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The Effect of Ophthalmic and Systemic Formulations of Latilactobacillus sakei on Clinical and Immunological Outcomes of Patients With Dry Eye Disease: A Factorial, Randomized, Placebo-controlled, and Triple-masking Clinical Trial

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Mojtaba Heydari at Shiraz University of Medical Sciences
Mojtaba Heydari
Mehdi Kalani
Mehdi Kalani
Mehdi Kalani
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Younes Ghasemi
Younes Ghasemi
Younes Ghasemi
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Mahmood Nejabat at Shiraz University of Medical Sciences
Mahmood Nejabat
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Abstract and Figures

Dry eye disease (DED) is one of the most prevalent eye diseases. This study aimed to evaluate the efficacy and safety of Latilactobacillus sakei (L. sakei) either as an ophthalmic bacterial lysate (drops, no live organism) or as an oral probiotic (capsules) on immunological and clinical outcomes of patients with DED. This study was a randomized, placebo-controlled, triple-masking clinical trial with four parallel arms. Patients were randomly assigned in a 2x2 factorial design combining active vs placebo capsules and active vs placebo eye drops in a 1:1x1:1 ratio. The ophthalmic drops are approved for use in the European Union as a medical device (CE registration code 0425-MED-004235). A total of 40 patients were evaluated. DED signs and symptoms decreased significantly by using active drops compared to placebo, as measured by the Ocular Surface Disease Index (OSDI), Tear Break-up Time (TBUT), and Schirmer I tests (all p<0.0001). Conversely, neither active capsules nor their interaction effect with active drops achieved significance vs placebo. There was also a significant decrease in the tear levels of IL-6 (p=0.0007), TNFα (p<0.0001), and IFNγ (p<0.0001) in patients receiving active drops. Intake of both active products (drops and capsules) was well tolerated. Postbiotic ophthalmic formulation containing L. sakei lysate significantly improved the signs and symptoms of DED and suppressed ocular surface inflammatory response. Conversely, oral intake of L.sakei as a probiotic capsule had no effect in these patients (ClinicalTrials.gov: NCT04938908).
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Vol:.(1234567890)
Probiotics and Antimicrobial Proteins (2024) 16:1026–1035
https://doi.org/10.1007/s12602-023-10079-1
1 3
RESEARCH
The Effect ofOphthalmic andSystemic Formulations
ofLatilactobacillus sakeion Clinical andImmunological Outcomes
ofPatients With Dry Eye Disease: AFactorial, Randomized,
Placebo‑controlled, andTriple‑masking Clinical Trial
MojtabaHeydari1,2 · MehdiKalani3 · YounesGhasemi1,4 · MahmoodNejabat2
Accepted: 18 April 2023 / Published online: 31 May 2023
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023
Abstract
Dry eye disease (DED) is one of the most prevalent eye diseases. This study aimed to evaluate the efficacy and safety
of Latilactobacillus sakei (L. sakei) either as an ophthalmic bacterial lysate (drops, no live organism) or as an oral
probiotic (capsules) on immunological and clinical outcomes of patients with DED. This study was a randomized,
placebo-controlled, triple-masking clinical trial with four parallel arms. Patients were randomly assigned in a 2x2 fac-
torial design combining active vs placebo capsules and active vs placebo eye drops in a 1:1x1:1 ratio. The ophthalmic
drops are approved for use in the European Union as a medical device (CE registration code 0425-MED-004235). A
total of 40 patients were evaluated. DED signs and symptoms decreased significantly by using active drops compared to
placebo, as measured by the Ocular Surface Disease Index (OSDI), Tear Break-up Time (TBUT), and Schirmer I tests
(all p<0.0001). Conversely, neither active capsules nor their interaction effect with active drops achieved significance
vs placebo. There was also a significant decrease in the tear levels of IL-6 (p=0.0007), TNFα (p<0.0001), and IFNγ
(p<0.0001) in patients receiving active drops. Intake of both active products (drops and capsules) was well tolerated.
Postbiotic ophthalmic formulation containing L. sakei lysate significantly improved the signs and symptoms of DED
and suppressed ocular surface inflammatory response. Conversely, oral intake of L.sakei as a probiotic capsule had no
effect in these patients (ClinicalTrials.gov: NCT04938908).
Keywords Dry eye disease· Latilactobacillus sakei· Postbiotic· Probiotic· Inflammation· Cytokines
Introduction
Dry eye disease (DED) is defined as a multifactorial disease
of the ocular surface characterized by a loss of tear film
homeostasis also accompanied by ocular symptoms resulting
from tear film instability and hyperosmolarity, ocular surface
inflammation and damage, or neurosensory abnormalities
[1]. Prevalence in population-based studies ranges from 5
to 50% depending on the diagnostic criteria [1]. Tear film
instability is normally associated with excessive evaporation,
resulting in increased concentration of electrolytes, (hyper-
tonic epithelial environment) [2], leading to the onset of
inflammation and tissue damage.
