Evidence and possible mechanisms of probiotics in the management of type 1 diabetes mellitus

Abstract

Abstract

Type 1 diabetes mellitus (T1DM) is one of the most common chronic immune-mediated diseases. The prevalence is worldwide especially among children and young adults. The destruction of the pancreatic β-cells due to some abnormalities in the immune system characterizes T1DM. Considering the high burden of the disease and its impact on human health, researchers have made great efforts during the last decades; investigating the disease pathogenesis and discovering new strategies for its management. Fortunately, probiotics have been found as potential remedies for T1DM. This review aims to explore the potentialities of probiotics in managing T1DM and its complications. Based on the outcomes of human and animal studies carried out from 2016 to 2021, the review hopes to assess the effectiveness of probiotics in the prevention and treatment of T1DM and its complications. We first tried to explain the disease's pathogenesis, and highlighted the possible mechanisms involved in these potentialities of probiotics. We concluded that, probiotics can be used as possible therapeutic tools for the management of T1DM. Possible mechanisms of action of probiotics include; the modulation of the gut microbiota, the regulation of inflammation-related cytokines, the production of short chain fatty acids (SCFAs), and the regulation of GLP-1. However, we recommend further studies especially human trials should be carried out to investigate these potentialities of probiotics.

Highlights

• T1DM is highly prevalent worldwide, causing high morbidity and mortality especially among children and young adults

• Gut microbiota plays a significant role in the pathogenesis of T1DM via an interconnection with the immune system

• Probiotics can be used as possible therapeutic tools for the management of T1DM

• Possible mechanisms of action of probiotics include the modulation of the gut microbiota, the regulation of inflammation-related cytokines, the production of SCFAs, and the regulation of GLP-1

Introduction

Type 1 diabetes (T1DM) also known as insulin-dependent, juvenile, or childhood-onset, is a chronic autoimmune disease characterized by the insufficiency in insulin production due to selective destruction of pancreatic β-cells [1, 2]. It is an illness typically identified among young age group with insulin deficiency [3]. T1DM could be identified through the production of urine (polyuria), excess thirst (polydipsia), constant hunger, weight loss, changes in vision, and tiredness [1, 4]. It can be classified into two; the majority of T1DM cases can be attributed to autoimmune-mediated damage of beta cells ( known as type 1a) while the marginal cases are due to idiopathic damage or failure of beta cells to make insulin (type 1b)[5]. However, there is another exceptional subtype of T1DM called diabetes LADA (Latent Autoimmune Diabetes of Adults), who’s characteristic is slow β-cell damage [6]. T1DM does not only bring complications but also affects many organs such as the heart, blood vessels, nerves, eyes, and kidney, and can lead to a significant morbidity and mortality in the world. T1DM complications have been categorized as microvascular complications, which comprise retinopathy, nephropathy, and neuropathy; and macrovascular ones including cardiovascular disease, cerebrovascular diseases and peripheral arterial disease [7, 8].

In several countries, immune-mediated diseases, mainly allergic and autoimmune diseases such as T1DM seem to have augmented in prevalence and are leading causes of mortality especially among kids and young people [9]. At least 500,000 kids have T1DM globally over the last 50 to 60 years [10]. T1DM prevalence has augmented, especially in developed nations [11]. For instance, the yearly prevalence in Finland (one of the countries with high T1DM incidence) was 12 per 100,000 children under 15 during the 1950s and raised to 65 per 100,000 in 2006 [12, 13]. According to the data from the national diabetes statistics reports, T1DM accounts for 5 to 10% of all diabetes; 210,000 kids and teenagers aged under 20 years or 25 per 10,000 US youths are suffering from diabetes, and this involves 187,000 suffering from T1DM. About 1.4 million adults of 20 of age and more representing 5.2% of all US adults with diabetes reported suffering from T1DM and are under insulin treatment. During the last years, the overall prevalence of T1DM has risen considerably [14, 15]. Furthermore, data from the EuroDIAB (European Diabetes) study disclosed that the T1DM prevalence among kids (both sex) aged 0 to 4 raised by 3.7%, 5–9 years augmented by 3.4% among males and 3.7% among females and 10 to14 years age groups grown by 3.3% in males and 2.6% in females annually in that order, during the last 25 years [16]. In China, about 5018 new cases of T1DM have been diagnosed according to data from a recent survey. Contrary to the general trends, the great majority of cases are diagnosed among adults above 20 years of age while the prevalence among kids was among the lowest [17]. This prevalence is on the rise since there has been a significant rise in new cases during the last two decades in the country[18].

Environmental, viral and genetic factors are the main triggers of T1DM. An autoimmune illness that commonly manifests during infancy but can develop or be diagnosed at any age [19–21]. Other known risk factors for T1DM development include gender, age, race, geographic location, seasonality [5], chemicals, diet [22, 23], the use of antibiotics, vitamin D levels, exposure to toxins, birth weight, and birth delivery route [24]. Also, children with T1DM have been shown to have a high risk of developing other conditions such as periodontal diseases [25].

