Dry Eye and Probiotics: Comparison
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Please note this is a comparison between Version 1 by Chang Ho Yoon and Version 2 by Nora Tang.

Probiotics are defined as live microorganisms that present health benefits when administered in adequate amounts. Prebiotics refer to substrates that microorganisms use to bestow health benefits upon host. Evidence regarding their effects on the ocular surface, especially dry eye, are now just emerging. Both rodent and human studies regarding gut microbiota in Sjögren’s syndrome and environmental dry eye are explored, and we discussed the effects of prebiotics and probiotics on dry eye in this section. 

  • dry eye
  • dysbiosis
  • gut microbiota

1. Prebiotics and Probiotics

Probiotics are defined as live microorganisms that present health benefits when administered in adequate amounts [1]. Prebiotics refer to substrates that microorganisms use to bestow health benefits upon the host [2]. Both probiotics and prebiotics have received much spotlight over the past decade for their advantages in coordinating gut microbiota to help ameliorate several diseases [3]. While several studies have obtained beneficial effects in several autoimmune diseases [3][4], evidence regarding their effects on the ocular surface, especially dry eye, is now just emerging (Table 1).
Table 1. Effects of probiotics or prebiotics on dry eye in rodent and human studies.
Author,

Year		 Tx Tx

Period		 Subjects Representative Gut Microbiota Change in OS/LG/dLN
Rodent Study
Kawashima,

2016 [5]		 Fish oil, lactoferrin, zinc, vitamin C, lutein, vitamin E, γ-aminobutanoic acid & E. faecium WB2000 2 days DS rats N/A Tear secretion↑

ROS↓(LG)
Kim,

2017 [6]		 L. casei, L. acidophilus, L. reuteri, B. bifidum & S. thermophiles 3 weeks NOD.B10.H2b N/A Tear secretion↑

Corneal staining↓

Inflammation focia↓(LG)

CD8+IFN-γhi T cell↓(dLN)

Treg cell↑(dLN)
Choi,

2020 [7]		 L. casei, L. acidophilus, L. reuteri, B. bifidum & S. thermophiles 3 weeks NOD.B10.H2b ↑Lactobacillus helveticus, L. hamsteri, L. reuteri, L. casei, L. brantae, L. amylovorous, Akkermansia municipila, Aerococcus viridans, B. bifidum, Streptococcus salivarius

↓Lactobacillus intestinalis		 Tear secretion↑

Corneal staining↓

Immune response genesb↓(LG)

IL-10↑(OS)

IL-1b↓(OS)
Human Study
Kawashima,

2016 [5]		 Fish oil, lactoferrin, zinc, vitamin C, lutein, vitamin E, γ-aminobutanoic acid & E. faecium WB2000 8 weeks DESc N/A Scored subjective symptomsd↓

Tear secretion↑
Chisari,

2017 [8]		 S. boulardii MUCL 53837 & E. faecium LMG S-28935 30 days DESe N/A Subjective dry eye symptomsf↓

TBUT↑

Tear secretion↑
Chisari,

2017 [9]		 B. lactis DSM 25566 & B. bifido DSM 25565 30 days DESe N/A Tear secretion↑

TBUT↑
Kawashima,

2019 [10]		 Hydrogen-producing milk 3 weeks DESc N/A TBUT↑ (♀)
a Inflammatory foci score; >50 inflammatory cells/focus = 1, 25–50 inflammatory cells/focus = 0.5; b Ptprc, Hmgb2, Psmb8, H2-Aa, H2-K1, Psme1, Tap1, Tap2 & Psmb9; c Subjects with dry eye symptoms, qualitative or quantitative disturbance of the tear film (Schirmer test ≤ 5 mm or TBUT ≤ 5 s) and total fluorescein staining score of at least 3 points.; d Total score, foreign body sensation, dry eye sensation and ocular fatigue (evaluated by Dry Eye-Related Quality-of-Life Score); e Subjects defined to have dry eye syndrome clinically or pathologically; f Dry eye symptom severity, frequency of pain or soreness in ocular fatigue, eyelid heaviness, eye redness and foreign body sensation (evaluated by Ocular Surface Disease Index); Tx, treatment; OS, ocular surface; LG, lacrimal gland; dLN, draining lymph node; DS, desiccating stressed; B6, C57BL/6J mice; ROS, reactive oxygen species; DES, dry eye syndrome; TBUT, tear break up time; ♀, female; 8-OHdG, 8-hydroxydeoxyguanosine.
 