DED is categorized into important types of tear produc-
tion deficiency, evaporation excess, and mixed type. Dif-
ferent pathologies like Sjogren Syndrome, graft versus
host disease, ocular cicatricial pemphigoid, lacrimal ducts
* Younes Ghasemi
ghasemiy@sums.ac.ir
* Mahmood Nejabat
nejabatm@sums.ac.ir
1 Pharmaceutical Sciences Research Center, School
ofMedicine, Shiraz University ofMedical Sciences, Zand
St., Shiraz, Iran
2 Poostchi Ophthalmology Research Center, Department
ofOphthalmology, School ofMedicine, Shiraz University
ofMedical Sciences, Shiraz, Iran
3 Alborzi Clinical Microbiology Research Center, Shiraz
University ofMedical Sciences, Shiraz, Iran
4 Department ofPharmaceutical Biotechnology, School
ofPharmacy, Shiraz University ofMedical Sciences, Shiraz,
Iran
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
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... It also decreased oxidative stress and inflammatory cytokine production in the DED model. Concerning the utilization of probiotics, Heydari et al. (2023) evaluated the effectiveness and safety of administering Latilactobacillus sakei both orally and topically in DED patients. The study found that while both methods were safe, topical administration was more effective at reducing inflammation (inhibition of inflammatory factors such as IL-6, TNF-α, and Interferon-gamma) and improving tear stability (Heydari et al., 2023). ...
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Background Post-menopausal osteoporosis is a concern of health organizations, and current treatments do not seem enough. Postbiotics as bioactive compounds produced by probiotics may be an attractive alternative for bone health. In this study, we prepared, formulated, and compared the effects of cell lysate and supernatant of five native probiotic strains ( Lactobacillus acidophilus , Lactobacillus reuteri , Lactobacillus casei , Bifidobacterium longum , and Bacillus coagulans ) in ovariectomized (OVX) rats. Methods The probiotic strains were isolated, and their cell-free supernatants and biomasses as postbiotics were extracted and formulated using standard microbial processes. The Sprague-Dawley rats were fed by 1 × 10 ⁹ CFU/ml/day postbiotic preparations for 4 weeks immediately after ovariectomy. Dual-energy X-ray absorptiometry (DEXA) scans were accomplished to evaluate femur, spine, and tibia BMD. The serum biochemical markers [calcium, phosphorus, and alkaline phosphatase] were assessed. Results Postbiotics could considerably improve the global and femur area in OVX rats. In the case of global bone mineral density (BMD), Lactobacillus casei lysate and supernatant, Bacillus coagulans lysate and supernatant, lysate of Bifidobacterium longum and Lactobacillus acidophilus , and Lactobacillus reuteri supernatant significantly increased BMD. We found Bacillus coagulans supernatant meaningfully enriched tibia BMD. Conclusion Postbiotic could ameliorate bone loss resulting from estrogen deficiency. Also, the effects of postbiotics on different bone sites are strain-dependent. More clinical studies need to explore the optimal administrative dose and duration of the specific postbiotics in protecting bone loss.
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Purpose: The study investigates the regulatory effects exhibited by lysate of Lactobacillus sakei pro-Bio65 (4%; L.SK) on the human conjunctival epithelial (HCE) cell line. Methods: Trypan blue and methylthiazol tetrazolium (MTT) methods were used to assess cell growth and viability. Mitochondrial membrane potential was assessed by JC-1 staining and cytofluorimetric detection methods. The antioxidant pattern and the intracellular reactive oxygen species (ROS) levels were analyzed by spectrophotometric and spectrofluorimetric methods. NF-κB luciferase activity was quantified by luminometric detection. NF-κB nuclear translocation, as well as mitochondrial morphology, were investigated by immunofluorescence using confocal microscopy. Cytokines and COX2 expression levels were determined by Western blot analyses. Results: This study demonstrates that L.SK exposure does not influence HCE cell proliferation and viability in vitro. L.SK paraprobiotic induces mild-low levels of intracellular ROS. It is coupled to changes in the mitochondrial membrane potential (ΔΨm), in a context of a regular mitochondrial-network organization. The negative modulation of tumor necrosis factor alpha (TNF-α) expression levels and rising antioxidant defense efficiency, mediated by the upregulation of glutathione (GSH) and increased antioxidant enzymatic activities, were observed. Conclusions: This study demonstrates that L.SK empowers the antioxidant endogenous efficiency of HCE cells, by the upregulation of the GSH content and the enzymatic antioxidant pattern, and concurrently reduces TNF-α protein expression. Translational relevance: Although the obtained in vitro results should be confirmed by in vivo investigations, our data suggest the possibility of L.SK paraprobiotic application for promoting eye health, exploring its use as an endogen antioxidant system inducer in preventing and treating different oxidative stress-based, inflammatory, and age-related conditions.