Given all the information mentioned above about T1DM, it is necessary to look for a management solution. Even though it represents only the minor part of all diabetes patients, it is a life-threatening disorder mainly for children and young adults. Concerning T1DM treatment strategies, about a century ago, insulin had been discovered and was being used till 50 years later when sulfonylureas and biguanides had been found [26]. However, insulin had been revealed as not only a friend but a foe in the occurrence of T1DM. According to a study, insulin functions as a friend since it promotes the compensation of β-cell. However, it becomes a foe since it also contributes to the decompensation of β-cell [27]. There is therefore, a need for a new treatment strategy. Interestingly, as a result of many studies (animals and humans), probiotics have been found to have great potentials in the modulation of the gut microbiota (GM) and management of diseases such as T1DM[28]. According to W.H.O, probiotics are "live microorganisms which, when administered in adequate amounts, confer a health benefit on the host" [29]. It is naturally referring to existing microorganisms that normally facilitate the health improvement on the host body when consumed in suitable amounts and a proper diet [30–33]. Probiotics have been documented for their numerous health-promoting roles and alleviating physiological and psychological hitches and pains, improving intestinal health and immune responses [34, 35]. Besides, probiotics have been recommended as interesting coadjuvent in managing associated metabolic diseases including T1DM. Nevertheless, the results are not consistent and their varied effects' mechanisms are understudied [36]. Numerous experiments (animal and humans) have been conducted to assess probiotics' health-promoting status during the previous years [37–39]. Recent researches have also evoked the efficacy of probiotics in the management of T1DM [40, 41], and positive results had been reported. However, recommendations are made on some other focuses such as the need to consider the investigations on the possible mechanisms of actions. Thus, the aim of this review is to explore and confirm the potentialities of probiotics in the management of T1DM and its complications. Moreover, this review aims to highlight the possible mechanisms through which probiotics act in the management of T1DM and its complications.

Understanding the Pathogenesis of T1DM

Overview: Immunologic cells and Molecules involved

T1DM is a long-term autoimmune disorder caused by the lack of insulin secretion due to the (β)-cell death in the islet of Langerhans [42]. Autoimmune diseases are diseases resulting from self-tissue attacks due to an individual's immune system [43]. Immunologically, T1DM is mediated through autoreactive lymphocytes activation, autoantibodies production, and the pancreatic β-cells destruction by T-cells in individuals with genetic predispositions [44]. The pathogenesis of T1DM results from multifarious contacts of the pancreatic β-cell with the innate and adaptive immune system cells [45]. Known immune cells implicated in the destruction of the (β)-cells are the lymphocytes CD4 + , CD8 + T cells, and macrophages, which act after their infiltration in the islets [46]. However, other immune cells such as lymphocytes B cells are also known as pivotal regulators of the immune system and autoimmunity, highly implicated in T1DM pathogenesis, more precisely in the autoimmune destruction of the pancreatic islets. B cells are known to be able to promote T1DM through the presentation of islet-derived peptides to the autoreactive T-cells, the production of autoantibodies against β‐cells antigens and the secretion of proinflammatory cytokines [47, 48]. The destruction of the (β)-cells is due to immune attacks mainly by Lymphocyte cytotoxic T-cells that suddenly become very active and destroy the healthy β‐cells. Next, this phenomenon is followed by the penetration of the other immune cells such as macrophages, causing the insulitis or the inflammation of the islets and consequently the deficiency in insulin production due to the β‐cells destruction [49]. The autoreactive immune reaction occurs in the pancreatic lymph nodes (PLNs) that continuously provide autoreactive lymphocyte T-cells. Acting as natural immune effectors, the remaining immune cells, mainly the macrophages and dendritic cells (DCs), are responsible for the activation of the cytotoxic T‐cells. Also, in the context of the Major Histocompatibility Complex class II (MHC II) molecules, these two mentioned immune cells act as antigen‐presenting cells (APCs) thereby, activating the T-cells and contributing to the pathogenesis of T1DM by the adaptive immune response pathway [49].

T1DM is also caused by the dysfunction of indoleamine 2, 3 dioxygenase 1 (IDO 1), the enzyme that metabolizes tryptophan and exerts potent immunoregulatory effects on DCs. The defect in the catabolism of tryptophan by IDO-1 leads to the wrong dysfunction of DCs resulting in an impaired tolerogenesis [50]. Also, β-cells death results from the secretion of granzymes or perforin by CD8 + T-cells, which have direct cytotoxicity effects on them [49].

Factors contributing to the occurrence of T1DM

The etiology of T1DM is multifaceted and can result from both environmental and genetic factors similarly to the other autoimmune diseases [51]. Apparently, the immune response against the β cells leading to the occurrence of T1DM are triggered by genetic and environmental factors [52].