2. Effects Seen in Animal Studies

NOD.B10.H2b (NOD) mice treated with prebiotic xylooligosaccharides resulted in reduced sialadenitis and insulitis by increasing regulatory macrophages and activating Treg cells while lowering cytotoxic T cells [11]. Interestingly, this study also observed that a combination with antibiotics increased the clinical benefits of prebiotics regarding insulitis but not sialadenitis [11], which implies that each species of gut microbiota affects each target organ in a different manner. On the other hand, recent animal studies regarding dry eye and probiotics have commonly observed that while antibiotics treatment increases dry eye, prebiotics and probiotics induce clinical benefits with mitigation of inflammatory cells (Table 1). Kawashima et al. observed that E. faecium WB2000 mixed with fish oil increased tear secretion and decreased reactive oxygen species production in lacrimal glands (LGs) of desiccating-stressed rats [5]. Two studies have observed that a probiotic composed of L. casei, L. acidophilus, L. reuteri, B. bifidum, and S. thermophiles for 3 weeks in NOD mice restored corneal barrier disruption and increased tear secretion [7][6]. We noticed a decrease in inflammatory cell infiltration in LG and CD8+ IFN-γHi cells in the lymph nodes, while Treg cells increased [6]. While using the same probiotic in the same SS model, Choi et al. observed that proteins related with antigen presentation decreased in the LGs [7].
These animal studies indicate that probiotics and prebiotics can affect the gut microbiota and carry out variable clinical and immunological changes. Given that T and B cells are the main source of the mechanism in Sjögren’s syndrome (SS) subjects while T cells are more dominant in environmental dry eye syndrome (DES), probiotics’ and prebiotics’ effects on the gut microbiota and subsequently to clinical and immunological manifestations may differ according to the type of studied animal model. These possible differences among studied animals should be considered in future animal studies.
 

3. Effects Seen in Clinical Studies

Clinical benefits from probiotics on dry eyes have been investigated in a few human studies (Table 1). Though E. faecium is known for being an opportunistic pathogen, some of its strains are validated to be safely used as probiotics [12]. Some strains possess pathways to enable the production of essential amino acids and vitamins, which are important in human health [12]. Likewise, Kawashima et al. observed that intake of E. faecium WB2000 mixed with fish oil for 8 weeks alleviated subjective symptoms with increased tear secretion in DES subjects [5]. Similarly, a mixture of E. faecium LMG S-28935 and Saccharomyces boulardii MUCL 53837 decreased subjective symptoms with an increase in both tear secretion and tear break-up time [8]. Saccharomyces is also a well-known short-chain fatty acids (SCFAs)-producing bacteria [13]. Lactobacillus and Bifidobacterium, renowned for their many species associated with lactic acid and acetic acid production, are regarded as the main ingredient for various probiotics [14]. A pilot study by Chisari et al. reported that a 30-day supplementation of B. lactis and B. bifido significantly increased tear secretion and tear break-up time in 20 DES subjects compared to placebo [9]. Additionally, a processed H2-producing milk, as a prebiotic supplement, exhibited similar clinical effects in DES subjects [10]. Despite these positive clinical results, the safety of probiotics use in immunocompromised SS subjects is warranted, where administration of Lactobacillus spp. was reported to possibly act as an opportunistic pathogen [15]. However, overall, clinical studies have observed probiotics to be safe and to not only alleviate subjective symptoms but also increase both tear secretion and tear break-up time. These clinical results suggest the advantages of diverse probiotics as a supplementary treatment to DES. Therefore, future clinical studies concerning SS subjects are now necessary to further elucidate and expand probiotics’ benefits.

