Delphi Consensus Statement on the Role of Probiotics in the Treatment of Atopic Dermatitis

Background Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by intense itching and recurrent eczematous lesions. Important factors in the etiopathogenesis of AD include genetic predisposition, epidermal barrier dysfunction, immune dysregulation, and gut and skin dysbiosis. Probiotics could be a potential preventive strategy for allergies including AD through immune system modulation as well as enhancement of the epithelial barrier integrity. To further understand the role of probiotics in the management of AD, a Knowledge, Attitude, and Practices (KAP) survey was conducted. Materials and methods A steering committee comprising nine experts formulated consensus recommendations on the role of probiotics in the management of AD and associated flare-ups through the use of the Knowledge, Attitude, and Practices questionnaire while analyzing literature reviews and responses from a national panel consisting of 175 members. The evidence strength and quality were evaluated based on the Agency for Healthcare Research and Quality (AHRQ) criteria. The acceptance of expert opinions as recommendations was considered upon receiving an endorsement from ≥70% of the panelists, as indicated by a Likert scale. Results The national panel emphasized that the improvement in nutritional status, immunomodulatory properties, and beneficial effects on the gastrointestinal (GI) tract and skin support the use of probiotics in AD. The panel agreed that probiotics should be a part of the complementary therapy in the management of AD and associated flare-ups. Mostly, a probiotics supplementation duration of eight to 12 weeks is preferred by dermatologists. Probiotics, when used as an adjuvant therapy, may serve as a strategy to reduce steroid usage or maintenance therapy in high-risk cases with flares. Conclusion A Delphi-mediated KAP response provides a real-life approach to the use of probiotics in the management of AD. It suggests that probiotics could be useful as an adjuvant therapy in the management of AD and associated flare-ups when used along with traditional treatment.


Introduction
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by intense pruritus and recurrent eczematous lesions [1].Globally, it affects up to 20% of children and up to 10% of adults [2].The pathogenesis of AD involves multiple factors like genetic predisposition, epidermal barrier dysfunction, systemic and local immune dysregulation, and gut and skin dysbiosis [3,4].
The AD management in childhood is challenging.Topical corticosteroid (TCS) administration might control the symptoms, especially in children with mild and moderate eczema.However, the occurrence of relapses is common.Moreover, prolonged and excessive use of TCSs implies a risk of systemic side effects and may cause skin atrophy, striae, rosacea, perioral dermatitis, acne, and purpura [5,6].Evidence suggests that AD derives from a T-cell imbalance with the predominance of Th2 differentiation of naïve CD4+ T cells, which results in a greater production of IL-4, IL-5, and IL-13, which could be locally affected both by the activation of IgE and in eosinophils.Recently, it has been reported that probiotics could be a potential preventive strategy for allergies including AD through immune system modulation through the rebalancing of the Th1 and Th2 response as well as the enhancement of the epithelial barrier integrity [3,7].
The WHO has defined probiotics as live microorganisms, which when administered in adequate amounts, confer a health benefit on the host [8].Lactobacillus and Bifidobacterium are the most commonly used probiotic strains.
Probiotics can be used as an adjuvant therapy in patients with moderate to severe AD [9].Recently, a metaanalysis of 17 randomized, placebo-controlled trials that included AD patients under the age of 18 years showed the beneficial effect of probiotics on reducing the severity of AD [10].
To further assess the scope of, potential of, and contemporary practices for the management of AD with probiotics in real-world settings of India, this Knowledge, Attitude, and Practices (KAP) survey was conducted.

Materials And Methods
A KAP survey questionnaire was designed to explore the role of probiotics in treating AD within the Indian context.To ensure its validity, a panel of 10 experts, comprising practicing dermatologists experienced in developing consensus statements, undertook the validation process.The meeting for the same was held in August 2023.The KAP survey was distributed to 175 healthcare professionals (HCPs) across India specializing in AD management, and they were asked to provide their responses within 30 days.
In December 2023, a second round of meetings took place, centering on the examination of responses, literature review, and the development of consensus recommendations regarding the role of probiotics in AD management.The steering panel, comprising 10 experts, reviewed the literature and developed clinical recommendations.The establishment of the level of evidence (LoE) was achieved through an exhaustive review of publications accessible in indexed databases such as PubMed and Google Scholar using keywords such as Probiotics, Atopic Dermatitis, Atopic Flare-ups, Lactobacillus rhamnosus GG, Eczema, and Immune Dysregulation.
The resulting consensus recommendations, derived from a problem-based clinical assessment approach, were used to consider the strength and quality of the evidence in accordance with the criteria set by the Agency for Healthcare Research and Quality (AHRQ), coupled with the general expert opinion shared by the panel.LoEs were assigned to various study types, categorizing meta-analyses, randomized, case-cohort longitudinal, cross-sectional case-control, and case reports as Level I, II, III, IV, and V, respectively.The acceptance of expert opinions as recommendations were considered upon receiving an endorsement from ≥70% of the panelists, as indicated by a Likert-type scale score (1: Strongly Disagree, 2: Disagree, 3: Neutral, 4: Agree, and 5: Strongly Agree) during the meeting.Descriptive statistical analyses, encompassing mean, median, and proportion assessments, were conducted for each response by using the Microsoft Excel 2016 version (Microsoft Corporation, Redmond, Washington, United States).A detailed study procedure flow chart is depicted in Figure 1.