Genetic factors

Genetic factors are linked to the activation of the cytotoxic T-cells. For instance, whole-genome screens have pointed out that more than 15 loci are linked to T1DM. Other two genes closely connected to T-cell activation have been recognized later [46]. An allele of the gene for a negative regulator of T-cell activation, cytotoxic T lymphocyte antigen 4 (CTLA4), present on chromosome 2q33, is the third predisposition locus for T1DM and linked to the abundance of regulatory T-cells [46]. Moreover, the candidate gene approach has studied susceptible genes for T1DM, and some key genes like HLA and insulin gene (INS) had been identified[53]. Findings from researches have effectively acknowledged numerous genes that are in charge of the occurrence of T1DM during the past few decades [51]. It has been further confirmed that the alteration or manipulation of these genes by gene therapy approach for example could possibly offer a more holistic disease management or even heal T1DM[51], hence genetic factors are involved in the pathogenesis of T1DM.

Environmental factors

Some environmental factors, mainly viral infections are known to be linked to the onset of T1DM. More precisely, enterovirus [45], rotavirus, and rubella [46] have been known as the most common viral infections associated with T1DM. Enteroviral major capsid protein VP1 and RNA were identified in islets of individuals newly diagnosed with T1DM along with high-expression of the MHC-I [45]. Furthermore, other environmental factors that have been mentioned to be linked to the onset of T1DM include the GM. The gastrointestinal tract, made of the greatest surface area in the human body, is heavily colonized by 500 to 1000 diverse bacterial species [54]. During the last years, many researchers have elucidated the relationship between the host and the GM about health and disease. Alteration in the GM composition had been emphasized by evidence from human studies to have a significant role in the progression of T1DM [55]. Moreover, T1DM sufferers have been found with more unstable and less diverse gut microbiome than healthy subjects. Similarly, changes in the ratio of Firmicutes to Bacteroidetes have been noticed in these T1DM sufferers, indicating the association of the GM to the immune system [54]. A case–control study evaluating the dissimilarities in the GM composition of kids with T1DM and healthy ones revealed similar findings. This study showed important disparities in the abundance of Bifidobacterium, lactobacillus, and clostridium among the two groups [56]. A systematic review assessing the relationship between the GM and T1DM disclosed that alterations in the gut microbiota composition are correlated to T1DM [57]. Moreover, the microbial environment influences the incidence of T1DM in NOD mice. This finding had supported the important role of the GM in the onset of T1DM [58]. Numerous environmental exposure, including infant and adult diet, sufficiency in vitamin D, early life exposure to some viruses such as enteroviruses, low diversity in the gut microbiome, are associated with the development of T1DM [59]. Therefore, the GM is incontestably one of the environmental factors involve in the pathogenesis of T1DM. However, there is one question remained unanswered; how does the GM is connected to the immune system and trigger T1DM?

Gut microbiota (GM), immune system and T1DM

About 60 phyla of bacteria are identified presently, including a quiet few, mainly Firmicutes, Bacteroides, Actinobacteria, Cyanobacteria, Spirochaetes Fusobacteria, Proteobacteria, and Verrucomicrobia exist in the human intestine [60]. The two predominant bacteria phyla in the human gut are Gram-negative Bacteroides and Grampositive Firmicutes (Lactobacillus spp., Bacillus spp Clostridium spp [61]. The largest phyla of bacteria are Firmicutes encompassing over 200 bacterial genera, while Bacteroides comprise about 20 [62]. GM as a pivotal factor in the occurrence of several disorders (namely allergic and autoimmune diseases including T1DM) and considered an endocrine organ implicated in the energy homeostasis maintaining and the host immunity [63, 64]. The bacteria residing in the gut are known to modulate the host’s innate immune response for the immune cells’ response to infections to occur more quickly [63]. The gut is the starting point of autoimmune stimulations; the external environment is in contact with the intestine and its microbiota. There is a multifaceted site for the interaction with the mucosal immune system and, reasonably, with the gut associated lymphoide tissus (GALT), which has a huge composite of immune cells [49]. Several immune niches are known to be contained by the intestine; these include the GALT, which serve as a site for the priming and differentiation of adaptative immune cells. On the other hand, the intestinal epithelium and lamina propria are the residence places for antigen-experienced lymphocytes and stay for the long term as devoted effectors or regulatory cells [65]. Furthermore, it has been found that the microbiota boosts the mucus layer on the intestinal mucosa throughout the direct competition for nutrients, and this process excites the immune system of the gut with the assist of the GALT [66]. More precisely, the immune system is known to be linked to a rise in the abundance of anaerobic bacteria in the gut when immunoglobulin-A is absent. Moreover, the components of the innate immune system are known to impact the GM [66]. Therefore, there is an interconnection between the gut microbiome and the immune cells.

