients with retinopathy compared to diabetics or controls.	DR: ↓ Bacteroidetes and Actinobacteria versus HC	↑ Shannon diversity in DM and DR versus HC
Filippelli et al. [46]	Intestinal microbiome: a new target for chalaziosis treatment in children?	Prospective pilot study	26 children with chalazions	8.3	65%	n/a	Chalazion	none	Probiotic supplementation	Decreased time to resolution of Chalazion in probiotic group (P < 0.0001)	no adverse effects	Probiotic contained Streptococcus thermophilus, Lactococcus lactis, & Lactobacillus delbrueckii
Berkowitz et al. [27]	“More Guts Than Brains?”-The Role of Gut Microbiota in Idiopathic Intracranial Hypertension.	Prospective pilot study	25 patients with IIH 20 healthy control patients	35.12 48.5	n/a	n/a	Idiopathic intracranial hypertension	Fecal DNA sequencing	acetazolamide examined in IIH patients	none	IIH patients had lower microbiota diversity compared to control, Acetazolamide treated patietns showed increased lactobacillus	IIH: ↓ Lactobacillus ruminis, ↓ Atopobium parvulum, ↓ Megamonas hypermegale, ↓ Ruminococcus gnavus, ↓ Streptococcus sp. (beneficial microbiota)	Acetazolamide treated patients: ↑ Lactobacillus brevis (beneficial microbiota
Filippelli et al. [45]	Effectiveness of oral probiotics supplementation in the treatment of adult small chalazion.	Prospective pilot study	20 adults with chalazion	48.25	65%	n/a	Chalazion	none	Probiotic supplementation	Decreased time to resolution of small size Chalazion in probiotic group (P < 0.039) Failure to resolve medium or large chalaion ≥ 2 mm	no adverse effects	Probiotic contained Streptococcus thermophilus, Lactococcus lactis, & Lactobacillus delbrueckii
Moubayed et al. [59]	Screening and identification of gut anaerobes (Bacteroidetes) from human diabetic stool samples with and without retinopathy in comparison to control subjects.	Cross sectional study	9 patients with diabetes 8 Patients with DR 18 healthy controls	n/a	44% 25% 43%	n/a	Diabetes and Diabetic Retinopathy	Fecal DNA sequencing	none		Higher ratio of bacteroides in diabetic groups than controls, No difference between those with and without retinopathy	DM & DR: ↑ Bacteriodetes, ↓ Firmicutes: ratio,
Napolitano et al. [47]	Probiotic Supplementation Improved Acute Anterior Uveitis of 3-Year Duration: A Case Report.	Case Report	1 patient with autoimmune uveitis	21	100%	n/a	Uveitis	none	probiotic supplementation	BCVA from 3/10 to 4/10 and decreased proteins and mutton-fat deposits after 2 months	none	Probiotic contained Bifidobacterium lacti, Bifidobacterium bifidum, & Bifidobacterium breve
Huang et al. [20]	Dysbiosis and Implication of the Gut Microbiota in Diabetic Retinopathy.	Cross sectional study	25 DM without DR 25 DM with DR 25 healthy controls	62.5 60.3 57.8	56% 40% 64%	100% Chinese	Diabetes and Diabetic Retinopathy	16 S RNA sequencing	none	none	Reduced diversity in both DM and DR groups compared to control group.	DM & DR: ↑ Bifidobacterium, ↑ Lactobacillus, ↓ Bacteriodetes, ↓ Escherichia-Shigella, ↓ Faecalibacterium, ↓ Eubacterium_hallii_group, ↓ Clostridium versus HC	↓ α and β diversities in the DM and DR groups compared with HC group