Results
The study aimed to assess the current usage of oral probiotics in the management of AD by gathering insights from 175 practicing dermatologists.To achieve this, a KAP-based questionnaire was employed.This survey tool was designed to capture detailed information on the perceptions, experiences, and clinical practices of these healthcare professionals regarding the use of probiotics, particularly Lactobacillus rhamnosus GG (LGG), in treating AD.The participating dermatologists were located in various regions across India, which ensured a diverse and representative sample.The collected responses were meticulously compiled and subjected to a comprehensive analysis to identify trends, common practices, and potential areas for improvement in the application of probiotics in dermatology.These questions assessed various aspects of the clinical use of probiotics in managing AD.They explored the perceived role and timing of probiotics, the effectiveness of specific strains like LGG, and the recommended duration of treatment.The questions also evaluated beliefs about the broader benefits of probiotics, such as improving nutritional status, immune response, and overall gastrointestinal and skin health.Additionally, they investigate the acceptance of probiotics as a complementary therapy and their potential to reduce the use of topical immunosuppressants in AD treatment.Table 1 shows the structured questionnaire.

Discussion
Skin barrier abnormalities are considered as the initial step in the pathogenesis of AD.Barrier defects may be linked to lack of filaggrin, altered skin microbiome, altered composition of lipids in stratum corneum, and deficiency of antimicrobial peptides (AMPs).A Th2 predominance characterizes the immune response in AD, leading to chronic inflammation.This Th2-skewed response, independent of skin barrier abnormalities, perpetuates the disease.Chronic inflammation results in epidermal hyperplasia and immune cell infiltration, worsening the condition.While skin barrier abnormalities initiate AD, Th2 predominance sustains it.Thus, effective management of AD requires addressing both skin barrier defects and immune system responses.Skin barrier dysfunction leads to chronic inflammation with epidermal hyperplasia and cellular infiltrates [11,12].Figure 2 describes the pathophysiology of AD.

FIGURE 2: Pathophysiology of atopic dermatitis
Adapted from Tomáš Kebert & umimeto.org,2020 [13]; CC BY-SA 4.0 The gut microbiome can impact cutaneous pathology, physiology, and immune responses by causing metastasis of gut microorganisms and their metabolites to the skin [14].Patients with AD show microbiota abnormalities with an increased growth of Staphylococcus aureus along with a reduction in Propionibacterium, Streptococcus, and Acinetobacter.AD patients also have gut microbiota abnormalities showing a decrease in beneficial microbes like Lactobacillus and Bifidobacterium and increased Escherichia coli, S. aureus, and Clostridium difficile [11].Figure 3 shows the gut dysbiosis in AD.Children and infants with AD are generally treated with TCSs, antihistamines, and antibiotics.However, these medications are associated with different adverse effects, and stopping the treatment can cause the recurrence of AD symptoms.The long-term use of TCSs may trigger new onset atopic dermatitis [15].TCSs are associated with multiple cutaneous side effects like skin atrophy, purpura, telangiectasia, hypopigmentation, acneiform eruptions, striae, and focal hypertrichosis [16].Several studies show that probiotics supplementation may be an effective choice in reducing the incidence as well as in the treatment of atopic dermatitis [17][18][19].A meta-analysis of 20 randomized controlled trials assessing probiotics alone or in combination with prebiotics in children with AD showed a significant decrease in SCORing AD (SCORAD) severity scores, suggesting a consistent pattern in alleviating AD symptoms in children without food allergies [20].

FIGURE 3: Gut dysbiosis in atopic dermatitis
Probiotics exert beneficial effects on the host by causing an enhancement in intestinal barrier function, the suppression of pathogens, and immune modulation [11].Probiotics enhance intestinal barrier function by promoting mucin secretion from goblet cells (MUC1, MUC2, and MUC3), limiting bacterial movement.They also increase AMP production, preventing bacterial growth, and improve tight junction stability through the upregulation of proteins like claudin-1, occludin, and zonula occludens (ZO).This, in turn, reduces the permeability of the epithelial layer to potential pathogens.Probiotics produce antimicrobial factors like AMPs, short-chain fatty acids (SCFAs), and bacteriocins to suppress or eliminate pathogens.Additionally, SCFAs such as butyrate help modulate the expression of occludin and ZO, enhancing epithelial barrier integrity.Probiotics influence the maturation of dendritic cells (DCs) by regulating their differentiation into either mature form or tolerogenic form in response to pro-inflammatory or anti-inflammatory stimuli.Probiotics balance Th1/Th2 immune response by stimulating Th1 and suppressing Th2 responses.Additionally, probiotics induce regulatory T cell (Treg) generation, fostering immune tolerance and impacting allergic diseases [11].Table 2 shows the summary of clinical trials showing favorable outcomes with probiotics in AD.