As evidence, finding revealed that, concerning the gut composition, the non existence of Bifidobacterium species contrasting with a high amount of bacteria from genus Bacteroides in feces is positively correlated to the appearance of autoantibodies, which target the islet β-cells of the pancreas [67]. Curiously, many studies have pointed out that the great influence of the gut on various aspects of the host biology, such as the metabolism and the immune system [68]. It has been well documented that GM can have an interaction with non-enteral cells, namely immune cells, and hepatocytes, and produce molecules like short chain fatty acids (SCFAs), indole derivatives, polyamines, and secondary bile acid [69]. Findings from other studies disclosed that relating to the gut microbiome and T-cells, the maturation of particular subsets of lymphocytes is regulated by the local microbiota. For example, in the gut, some specific species of Clostridia contribute to the production of Th17 cells [70]. Other findings during the early post-natal period, the contacts between the immune system and the GM plays a key role in the immune system’s maturation, modulation, and response to self-antigens all along with the lifespan. Consequently, many have recommended that dysbiosis may have a role in the progression of disorders related to immune deregulation, especially allergies, autoimmune, and inflammatory diseases [69]. Furthermore, it is known that the mechanism through which GM modulates the immune system is the production of molecules with immunomodulatory and anti-inflammatory activity able to have an impact on the immune cells. In fact, in the T1DM pathogenesis, cytotoxic actions on the β-cells are induced by pro-inflammatory cytokines, namely IL-1β, IFN-γ, tumor necrosis factor (TNF)-α, released by macrophages, which consequently leads to β-cell death [49]. Therefore, with regards to the previously mentioned examples and findings, it is obvious that the GM is strongly implicated in the pathogenesis of T1DM. An imbalance in the GM composition may be the origin of the immune reactions leading to the β-cells damage in T1DM.

Probiotics for the management of T1DM: Possible Mechanisms of Action

Through the gut microbiome (gut microbiota)

The microbes colonizing humans and their genes are mostly found in the gastrointestinal tract are called gut microbiome or microbiota (GM) [71]. The GM composition can be highly impacted by several environmental factors such as diet and antibiotics [72]. Researchers found that probiotics wield their effects using diverse ways of action such as their aptitude to control the composition of the intestinal microbiota, manipulate the metabolic profile of intestinal microbiota, ameliorate the intestinal barrier function and integrity, and stimulate molecules with influences on humoral and cellular immune responses [67, 73]. Emergent studies have pointed out the importance of GM in human health; some probiotics such as yoghurt appear to interact with the gut microbiota [74]. A predictive model proposed that probiotics act on the systemic immune responses, guarantee the homeostasis of the normal microbiota in the intestinal mucosa, and consequently administered as an adjuvant remedy to manage immune-mediated illnesses. Suggested ways to reach that efficacy comprise mucus production, antimicrobial peptide making, the preservation of the activity of the gastrointestinal–epithelial barrier, securing sufficient connections between the GM and the mucosal immune cells, and lastly, in response to pathobionts, serving the activation of the host immune system [75]. The consumption of specific probiotics strains had been shown to result in numerous health beneifts such as the right control of gut membrane integrity and permeability, thus prevent gut leakiness and inflammation [70], which is strongly involved in T1DM pathogenesis. A study investigated the statement claiming that the probiotic Lactobacillus rhamnosus GG instigated the intestinal barrier's maturation through claudin-3 expression. Similarly, claudin had also been said to be induced by Lactobacillus johnsonii [54]. Findings include standardization of disturbed microbiota composition, intestinal maturation, diminished pathogenic load and infections, and a better immune response in kids who were administrated probiotics during some preclinical studies [36]. Carbohydrate fermentation and digestion, the polarization of specific immune responses, vitamin synthesis, and the prevention of colonization by pathobionts are the major contributions of the microbiota to the host. Studies in germ-free (GF) mice disclosed that the GM is essential in the right immune system mellowing, such as the GALT growth, known for its significant task in the gut mucosa, intolerance induction autoantigens [75].

Through the production of Short Chain Fatty Acids (SCFAs)