References

  1. Hill, C.; Guarner, F.; Reid, G.; Gibson, G.R.; Merenstein, D.J.; Pot, B.; Morelli, L.; Canani, R.B.; Flint, H.J.; Salminen, S.; et al. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat. Rev. Gastroenterol. Hepatol. 2014, 11, 506–514.
  2. Gibson, G.R.; Hutkins, R.; Sanders, M.E.; Prescott, S.L.; Reimer, R.A.; Salminen, S.J.; Scott, K.; Stanton, C.; Swanson, K.S.; Cani, P.D.; et al. Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat. Rev. Gastroenterol. Hepatol. 2017, 14, 491–502.
  3. Tsai, Y.-L.; Lin, T.-L.; Chang, C.-J.; Wu, T.-R.; Lai, W.-F.; Lu, C.-C.; Lai, H.-C. Probiotics, prebiotics and amelioration of diseases. J. Biomed. Sci. 2019, 26, 1–8.
  4. Liu, Y.; Alookaran, J.J.; Rhoads, J.M. Probiotics in Autoimmune and Inflammatory Disorders. Nutrients 2018, 10, 1537.
  5. Kawashima, M.; Nakamura, S.; Izuta, Y.; Inoue, S.; Tsubota, K. Dietary Supplementation with a Combination of Lactoferrin, Fish Oil, and Enterococcus faecium WB2000 for Treating Dry Eye: A Rat Model and Human Clinical Study. Ocul. Surf. 2016, 14, 255–263.
  6. Kim, J.; Choi, S.H.; Kim, Y.J.; Jeong, H.J.; Ryu, J.S.; Lee, H.J.; Kim, T.W.; Im, S.-H.; Oh, J.Y.; Kim, M.K. Clinical Effect of IRT-5 Probiotics on Immune Modulation of Autoimmunity or Alloimmunity in the Eye. Nutrients 2017, 9, 1166.
  7. Choi, S.H.; Oh, J.W.; Ryu, J.S.; Kim, H.M.; Im, S.-H.; Kim, K.P.; Kim, M.K. IRT5 Probiotics Changes Immune Modulatory Protein Expression in the Extraorbital Lacrimal Glands of an Autoimmune Dry Eye Mouse Model. Investig. Opthalmology Vis. Sci. 2020, 61, 42.
  8. Chisari, G.; Chisari, E.M.; Ozyalcin, E.; Borzì, A.M.; Chisari, C.G. Aging Eye Microbiota in Dry Eye Syndrome in Patients Treated with Enterococcus faecium and Saccharomyces boulardii. Curr. Clin. Pharmacol. 2018, 12, 99–105.
  9. Chisari, G.; Chisari, E.M.; Francaviglia, A.; Chisari, C.G. The mixture of bifidobacterium associated with fructo-oligosaccharides reduces the damage of the ocular surface. La Clin. Ter. 2017, 168, e181–e185.
  10. Kawashima, M.; Tsuno, S.; Matsumoto, M.; Tsubota, K. Hydrogen-producing milk to prevent reduction in tear stability in persons using visual display terminals. Ocul. Surf. 2019, 17, 714–721.
  11. Hansen, C.H.F.; Larsen, C.S.; Petersson, H.O.; Zachariassen, L.F.; Vegge, A.; Lauridsen, C.; Kot, W.; Krych, Ł.; Nielsen, D.S.; Hansen, A.K. Targeting gut microbiota and barrier function with prebiotics to alleviate autoimmune manifestations in NOD mice. Diabetologia 2019, 62, 1689–1700.
  12. Ghattargi, V.; Gaikwad, M.A.; Meti, B.S.; Nimonkar, Y.S.; Dixit, K.; Prakash, O.; Shouche, Y.S.; Pawar, S.P.; Dhotre, D. Comparative genome analysis reveals key genetic factors associated with probiotic property in Enterococcus faecium strains. BMC Genom. 2018, 19, 652.
  13. Azad, M.; Kalam, A.; Sarker, M.; Li, T.; Yin, J. Probiotic Species in the Modulation of Gut Microbiota: An Overview. Biomed Res. Int. 2018, 2018, 9478630.
  14. Papizadeh, M.; Rohani, M.; Nahrevanian, H.; Javadi, A.; Pourshafie, M.R. Probiotic characters of Bifidobacterium and Lactobacillus are a result of the ongoing gene acquisition and genome minimization evolutionary trends. Microb. Pathog. 2017, 111, 118–131.
  15. MacGregor, G.; Smith, A.J.; Thakker, B.; Kinsella, J. Yoghurt biotherapy: Contraindicated in immunosuppressed patients? Postgrad. Med. J. 2002, 78, 366–367.
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