Evidences from animal models and humans have implied the involvement of alterations in the gut microbiota in development of some autoimmune diseases. Dysbiosis observed in autoimmune diseases is associated with decreased bacteria function and diversity, impaired epithelial barrier function, inflammation, and decreased regulatory T cells in the gut mucosa. Studies suggest that probiotics influence systemic immune responses, ensure the homeostasis of the healthy microbiota in the intestinal mucosa, and could, therefore, be used as adjuvant therapy to treat immune-mediated diseases. The mechanisms proposed to achieve this include mucus secretion; antimicrobial peptide production; the maintenance of the function of the gastrointestinal-epithelial barrier, ensuring adequate interactions between the gut microbiota and the mucosal immune cells; and, finally, helping the activation of host immune system in response to pathobionts. Here, we described several reports concerning probiotic applications in several animal models of autoimmune diseases and data of the main clinical trials concerning the applicability of probiotics in type 1 diabetes, multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus.
- barrier disruption
Thousands of years ago, Hippocrates, father of medicine, coined the concept that food would serve as medicine and postulated, “Let food be thy medicine, and let medicine be thy food.” Nowadays, the concept of food as a medicine appeared as functional foods, referring to any foods or ingredients with nutritional value and that promote a health benefit to the host . Probiotics, prebiotics, and synbiotics are the most popular ingredients used as functional foods and dietary supplements .
According to the World Health Organization (2002) and the International Scientific Association for Probiotics and Prebiotics (2013), probiotics is defined as “a live organism, which provides a benefit to the host when provided in adequate quantities” [2, 3, 4]. Most commonly used probiotic includes lactic acid-producing bacteria, such as
2. Intestinal dysbiosis in autoimmune diseases
Evidence from animal models has implied the involvement of intestinal dysbiosis in development of some autoimmune diseases [24, 25, 26]. Dysbiosis observed in autoimmune diseases is associated with decreased bacteria function and diversity, impaired epithelial barrier function, inflammation, and decreased regulatory T cells (Treg cells) in the gut mucosa [7, 8]. The hypotheses proposed to link dysbiosis with autoimmune diseases include molecular mimicry, bystander T cell activation, and the amplification of autoimmunity by pro-inflammatory cytokines, which is elicited by dysbiotic gut microbiota . In 2016, Lerner and colleagues, from Institute Wendelsheim, in Germany, proposed the posttranslational modification of luminal proteins, promoted by enzymes from altered microbiota, which modify substrates in a different way than performed under homeostatic conditions. The defective posttranslational modification of luminal proteins could generate neo-epitopes that may become immunogenic and induce systemic autoimmunity and trigger autoimmune diseases .
Here, we described several reports concerning probiotic applications in several animal models of autoimmune diseases and data of the main clinical trials concerning the applicability of probiotics in type 1 diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis (RA), and systemic lupus erythematosus.
3. Probiotics in autoimmune diseases
Studies suggest that probiotics influence systemic immune responses, ensure the homeostasis of the healthy microbiota in the intestinal mucosa, and could, therefore, be used as adjuvant therapy to treat immune-mediated diseases . The mechanisms proposed to achieve this include mucus secretion, antimicrobial peptide production, the maintenance of the function of the gastrointestinal-epithelial barrier, decreasing oxidative stress, ensuring adequate interactions between the gut microbiota and the mucosal immune cells, and, finally, helping the activation of host immune system in response to pathobionts .
3.1. Type 1 diabetes
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by autoimmune reactions against the insulin-secreting pancreatic β-cells, resulting in exogenous insulin dependence to control blood glucose levels . The etiopathogenesis may involve the interaction of predisposing human leucocyte antigens (HLA) alleles and environmental factors, such as viral infections, vitamin deficiencies, and disruption of the gut microbiota . According to the International Diabetes Federation, more than 96,000 children and adolescents under 15 years will be diagnosed with T1D annually worldwide, and this number is estimated to be more than 132,600 when the age range extends to 20 years .
The role of the gut microbiota in T1D etiology has been the subject of research over the last decade to clarify its role in disease development and determine preventive approaches, such as diet manipulation and probiotic administration . Several researches have been carried out to verify whether the administration of probiotics may improve the prognosis of diabetes through modulation of gut microbiota. Probiotics have been identified as effective adjuvants in insulin resistance therapies [14, 15, 16]. This health claims apparently stem from the ability of probiotics to secrete antimicrobial substances, competing with other pathogens, strengthening the intestinal barrier, and modulating the immune system .
3.1.1. Probiotics in animal models of autoimmune diabetes
The intestinal microbiota might modulate the autoimmune T1D pathogenesis via two mechanisms, recently proposed by Knip and Honkanen , from the University of Helsinki, in Finland. In the first phase, an impaired tolerance process in infancy leads to a susceptibility to develop autoimmune diseases, such as T1D, and may result in appearance of autoreactive T cells and autoantibodies. At the second phase, the intestinal dysbiosis predisposes children with genetic susceptibility and positive autoantibodies to develop clinical disease .