Also known as volatile fatty acids, SCFAs are organic acids mainly produced in the gastrointestinal tract in millimolar amounts and majorly in high quantity in predominant anaerobic microorganism areas. The most common SCFAs are acetic acid, propionic acid, and butyric acid. SCFAs symbolize the principal carbon flow from the diet to the host microbiome and an energy source for the host and gut bacteria [60, 76]. SCFAs are known for their important roles in maintaining the host's health, such as maintaining intestinal and immune homeostasis. SCFAs have been proven to have protective effects in the early onset of T1DM in a cohort TEDDY (The Environmental Determinants of Diabetes in the Young) study carried out among children [77]. Also, SCFAs derived from the GM can manipulate different types of cells, among which the immune cells and the pancreatic β-cells are implicated in T1DM pathogenesis [78]. Nevertheless, their production need adequate substrates such as dietary fibers, prebiotics, and probiotics. It is revealed that probiotics can boost the production of the SCFAs [60]. For instance, in fit adults, probiotic intake accelerates the production of SCFAs, fecal moisture, frequency of defecation, and quantity of stools. By acting so, probiotics influence the immune system [36]. Also, researches revealed that, in the mature gut, permeability is wrought by GM from the dilapidation and fermentation of carbohydrates into SCFAs. Butyrate is known for its capability to ameliorate the intestinal barrier by normalizing the assemblage of tight junctions [54]. Besides, other functions of SCFAs, their ability to restore and facilitate the functions of the intestinal mucosa barrier is prominent [79]. SCFAs promote intestinal epithelial cells' production by intestinal mucosin and mucus excretion, inhibit the pro-inflammatory factors production, and increase anti-inflammatory cytokines' production IL-10, then trigger Treg cell function [79]. SCFAs can also provide power to enterocytes and diminish the making of toxic substances and inflammation through the inhibition of the development of dangerous bacteria [79]. As described, probiotics are needed for the production of SCFAs, which play an important role in the delay of T1DM.

Through the control of inflammatory cytokines’ production

The beneficial role of probiotics in intestinal mucosa ranges from the control of the secretion of proinflammatory cytokines, such as IFN-γ, TNF-α, and IL-12, generally through the induction of the maturation and activity of regulatory T cells in the intestinal mucosa [32, 67]. Interestingly, the intake of probiotic strains has been revealed to decline the concentration of cytokines such as IL-6, IL-1β, and TNF-α whereas rising that of anti-inflammatory cytokines, such as transforming growth factor-β (TGF-β) and IL-10, which, as a reminder, are heavily involved in T1DM pathogenesis [49]. A randomized control trial carried out to investigate the effect of Lactobacillus casei 01 on inflammatory biomarkers found a significant decrease of proinflammatory cytokine level was in the probiotic fed group [80]. Also, untimely intake of VSL#3 was found to prevent in NOD mice diabetes. In that study, a low case of insulitis and a low rate of β-cell damage were observed among mice under test group. These positive effects were linked to an augmented making of IL-10 from Peyer’s patches and the spleen and increased IL-10 appearance in the pancreas, where IL-10-positive islet-infiltrating mononuclear cells were observed [81]. Similarly, another study revealed that the use of VSL#3 stops the expression of IL-1β, whereas it improves the production of protolerogenic constituents of the inflammasome, mainly IL-33 and indoleamine 2, 3-dioxygenase (IDO) [75]. Also, the use of several probiotics in a randomized clinical trial disclosed an improvement of inflammation biomarkers in subjects with diabetes [82]. Lactobacillus reuteri 6475 secretory components have been revealed with an anti-TNF-α effect [83]. Bacillus coagulans were also found to reduce serum amyloid level and diminish the proinflammatory cytokines TNF-α in the rat model [84]. Additionally, the intake of B. breve CNCM I-4035 was followed by an important augmentation in fecal IgA content and an augmentation of the plasmatic concentrations of IL-4 and IL-10, while the concentrations of IL-12 declined. L. rhamnosus and L. casei use also displayed the same outcomes [36]. IL-10 is an anti-inflammatory cytokine with numerous pleiotropic properties in immunoregulation and inflammation. Also, IL-10 is known for its ability to impede the activation, and the effector function of several immune cells such as T-cells and macrophages are highly implicated in the pathogenesis of T1DM [81, 85]. Similarly to the previously mentioned examples, many other probiotics strains such as lactobacillus plantarum 06CC2, Lactobacillus paracasei KW3110 have been revealed to have the ability to improve the activity of the cytokines such as interleukin-12 (IL-12), interferon-gamma (interferon-ɣ), thereby protecting against viral infections as one of the environmental factors contributing to the progression of T1DM [86]. The regulation of proinflammatory signaling pathways by suppressing TLR signaling is another mechanism of action for some probiotics. Toll-like receptors (TLRs) are a set of proteins that is not only important in the innate immune system but are also implicated in inflammatory processes [87, 88]. Therefore, suppressing the TLR signaling is a way to prevent inflammation, which is also involved in the T1DM pathogenesis.

Through the regulation of Glucagon-like peptide-1 (GLP-1) production

Derived from proglucagon, GLP-1 is a peptide of 36 or 37 amino acids. Its role is to improve the release of glucose-dependent insulin, suppress the secretion of Glucagon, decrease glycemia in T1DM patients and diminish food intake [89]. GLP-1 is majorly produced by the endocrine L-cells of the colon and distal small intestines [90]. It is known as a potential incretin hormone, able to regulate under some conditions, insulin production. Furthermore, it is known to have an impact on β-cells in normal physiological circumstances [91]. More precisely, GLP-1 is known to be able to normalize the β-cells growth. Interestingly, the probiotic strain lactobacillus kefiranofaciens M and lactobacillus kefiri K can impede the onset of T1DM by raising the GLP-1 synthesis [92]. Therefore, from the previously described role of GLP-1 in the context of T1DM, boosting its production may be one of the ways of preventing T1DM (Fig. 1).

