ACADEMIA Letters Probiotic supplements for children with type 1 diabetes: perceived benefits versus long-term concerns Devi Dayal Latika Rohilla Probiotics are associated with several health benefits, including the normal regulation of gut membrane integrity and permeability, thereby preventing gut leakiness, endotoxemia, and inflammation [1]. Quite understandably, probiotic supplementation of several food items such as milk, cheese, yogurt, etc., has gained popularity in recent years. Probiotic supplements are now considered a major driver of the functional food market that is projected to reach 64 billion USD by 2023 [2]. The medical use of probiotics has also become a subject of intense research commensurate with the recent revolutionization in gut microbiota identification methods and a renewed focus on microbiome studies [1, 2]. Several common autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, celiac disease, and type 1 diabetes (T1D), which have disturbances of the gut microbiome, are apparent candidates for probiotic supplementation [1, 3]. And while the effects of probiotic treatment are complex and not entirely determined in a truly rigorous scientific manner, it is widely believed that probiotics are beneficial in helping the intestine stabilize bacterial content through at least two known pathways viz. pattern recognition receptors pathway and short-chain fatty acids pathway [1]. The gut microbiome changes, in turn, are believed to exert changes in the immune system in patients with autoimmune conditions. Probiotics thus find their application in the prevention or treatment of autoimmune diseases, including T1D. The incidence of T1D has increased tremendously over the past few decades, and it has become a significant public health concern worldwide [4, 5]. The major factors that drive the increased incidence of T1D are modern lifestyles and rapid environmental changes that have predominantly led to changes in food intake [6]. Consequently, there are alterations of epigenetic regulations of the genome and composition of gut microbiota, which may ultimately play Academia Letters, March 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0 Corresponding Author: Devi Dayal, drdevidayal@gmail.com Citation: Dayal, D., Rohilla, L. (2021). Probiotic supplements for children with type 1 diabetes: perceived benefits versus long-term concerns. Academia Letters, Article 564. https://doi.org/10.20935/AL564. 1 a role in the pathogenesis of T1D through immune dysfunction. A recent review indicates that the amelioration of gut dysbiosis using specific probiotics (and prebiotics) is associated with a decline in the autoimmune response and improved gut integrity [7]. However, the inability to completely abrogate autoimmune diabetes even in animals could be a drawback in the clinical application of probiotics in the prevention or treatment of autoimmune diabetes [8]. Despite the promising outcomes shown in several animal studies, the use of probiotics in children with T1D has shown mixed results. In the TEDDY cohort, early exposure to probiotic supplements was reported to reduce the risk of T1D in children at high risk of acquiring the disease [9]. There is also some evidence of a beneficial effect of probiotic supplementation on glycemic control in children with T1D [7]. The beneficial effects on glycemic control or improvement in residual beta-cell function occur over a long-term and sustained supplementation similar to other immunotherapeutic interventions in T1D [7, 10]. In this context, the study by Wang Y et al. assumes great significance and made an interesting read [11]. In meticulously conducted experiments, the authors have highlighted two important aspects of commercial probiotic supplements. First, they show that these supplements have poor tolerance to acids and bile salts, which affects their survivability in the gut, where these are presumed to produce a beneficial alteration of microbiota [11]. Secondly, and more importantly, the authors demonstrate a remarkable ability of probiotics to adapt quickly and acquire resistance to antibiotics. It is well known that commercial probiotic strains are deliberately engineered to carry resistant determinants during the manufacturing process. The resistant genes carried on mobile elements of probiotics can be transferred by horizontal gene transfer to resident gut bacteria, which over time can accumulate resistant determinants that may, in turn, be transferred to opportunistic pathogens within the gastrointestinal tract [12]. Wang Y et al. also cite previous studies showing that transfer of these resistant genes to other pathogens can occur easily due to relatively stable conditions in the gut such as temperature, nutrients, and food debris, as well as the presence of rich microflora that favor horizontal gene transfer [13, 14]. The consequences of such acquired antibiotic resistance due to the long-term use of probiotic supplements are dangerous. In the event of an infection, bacterial pathogens that have acquired resistant genes may become antibiotic-resistant and eventually exhaust antibiotic options. Therefore, the effects of probiotics are a “‘double-edged” sword in children with T1D quite similar to their use in other autoimmune conditions in humans as well as in livestock and agriculture [15]. In addition to the risk of trafficking of antibiotic-resistance genes, the use of probiotics may cause localized and/or systemic infections by penetrating the intestinal mucosa [16]. Probiotics also cause localized metabolic disturbances in the gut that may lead to opportunistic infections by bacteriophages virulence factors and metabolites of probiotics Academia Letters, March 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0 Corresponding Author: Devi Dayal, drdevidayal@gmail.com Citation: Dayal, D., Rohilla, L. (2021). Probiotic supplements for children with type 1 diabetes: perceived benefits versus long-term concerns. Academia Letters, Article 564. https://doi.org/10.20935/AL564. 