Jayasudha et al. [33]	Implicating Dysbiosis of the Gut Fungal Microbiome in Uveitis, an Inflammatory Disease of the Eye.	Cross sectional study	24 healthy controls 14 uveitis patients	45.9 43.6	85%	100% Indian	Uveitis	Fungal RNA sequencing	none	none	gut fungal richness and diversity were significantly decreased in uveitis patients compared to healthy controls	UVT: ↑ Malassezia restricta, ↑ Candida albicans, ↑ Candida glabrata, ↑ Aspergillus gracilis (pathogenic)
Chakravarthy et al. [34]	Alterations in the gut bacterial microbiome in fungal Keratitis patients.	Cross sectional study	31 healthy controls 32 fungal keratitis	42.2 47.1	51.6% 40.6%	100% Indian	Keratitis	16 s RNA sequencing	none	none	no significant difference in fungal dysbiosis, but bacterial richness and diversity in FK patients was significantly decreased	Keratitis: ↓Bifidobacterium, ↓Lactospira, ↓Faecalibacterium, ↓Lachnospira, ↓Ruminococcus, ↓ Mitsuokella, ↓ Megasphera and ↓ Lachnospiraceae (antiinflammatory mircobiota)	Keratitis: ↑ Aspergillus, ↑ Candida (pathogenic mycobiota)
Zysset-Burri et al. [42]	Retinal artery occlusion is associated with compositional and functional shifts in the gut microbiome and altered trimethylamine-N-oxide levels.	Cross sectional study	29 non arteritic RAO 30 healthy controls	69.4 69.0	51.7% 46.7%	n/a	Retinal Artery Occlusion	Fecal DNA sequencing	none	none	alterations in gut microbiome and elevated TMAO (risk factor for CV dz) levels in patients with RAO	RAO: ↑ Actinobacter,↑ Bifidobacterium,↑ Bacteroides stercoris, ↑Faecalibacterium prausnitzii	TMAO significantly higher in patients with RAO, p = 0.023
Skondra et al. [60]	The early gut microbiome could protect against severe retinopathy of prematurity.	Cross sectional study	6 type 1 ROP neonates 4 preterm neonates with similar baseline comorbidities	24.1 weeks 25.6 weeks	n/a	n/a	Retinopathy of Prematurity	16 s RNA sequencing	none	none	significant enrichment of enterobacteriaceae in type 1 ROP patients, with decreased amino acid metabolism pathways	Enterobacteriaceae enrichment in ROP patients at 28 weeks (P < 0.05)
Jayasudha et al. [35]	Alterations in gut bacterial and fungal microbiomes are associated with bacterial Keratitis, an inflammatory disease of the human eye.	Cross sectional study	21 health controls 19 bacterial keratitis	48.8	n/a	100% Indian	Keratitis	Fecal DNA sequencing	none	none	increase in number of anti-inflammatory organisms in HC compared to BK	Keratitis: ↓Dialister, ↓Megasphera, ↓Faecalibacterium, ↓Lachnospira, ↓Ruminococcus, ↓ Mitsuokella, ↓ Firmicutes, ↓ Veillonellaceae, and ↓ Lachnospiraceae (antiinflammatory mircobiota)	Keratitis: ↑ Aspergillus, ↑ Malassezia (pathogenic mycobiota)
Chakravarthy et al. [34]	Dysbiosis in the Gut Bacterial Microbiome of Patients with Uveitis, an Inflammatory Disease of the Eye.	Cross sectional study	13 uveitis 13 healthy controls	44.5 43.1	84.6% 84.6%	100% indian	Uveitis	16 s RNA sequencing	none	none	reduced diversity of several anti-inflammatory organisms in uveitis patients microbiomes and decreased probiotic and antibacterial organisms	UVT: ↓ Faecalibacterium, ↓Lachnospira, ↓Ruminococcus, ↓ Ruminococcaceae and ↓ Bacteroides (antiinflammatory mircobiota)
Khan et al. [61]	Association Between Gut Microbial Abundance and Sight-Threatening Diabetic Retinopathy.	Case control study	37 sight threatening DR 21 DM no DR	57.5 57.5	33.4% 38.1%	n/a	Diabetes and Diabetic Retinopathy	bacteroidetes to firmicutes ratio (B/F)	none	none	No difference in gut microbioal abundance between the 2 populations	DR: Increased Bacteroides:Furmicutes ratio compared to controls, p = 0.049