Fig. 1.

Probiotics mechanism of actions in the management of T1DM. Probiotics help improve the health conditions of T1DM patients by sustaining the integrity and permeability of the gut microbiota resulting in an improvement of the immune response. Probiotics are also able to boost the production of SCFAs. Furthermore, they are able to inhibit the release of inflammatory cytokines

Probiotics as possible remedy to T1DM: Evidence from Experimental Studies

Animal studies

Mice models

For the effect of Akkermansia muciniphila a probiotic strain on T1DM in mice model, has capacities to induce not only the remodeling of the GM but also the regulation of islet autoimmunity in NOD (Non-Diabetic Obese) mice [93]. Furthermore, probiotic strains that belong to the probiotic families namely Bifidobacteriaceae and Lactobacillaceae and genus Streptococcus thermophilus had been revealed with the ability to improve T1DM conditions in NOD mice through an interesting organization of the gut microbiota formula. It also impacted the intestinal inflammation by keeping the gut immune homeostasis and hindering the IL-1β appearance [75]. Jing Zhang and his team demonstrated from their laboratory that in mice, Lactobacillus reuteri has the propriety of preventing T1DM-induced bone loss and marrow adiposity [83]. In a T1DM C57BL/6 mice model study, Amro Abdelazez and his team have demonstrated that the probiotic strains Lactobacillus brevis KLDS 1.0727 and KLDS 1.0373, have the capabilities to decrease glycemia [94]. Furthermore, the oral intake of L. kefiranofaciens M and L. kefiri K, which are probiotic strains, had been found efficacious in the induction of IL-10 synthesis in the pancreas. This was an animal study on STZ-induced C57BL/6 mice [92]. As a reminder, the synthesis of IL-10 is important to restrain the quantity of T-helper (Th) cell 1-associated cytokines (IL-1β, IL-6, and IL-2) and pro-inflammatory cytokines (TNF-α) available in the pancreas [92]. The probiotic strain Saccharomyces boulardii THT 500,101 used to treat STZ-diabetic mice had been revealed efficacious since the authors found that this strain can modify the gut microbiota, improve hyperglycemia, and dyslipidemia [95]. Probiotic strains of Bifidobacterium species (spp.) also were disclosed to be negatively linked to β-cell autoimmunity in a study on STZ-induced diabetic mice. It was found that the intake of Bifidobacterium spp induced a decrease in the expression of some interleukin and immune markers involved in autoimmunity [96]. The probiotic strain Leuconostoc mesenteroides EH-1 had also been revealed with potentialities to decrease blood glucose and IL-6 concentration and raise insulin level in Streptozotocin (STZ)-induced T1DM mice [78]. Clostridium butyricum CGMCC0313.1 daily administration to female NOD mice in a study was found with positive effects on T1DM such as mitigation of insulitis, delay of T1DM onset, and improvement of metabolic dysfunctions [97].

Rat models

Using rat model, a team of researchers investigated the influence of the intake of γ-aminobutyric acid (GABA)-producing Lactobacillus brevis DPC 6108 and pure GABA on the onset of diabetes in streptozotocin (STZ)-induced diabetic Sprague Dawley rats. The authors revealed that there had been an attenuation of the hyperglycemia caused by diabetes [98]. L. rhamnous MTCC5957, L. rhamnous MTCC5897, and L. fermentum MTCC5898 used to prepare the probiotic fermented milk (PFM) has been shown in STZ-induced diabetic rats experiment to be efficacious in the management of T1DM and its complications [99]. Also, another study in NOD mice reported that enteral intake of Lactobacillus lactis-expressing HSP65-6IA2P2 has the potentialities to postpone the occurrence of T1DM in NOD mice [100]. Administration of a combination of several probiotics to NOD mice for 36 weeks was found effective in reducing T1DM incidence and insulitis. There had been an increase in βcell mass and reduction in gut permeability [101]. Probiotic combination with other products such as soy milk and omega-3 had beneficial effects on T1DM complications in diabetic rats [102].