2 [14]. Furthermore, the intestinal probiotic overgrowth may result in the establishment of probiotic mobilome, gas, and bloating of the intestine [14]. There is also a worry about the systemic effects of probiotics such as lactic acidosis, brain fogginess, and triggering of cytokine production that may cause other autoimmune diseases [14, 16]. While there is hope that future genomics approaches may be able to remove resistant determinants from probiotic strains prior to commercial applications, extreme caution is required during the long-term use of the currently available strains in children with T1D [11]. Therefore, the available probiotic preparations must meet the essential prerequisites as suggested in the expert consensus document on the scope and appropriate use of the term probiotic prepared by the International Scientific Association for Probiotics and Prebiotics in 2014 [17]. Furthermore, the regulatory authorities must keep a watch on the misconducts by probiotics manufacturers that include overestimation of bacteria, misidentification of probiotic strains, and unsupported health claims on product labels [11]. Considering the health benefits of probiotics, there is a need to conduct high-quality clinical trials to further understand their effects in autoimmune conditions, including T1D. Indeed, manipulation of the gut microbiome in children with T1D or children at high-risk for T1D using probiotics alone or in combination with other dietary supplements is the subject of several ongoing studies listed on clinicaltrials.gov [18]. We earnestly hope that the results of these studies and other ongoing studies listed elsewhere will help physicians in their decision-making while using probiotic supplements in children with T1D. A limitation of our article is that being a commentary, it provides only the salient points on the use of probiotics while the topic of probiotics for health benefits needs a comprehensive review. References 1. Marietta E, Mangalam AK, Taneja V, et al. Intestinal Dysbiosis in, and Enteral Bacterial Therapies for, Systemic Autoimmune Diseases. Front Immunol. 2020;11:573079. 2. Zheng M, Zhang R, Tian X, et al. Assessing the Risk of Probiotic Dietary Supplements in the Context of Antibiotic Resistance. Front Microbiol. 2017;8:908. 3. Kaur N, Bhadada SK, Minz RW, et al. Interplay between Type 1 Diabetes Mellitus and Celiac Disease: Implications in Treatment. Dig Dis. 2018;36:399-408. 4. Gupta BM, Dayal D. Pediatric type 1 diabetes research in the 21st century: a scientometric review. Pediatr Endocrinol Diabetes Metab. 2020;26:132-139. Academia Letters, March 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0 Corresponding Author: Devi Dayal, drdevidayal@gmail.com Citation: Dayal, D., Rohilla, L. (2021). Probiotic supplements for children with type 1 diabetes: perceived benefits versus long-term concerns. Academia Letters, Article 564. https://doi.org/10.20935/AL564. 3 5. Dayal D, Saini AG, Jayashree M, et al. Hospital based incidence, patterns of presentation and outcome of Type 1 diabetes: 12 years’ data from a tertiary care center in North India. Int J Diabetes Dev Ctries. 2015;35:103-7. 6. Islam ST, Srinivasan S, Craig ME. Environmental determinants of type 1 diabetes: a role for overweight and insulin resistance. J Paediatr Child Health. 2014;50:874-879. 7. Mishra SP, Wang S, Nagpal R, et al. Probiotics and Prebiotics for the Amelioration of Type 1 Diabetes: Present and Future Perspectives. Microorganisms. 2019;7:67. 8. Kim TK, Lee JC, Im SH, Lee MS. Amelioration of Autoimmune Diabetes of NOD Mice by Immunomodulating Probiotics. Front Immunol. 2020;11:1832. 9. Uusitalo U, Liu X, Yang J, et al. Association of Early Exposure of Probiotics and Islet Autoimmunity in the TEDDY Study. JAMA Pediatr. 2016;170:20-28. 10. Panjiyar RP, Dayal D, Attri SV, et al. Sustained serum 25-hydroxyvitamin D concentrations for one year with cholecalciferol supplementation improves glycaemic control and slows the decline of residual β cell function in children with type 1 diabetes. Pediatr Endocrinol Diabetes Metab. 2018;24:111-117. 11. Wang Y, Jiang Y, Deng Y, et al. Probiotic Supplements: Hope or Hype? Front Microbiol. 2020;11:160. 12. Broaders E, Gahan CG, Marchesi JR. Mobile genetic elements of the human gastrointestinal tract: potential for spread of antibiotic resistance genes. Gut Microbes. 2013;4:271280. 13. Thumu SCR, Halami PM. Conjugal transfer of erm(B) and multiple tet genes from Lactobacillus spp. to bacterial pathogens in animal gut, in vitro and during food fermentation. Food Res Int. 2019;116:1066-1075. 14. Lerner A, Matthias T, Aminov R. Potential Effects of Horizontal Gene Exchange in the Human Gut. Front Immunol. 2017;8:1630. 15. Imperial IC, Ibana JA. Addressing the Antibiotic Resistance Problem with Probiotics: Reducing the Risk of Its Double-Edged Sword Effect. Front Microbiol. 2016;7:1983. 16. Kothari D, Patel S, Kim SK. Probiotic supplements might not be universally-effective and safe: A review. Biomed Pharmacother. 2019;111:537-547. Academia Letters, March 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0 Corresponding Author: Devi Dayal, drdevidayal@gmail.com Citation: Dayal, D., Rohilla, L. (2021). Probiotic supplements for children with type 1 diabetes: perceived benefits versus long-term concerns. Academia Letters, Article 564. https://doi.org/10.20935/AL564. 4 17. Hill C, Guarner F, Reid G, et al. Expert consensus document. 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;11:506514. 18. Studies on probiotics in children with type 1 diabetes. Available at: https://www.clinicaltrials.gov/ ct2/results?cond=Type+1+diabetes&term=Children%2C+probiotics. Accessed on December 18, 2020. Academia Letters, March 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0 Corresponding Author: Devi Dayal, drdevidayal@gmail.com Citation: Dayal, D., Rohilla, L. (2021). Probiotic supplements for children with type 1 diabetes: perceived benefits versus long-term concerns. Academia Letters, Article 564. https://doi.org/10.20935/AL564. 5 View publication stats