Conclusions
The prevalence of AD is rising in the Indian population, presenting significant challenges in its management due to the need for prolonged treatment.This KAP survey offers valuable insights into the real-life application of probiotics in managing AD.The survey findings indicate that probiotics, particularly LGG, can be beneficial as an adjuvant therapy, helping to manage AD and associated flare-ups when used alongside traditional treatments.
Probiotics demonstrate potential in improving nutritional status, enhancing immune responses, and benefitting gastrointestinal and skin health, which supports their use in AD management.While further research is needed to confirm these benefits and optimize treatment protocols, this survey underscores the promising role of probiotics as part of a comprehensive treatment strategy for AD.
compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: The study was funded by Torrent Pharmaceuticals Ltd., Ahmedabad, India.Financial relationships: Pradeep Mane, Rathish Nair, and Krishnaprasad Korukonda declare(s) employment from Torrent Pharmaceuticals Ltd., Ahmedabad.Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

FIGURE 1 :
FIGURE 1: Study procedure flow chart KAP: Knowledge, Attitude, and Practices; AHRQ: Agency for Healthcare Research and Quality; LOE: level of evidence; LoA: level of agreement clinical practice, where would you like to place probiotics in the management of AD? right concentration are effective in the management of flare-ups in AD.
Image Credit: Author Pradeep Mane 2024 Thomas et al.Cureus 16(7): e64583.DOI 10.7759/cureus.645835 of 11 12 (p<0.05),improvement in IDQoL at week 12 (p<0.05)and number of days without rescue medications were higher in the probiotic group two probiotic strains (LGG and BB-12), each in a dose of 109 CFU six months Did not mention Lower incidences of eczema (p=0.036) were observed in the probiotic group as compared to the placebo group At two years, the frequency of atopic eczema in the LGG group (15/64 (23%)) was half that of the placebo group (31/68 (46%)) (p=0.008)At seven years, the overall risk for developing atopic eczema during the first seven years of life in children was significantly decreased in the LGG group than in the placebo group (42.6% vs. 66.1%)Did not mention Rautava et Double-blind, placebo-62 mothers with a family LGG (ATCC 53103); 2 × 1010 Four weeks prenatal, three Infants whose mothers received probiotics had significantly reduced risk of developing AD during the first two years of 2024 Thomas et al.Cureus 16(7): e64583.DOI 10.7759/cureus.life in comparison with infants whose mothers received placebo (15% and 47%, respectively (p=.0098) 12 in the probiotic group (p<0.001),Use of topical corticosteroids to treat flares decreased significantly in the probiotic group as compared to the placebo group (p<0.003)months in the probiotic group (p=0.03).Probiotics group required topical immunosuppressant less frequently at six and nine months (p<0.05).0001)andimprovement in DLQ index (p=0.021) in the probiotic group, Probiotics reduced microbial translocation (p=0.050),immune activation (p<0.001), and improved Th17/Treg (p=0.029) and Th1/Th2 (p=0.028)ratios.

3
Lactobacillus rhamnosus GG strain is more effective for the prevention of AD than other commercially available probiotics.
5The improvements in nutritional status, nutrient digestion, and specific and non-specific immune response, and the beneficial effects on the gastrointestinal tract and skin, support the use of probiotics in patients with AD.

TABLE 1 : KAP questionnaire with responses on the clinical role and positioning of probiotics in AD
AD: atopic dermatitis; KAP: Knowledge, Attitude, and Practices

TABLE 2 : Summary of clinical trials showing favorable outcomes with probiotics in atopic dermatitis (AD)
SCORAD: SCORing AD; IDQoL: Infants' Dermatitis Quality of Life; DLQ: Dermatology Life Quality; AE: adverse event

Table 3
lists the recommendations for the use of oral probiotics in the treatment of AD.

TABLE 3 : Recommendations on the use of oral probiotics in the treatment of atopic dermatitis (AD)
However, this study has several limitations.The sample size of 175 dermatologists may not fully represent all regions of India.The study lacked direct patient outcomes and longitudinal data, limiting conclusions about long-term efficacy and safety.Additionally, relying on the published literature means unpublished data can alter current recommendations.