Human studies assessing the effects of probiotics on T1DM

Positive revelations were also made in human trials conducted to investigate the effects of probiotics intake on T1DM and its complications. A prospective cohort study conducted in ‘’the TEDDY study’’, with the purpose to investigate the consequences of the premature probiotic intake on islet autoimmunity among kids characterized as having high genetic risk for T1DM. The study outcomes disclosed that the early dietary intake (mainly within the 27 days after birth) of probiotics, fundamentally Lactobacillus and Bifidobacterium, may reduce the threat of islet autoimmunity in kids [103]. In a double-blinded randomized control trial carried out among 42 healthy subjects with an unknown risk factor for T1DM to assess their responses to the intake of L. johnsonii N6.2. From thier findings, the intake of L. johnsonii N6.2 considerably reduced the abdominal pain, indigestion, and cephalic syndromes. According to the authors, the data have supported the safety and possibility of L. johnsonii N6.2 use in prevention trials among individuals at risk for T1DM [104]. In a recent study carried out among children and young adults with T1DM to evaluate the effect of 3 months intake of Lactobacillus Rhamnosus GG on immune system functions, findings showed that the probiotic conferred important anti-inflammatory effects [2]. Furthermore, the use of probiotic had been revealed to be linked to a considerable better blood sugar control and diminution of odds of metabolic syndrome and its components in a cross-sectional assessment of the relationship between the use of probiotics-containing products and different health markers in a huge number of T1DM subjects [105]. Also, the use of the probiotic Lactobacillus rhamnosus GG has revealed efficacious in the metabolism of systemic tryptophan (whose catabolism occurs through the GM) and the restraining of proinflammatory cytokines in childhood T1DM [106]. Furthermore, the probiotic strain Lactobacillus brevis CD2 had been proven to alleviate risk factors related to caries and gingival health in T1DM children in a randomized clinical trial [40]. These mentioned defections or periodontal diseases are some of the consequences of T1DM in children [25]. Some studies have found interesting outcomes from the combination of probiotics with other products. For example, the combination of gliclazide to some hypoglycemic agents, namely probiotics and bile acids, had resulted in more pronounced effects than when used alone. Even though the molecular mechanisms of interactions are not fully understood, it had been disclosed that there is a good synergy of impact resulting in a diminution of the blood sugar and enhancement of diabetes-related complications [41]. Even more, some studies carried out assessing the impacts of probiotics on other autoimmune disorders are reassuring [107–109]. As listed, the revelations from these studies support that the probiotics intake (used alone or in a combination), whether at a very young age or in adulthood, looks promising in reducing T1DM risk or in the management of its complications. However, all the probiotic strains used in the different studies did not provide such promising results. A randomized double-blind placebo-controlled clinical trial was carried out to study the prevention of allergy. There was no impact of probiotic use on the T1DM onset among children aged 13 or on islet cell autoimmunity among children aged 5 [110].

Summary of major animal and human studies on probiotic interventions and their findings related to T1DM are listed in Table 1.

Table 1.

Summary of major animal and human studies on the use of probiotics in the management of T1DM as described in Sects. 3.1 and 3.2