Yasar Bilge et al. [38]	Intestinal microbiota composition of patients with Behçet’s disease: differences between eye, mucocutaneous and vascular involvement. The Rheuma-BIOTA study.	prospective observational study	27 Behcet’s 10 control	40.8 38.9	63.0% 60%	n/a	Behcet Syndrome	16s RNA sequencing	none	none	significant differences in the relative abundance of some bacterial taxa between patients with BD and healthy controls	UVT: Differences in Lachnospiraceae
Moon et al. [62]	Gut dysbiosis is prevailing in Sjögren’s syndrome and is related to dry eye severity.	Prospective case-control study	12 healthy controls 10 with Sjogren’s 14 with envrionmental dry eye syndrome (DES)	47.5 58.5 46.3	100% 85.7% 75%	100% Korean	Sjogren Syndrome	16s RNA sequencing	none	Bacteriodetes, Actinobacteria, and Bifidobacterium significantly related to dry eye signs (NEI score, tear breakup time) (p < 0.05) Multivariate linear regression showed that tear secretion was strongly affected by Prevotella	gut microbiome showed significant differences in patients with Sjogrens than compared to controls & DES; no significant difference in alpha-diversity across all 3 groups	SS: ↑ Bacteriodetes, ↓ Firmicutes: Bacteroidetes ratio, ↓Actinobacteria, ↓ Bifidobacterium (compared to control and DES). ↓ Blautia, Dorea, Agathobacter (vs. controls). ↑ Prevotella, Odoribacter, Alistipes (vs. DES) DES: ↑ Veillonella and ↓ Subdoligranulum (vs. controls)	-↓ Firmicutes: Bacterioidetes ratio is known to be an early sign of gut dybsiosis -Chronic inflammatory dx (SLE, systemic sclerosis) show ↑ Bacteroidetes and reduced ratio, with ↓ Bifidobacterium and Lactobacillus -Actinobacteria (Bifidobacterium & Collinsella) thought to help with intestinal health due to regulating pathogens -Prevotella associated with rheum. arthritis
Gong et al. [26]	Gut microbiota compositional profile and serum metabolic phenotype in patients with primary open-angle glaucoma.	Prospective study	30 POAG patients 30 non-POAG patients/ controls	54.8 53.8	53.3% 53.3%	100% Chinese	Glaucoma	16 s RNA sequencing	none	Mean VA in POAG patients negatively correlated with Blautia (p = 0.034) Mean VF-MD in POAG patients negatively correlated with Megamonas (p = 0.035) average RNFL thickness positively correlated with Streptococcus (p = 0.037)	Bacterial profiles in the gut microbiome had significant differences between the POAG and control patients	POAG: ↑ Prevotellaceae, unidentified_Enterobacteriaceae, Escherichia coli, ↓ Megamonas, Bacterioides_plebeius (vs. controls)	Prevotella shown in mouse models to worsen epithelial inflammation in colitis and thrived in pro-inflammatory environments
Ye et al. [19]	Alterations of the Gut Microbiome and Metabolome in Patients With Proliferative Diabetic Retinopathy.	Prospective study	45 PDR patients 90 T2M without DR (controls)	59.9 60.9	44.4% 44.4%	100% Chinese (Han)	Diabetes and Diabetic Retinopathy	16 s RNA sequencing	none	none	PDR associated with reduced microbiome diversity than controls, with significant depletion of 22 familes and enrichment of 2 familes in the PDR group	PDR: ↓ Coriobacteriaceae, Veillonellaceae, Streptococcaceae and ↑ Burkholderiaceae and Burkholderiales_unclassified (vs. controls)