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Lactobacillus Sakei Pro-Bio65 Reduces TNF-α Expression and Upregulates GSH Content and Antioxidant Enzymatic Activities in Human Conjunctival Cells
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Full-text available
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Citation: Iorio R, Petricca S, Luzi C, Bellio P, Cristiano L, Festuccia C, Amicosante G, Celenza G. Lactobacillus sakei pro-Bio65 reduces TNF-α expression and upregulates GSH content and antioxidant enzymatic activities in human conjunctival cells. Trans Vis Sci Tech. 2021;0(0):3257, https://doi.org/10.1167/tvst.0.0.3257 Purpose: The study investigates the regulatory effects exhibited by lysate of Lactobacil-lus sakei pro-Bio65 (4%; L.SK) on the human conjunctival epithelial (HCE) cell line. Methods: Trypan blue and methylthiazol tetrazolium (MTT) methods were used to assess cell growth and viability. Mitochondrial membrane potential was assessed by JC-1 staining and cytofluorimetric detection methods. The antioxidant pattern and the intra-cellular reactive oxygen species (ROS) levels were analyzed by spectrophotometric and spectrofluorimetric methods. NF-κB luciferase activity was quantified by luminomet-ric detection. NF-κB nuclear translocation, as well as mitochondrial morphology, were investigated by immunofluorescence using confocal microscopy. Cytokines and COX2 expression levels were determined by Western blot analyses. Results: This study demonstrates that L.SK exposure does not influence HCE cell proliferation and viability in vitro. L.SK paraprobiotic induces mild-low levels of intracellular ROS. It is coupled to changes in the mitochondrial membrane potential (m), in a context of a regular mitochondrial-network organization. The negative modulation of tumor necrosis factor alpha (TNF-α) expression levels and rising antioxidant defense efficiency, mediated by the upregulation of glutathione (GSH) and increased antioxidant enzymatic activities, were observed. Conclusions: This study demonstrates that L.SK empowers the antioxidant endogenous efficiency of HCE cells, by the upregulation of the GSH content and the enzymatic antiox-idant pattern, and concurrently reduces TNF-α protein expression. Translational Relevance: Although the obtained in vitro results should be confirmed by in vivo investigations, our data suggest the possibility of L.SK paraprobiotic application for promoting eye health, exploring its use as an endogen antioxidant system inducer in preventing and treating different oxidative stress-based, inflammatory, and age-related conditions.
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Antibiotic treatment for dry eye disease related to meibomian gland dysfunction and blepharitis – A review
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  • Sep 2022
  • OCUL SURF
Background Dry eye disease (DED) is among the most prevalent ophthalmic conditions but is often underdiagnosed and mistreated. Antibiotics are regularly used to treat DED caused by meibomian gland dysfunction (MGD) or blepharitis, but their use has been questioned. Objective To critically evaluate the use of oral and topical antibiotics in DED management. Methods A literature search was conducted on November 15th, 2021, in the PubMed database. The search terms were: (antibiotics OR azithromycin OR doxycycline OR minocycline) AND (dry eye disease OR meibomian gland OR blepharitis anterior OR blepharitis posterior OR chronic blepharitis). All relevant original articles with English full-text were included. Case reports and review articles were excluded. Results The search provided 619 articles, of which 22 met the inclusion criteria. Oral and topical antibiotics appeared to have short-term positive effects on signs and symptoms of blepharitis- or MGD-related DED. However, these improvements often reverted upon cessation of treatment. The need for repeated treatments and mild adverse events were common. Conclusions Current evidence suggests that patients with blepharitis- or MGD-related DED experience short-term benefits of antibiotics. However, evidence for lasting improvement after completed treatment was lacking. Given the unclear long-term benefits, common side effects, and increasing antibiotic resistance seen globally, the existing literature is not sufficient to conclude that antibiotics are useful in long-term MGD management. A survival-analysis of a single round of antibiotics, in addition to the effects of repeated rounds of treatment, on DED parameters could provide useful insights.
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Therapeutic Implications of Curcumin in the Treatment of Inflammatory Eye Diseases: A Review
Article
  • Jun 2022
Curcumin is the main active constituent of the medicinal plant Curcuma longa L., used traditionally as a medicinal spice in several ancient civilizations. Different preclinical and clinical studies support the anti-inflammatory properties of curcumin in various inflammatory diseases. As inflammation has an essential role in the pathophysiology of many ocular diseases, curcumin has been suggested as a promising therapeutic agent with anti-inflammatory properties. Based on the extent of experimental and clinical evidence, curcumin can exert protective effects against the corneal, uveal, retinal, optic nerve, orbital, and lacrimal gland inflammatory disorders. Herein, the available literature on the beneficial effects of curcumin in inflammatory eye diseases is reviewed. The limitations and future directions of these investigations are also discussed.
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Are there Clinical Ways to Assess Inflammation in Dry Eye Disease?
Article
In the diagnostic process of dry eye disease, the detection of inflammatory activity is critical in order to evaluate the risk of progression and immunologic shift of the disease, to predict patient response to treatment, and to design an efficient therapeutic strategy, including artificial tear replacement, punctal occlusion or anti-inflammatory therapy. Even if it is difficult to quantify, some indicators of the presence of inflammation are collectible during the examination of the ocular surface in a first-line clinical setting. This review presents and critically discusses the assessment of inflammation in dry eye disease in clinical practice.
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