Probiotic strain	Model/Subjects/study type	Major findings or outcomes	References
Animal studies assessing the effects of probiotics on T1DM
-Akkermansia muciniphila	NOD (Non-Diabetic Obese) mice	Induction of gut microbiota remodeling Control of islet autoimmunity	[93]
Lactobacillus brevis KLDS 1.0727 and KLDS 1.0373	C57BL/6 mice	Considerable reduction of glycemia level Considerable reduction of blood plasma Histological assays of mice organs	[94]
Probiotic strains belonging to families Bifidobacteriaceae, Lactobacillaceae, and genus Streptococcus thermophilus	NOD mice	Improve the T1DM via positive modulation of GM composition Decrease the intestinal inflammation through the maintenance of gut immune homeostasis and inhibition of IL-1β expression	[75]
Lactobacillus brevis DPC 6108	Streptozotocin (STZ)-induced diabetic Sprague Dawley rats;	Attenuation of the hyperglycemia caused by the diabetes	[98]
Lactobacillus reuteri	Mice model	Stops T1DM-induced bone loss and marrow adiposity Prevention of TNF-α-mediated suppression of Wnt10b and osteoblast maturation markers	[83]
probiotic-fermented milk containing L. rhamnous MTCC5957, L. rhamnous MTCC5897, and L. fermentum MTCC5898	STZ-induced diabetic rats	A decrease in TNF-α and IL -6 concentrations Significant improvement of glucose metabolism, serum inflammation status, oxidative stress, serum lipid profile Significant reduction of mRNA expression of pick and g6pase genes coding the key enzymes of gluconeogenesis way	[99]
Lactobacillus lactis-expressing HSP65-6IA2P2	NOD mice	Prevent hyperglycemia Ameliorate glucose tolerance Decrease insulitis Increase regulatory immune reactions Balance in Tcells levels	[100]
L. kefiranofaciens M and L. kefiri K	STZ-induced C57BL/6 mice	Stimulate the production of IL-10 in the pancreas	[92]
Saccharomyces boulardii Tht 500,101	STZ -diabetic mice	Changes in the GM composition Amelioration of hyperglycemia, dyslipidemia Modulation of inflammatory profiles	[95]
strains belonging to Bifidobacterium spp.	STZ-induced diabetic mice	Negatively associated with β-cell autoimmunity	[96]
Leuconostoc mesenteroides EH-1	Streptozotocin (STZ)-induced T1DM mice	Decrease of blood glucose and IL-6 concentration Augmentation of insulin level	[78]
Clostridium butyricum CGMCC0313.1	female NOD mice	Mitigation of insulitis Delay of T1DM onset Improvement of metabolic dysfunctions	[97]
Lactobacillus acidophilus, Lactobaciluscasei, Lactobacillus reuteri, Bifidobacterium bifidium, and Streptococcus thermophiles	NOD mice	Reduction of T1DM incidence and insulitis Increase in βcell mass Reduction in gut permeability	[101]
Lactobacillus casei + soy milk + omega-3	T1DM rats	Improvement of stereological changes in the tibia and vertebra Raise of antioxidant activity Amelioration of the redox homeostasis	[102]
Human studies assessing the effects of probiotics on T1DM
Lactobacillus and Bifidobacterium,	TEDDY prospective cohort study with 8676 children genetically at increased risk for T1DM for 10 years	Reduction in the risk of islet autoimmunity	[103]
Lactobacillus johnsonii N6.2	A double blinded randomized trial among 42 healthy individuals Participants receiving 1 capsule/day containing 108 colony-forming units(CFU) for 8 weeks	Regulation of the penetration of monocytes, natural killer cells, circulating Teff, TH1 cells, and cytotoxic CD8 + T cells in the islets Reduction of the occurrence of abdominal pain, indigestion, and cephalic syndromes	[104]
Lactobacillus rhamnosus GG	A prospective randomized and single-blind study among 87 pediatric patients with T1DM for 3-month	Induction of anti-inflammatory activity	[2]
probiotics-containing products	1039 T1DM adult patients (mean age 46 ± 14 years, 45% men) for at least 8 weeks	Maintaining better glycemic control ameliorate conditions of metabolic syndromes, such as high blood pressure, high TG levels, and HDL-C	[105]
Lactobacillus rhamnosus GG	61 young (aged 3–18 years) T1DM patients for 3-month	Regulation of systemic tryptophan metabolism which occurs through the GM Restraining of proinflammatory profile	[106]
lactobacillus brevis CD2	Randomized clinical trial in 68 T1DM children for 60 days)	Amelioration of the risk factors related to caries and gingival health in	[40]
probiotic treatment in infancy	A cohort of 123 children with high risk of allergy in 13 year follow-up	No effect on the development of T1DM by the age of 13 years nor islet cell autoimmunity by the age of 5 years	[110]

Conclusion

T1DM is an autoimmune disease due to a selective destruction of β-cells by Tcells, which highly prevalent worldwide especially among children and young adults. Evidence from animal and human studies carried out to assess the effects of probiotics on T1DM have proven that probiotics reflect their definition. Evidence from the experimental studies explored in this review is proof that probiotics can impact the autoimmunity or autoimmune and anti-inflammatory diseases such as T1DM. Even though all the study results are not positively correlated, it is worthy to state that probiotics can be an alternative, adjuvant or preventive therapy in the management of T1DM and its complications. The mechanisms of probiotics on T1DM include the normalization of GM composition, which is linked to the immune system since T1DM is an autoimmune disease. Also, probiotics act on T1DM through the regulation of inflammation-related cytokines, the production of SCFAs, and the regulation of GLP-1. Hence, the effects of probiotics on T1DM must not be undervalued; rather, they may be a new approach to fight autoimmune, metabolic diseases, and inflammations such as T1DM. This review recommends more human studies on T1DM and human studies should not only be focused on RCTs but also on cohort and case controls studies to assess whether the regular intake of probiotics can be linked to the delay or prevention of T1DM.

Abbreviations

APCs

Antigen-presenting cells

β

Beta

DCs

Dendritic cells

GALT

Gut-associated lymphatic tissues

GM

Gut microbiota

T1DM

Type 1 diabetes

GLP-1

Glucagon-like peptide-1

HLA

Human Leukocyte Antigen

IDO

Indoleamine 2,3-dioxygenase

IFN

Interferon

TNF

Tumor necrosis factor

IL-10

Interleukin 10

L

Lactobacillus

LjN6.2

Lactobacillus johsonii Strain N6.2

Lr

Lactobacillus reuteri Strain

MHC

Major Histocompatibility Complex

TLRs

Toll-like receptors

STZ

Streptozotocin

SCFAs

Short-chain fatty acids

TEDDY

The Environmental Determinants of Diabetes in the Young

Author Contributions

KSD and OB have conceived and drafted the manuscript, KSD wrote the manuscript, and IC and OB have critically reviewed it. All the authors have approved the final version submitted for publication.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data Availability

Data sharing not applicable to this article as no data sets were generated or analyzed during the current study.

Declarations

Ethics approval and consent to participate

N/A

Conflict of interests

The authors declare that they have no conflict interests.