Zinkernagel et al. [23]	Association of the Intestinal Microbiome with the Development of Neovascular Age-Related Macular Degeneration.	Cross-sectional	12 nAMD 11 controls	78.4 72.5	33.3% 36.4%	N/A	Age related Macular Degeneration	Fecal DNA sequencing	none	none	Different bacterial compositions noted in the AMD cohort compared to controls	nAMD: ↑ Ruminococcus torque, Oscillibacter, Anaerotruncus, Eubacterium ventriosum Controls: ↑ Bacteroides eggerthii	Prior studies have associated Anaerotruncus and Eubacterium with increased inflammatory states/ elevated cytokine levels
Huang et al. [32]	Gut Microbiota Composition and Fecal Metabolic Phenotype in Patients With Acute Anterior Uveitis.	Cross-sectional	38 AAU 40 controls	33.9 36.0	36.8% 35%	N/A	Uveitis	16 s RNA sequencing	none	none	No significant difference in gut microbiota composition between AAU and controls; but fecal metabolite phenotype in AAU patients was significantly different from healthy controls	UVT: ↓ Roseburia, Lachnospiracea, Dorea, Blautia, Clostridum, Odoribacter, ↑ Veillonella (vs. controls) -- however significance for all were LOST after false discovery rate (FDR) correction	Roseburia and Veillonella positively correlates to linoleic acid (stimulates proinflammatory mediators in IBD)
Tecer et al. [37]	Succinivibrionaceae is dominant family in fecal microbiota of Behçet’s Syndrome patients with uveitis.	Case-control	7 Behcet syndrome(BS) + uveitis 12 Familial Mediterranean Fever (FMF) 9 Crohns Disease (CD) 16 healthy controls (HC)	35.6 32.2 35.0 39.4	28.6% 50% 66.6% 62.5%	N/A	Behcet Syndrome	16 s RNA sequencing	none	none	Significant differences in alpha diversity between the four groups. Prevotella copri was dominant in BS group (a known inflammatory bacteria)	BS: ↑ Veillonellaceae, Succinivibrionaceae, ↓ Bacteroidaceae (vs. controls) Prevotella copri was a predominant species in the BS, HC, and FMF groups but not the controls	Prevotella copri is a known inflammatory bacteria
Jayasudha et al. [21]	Gut mycobiomes are altered in people with type 2 Diabetes Mellitus and Diabetic Retinopathy.	Cross-sectional	24 T2DM with DR 21 T2DM 30 Healthy controls	54.5 57.5 52.2	25% 38.1% 43.3%	100% Indian	Diabetes and Diabetic Retinopathy	Fungal RNA s‘	none	none	More mycobiome dysbiosis in people with T2DM and DR than compared to healthy controls; mycobiome profiles and beta diversity differed between all three groups to some extent	21 genera ↓ and 5 genera ↑ in T2DM (Table 3), 18 genera reduced in DR (Table 4) [vs. controls] 6 genera ↓ in DR [vs. T2DM] (Table 5)
Mendez et al. [63]	Gut microbial dysbiosis in individuals with Sjögren’s syndrome.	Prospective case control	13 Sjogrens + dry eye 8 Sjogrens without dry eye 21 healthy controls	58.8 58.4 26.0	69% 62% 0%	N/A	Sjogren Syndrome	16 s RNA sequencing	none	Various classes of bacteria associated with signs/ symptoms of dry eye (Table 2 in table lists all of them)	Shannon’s diversity index showed no difference between groups. Faith’s phylogenetic diversity showed increased diversity in patients with Sjogrens vs. controls, especially for Sjogrens+dry eye vs. control (p = 0.02)	No differences in Bateroides:Firmicutes ratio between Sjogrens/ controls No significant difference between SDE and NDE groups in Sjogrens or difference in alpha-diversity Sjogrens overall: ↑ Actinomycetaceae, Eggerthellaceae, Lactobacillaceae, Akkermanciaceae, Coriobacteriaceae, and Eubacteriaceae (vs. controls)