The inflammasome signaling components are innate immune sensors that are highly influenced by the gut environment and play pivotal roles in maintaining intestinal immune homeostasis . Previous studies suggested the involvement of the gastrointestinal tract in the pathogenesis of islet autoimmunity. Thus, the modulation of gut-associated lymphoid tissue may represent a means to affect the natural history of the disease. Oral administration of probiotics can modulate local and systemic immune responses .
The earliest study to evaluate the efficacy of probiotics in T1D was published in 2005. The study performed by Calcinaro and colleagues, in the University of Perugia, in Italy, investigated the effects of oral administration of the probiotic VSL#3 in nonobese diabetic (NOD) mice development. VSL#3 was administered to female NOD mice three times a week starting from 4 weeks of age. Early oral administration of VSL#3 prevented diabetes development in NOD mice. Protected mice showed reduced insulitis and a reduced β-cell destruction. Prevention was associated with an increased production of interleukin (IL)-10 from Peyer’s patches and the spleen and with increased IL-10 expression in the pancreas, where IL-10-positive islet-infiltrating mononuclear cells were detected. The protective effect of VSL#3 was transferable to irradiated mice receiving diabetogenic cells and splenocytes from VSL#3-treated mice. Oral VSL#3 administration prevents autoimmune diabetes and induces immunomodulation by a reduction in insulitis. These data provide a sound rationale for future clinical trials of the primary prevention of T1D by oral VSL#3 administration .
Eleven years later, Kim and colleagues evaluated the effects of
Another work, performed in Yale University, by Peng and colleagues, in 2014, demonstrated that the protection from T1D development observed in MyD88-deficient NOD mice (MyD88−/−NOD) could be transferred to wild-type NOD mice [23, 24]. The gut bacteria isolated from MyD88−/−NOD mice, administered over a 3-week period, altered the family composition of the gut microbiome, mainly increasing the
In 2015, Le and colleagues, from the National Institute for Food Control, by using C57BL/6 J mice with streptozotocin-induced diabetes, evaluated whether
A study performed in Diabetes Research Institute, in Milan, Italy, by Dolpady and colleagues, in 2016, reported that the oral administration of a
Accumulating evidence supports that the intestinal microbiome is involved in T1D pathogenesis through the gut-pancreas axis. A recent study, performed in the University of British Columbia, in Canada, Brown and colleagues , aimed to determine whether the gut microbiota in the NOD mice played a role in T1D through the gut mucosa. To examine the effect of the intestinal microbiota on T1D onset, scientists manipulated gut microbes by fecal transplantation between NOD and resistant NOD mice (NOR) and by oral antibiotic and probiotic treatment of NOD mice. The intestinal microbiota from NOD mice harbored more pathobionts and fewer beneficial microbes in comparison with NOR mice. Fecal transplantation of NOD microbes induced insulitis in NOR hosts, suggesting that the NOD microbiome is diabetogenic. Moreover, antibiotic exposure accelerated diabetes onset in NOD mice accompanied by increased Th1 and Th17 cells in the mucosal-associated lymphoid tissues. The diabetogenic microbiome was characterized by a metagenome altered in several metabolic gene clusters. Furthermore, diabetes susceptibility correlated with reduced fecal short chain fatty acids. In an attempt to correct the diabetogenic microbiome, researchers administered VLS#3 probiotic to NOD mice and found that VSL#3 colonized the intestine poorly and did not delay diabetes onset. Authors concluded that NOD mice harbor gut microbes that induce diabetes and that their diabetogenic microbiome can be amplified early in life through antibiotic exposure. Protective microbes like VSL#3 are insufficient to overcome the effects of a diabetogenic microbiome .
Another recent work, performed in Jiangnan University, in China, Jia and colleagues , investigated whether administration of probiotic
3.1.2. Probiotic applications in T1D patients
Probiotic supplementation has been hypothesized to affect innate and adaptive immune responses to environmental antigens by supporting healthy gut microbiota and could therefore be used to prevent the onset of T1D-associated islet autoimmunity and treat the stablished disease .
In humans, a TEDDY study group, published in JAMA Pediatrics in 2016, evaluated the association between probiotic supplementation and islet autoimmunity in children with genetic risk for T1D, during their first year of life. This multicenter prospective cohort study (United States, Finland, Germany, and Sweden) investigated 7473 children ranging from 4 to 10 years old. Early probiotic administration (0–27 days of life) was correlated with a decreased risk of islet autoimmunity when compared with the group that received probiotics after 27 days of life or no supplementation. This study concludes that early probiotic supplementation could decrease the risk of islet autoimmune reactions in children with high-genetic-risk alleles for T1D .
A current clinical trial, performed by Medical University of Warsaw, in Poland, involves the evaluation of the effect of
3.2. Multiple sclerosis
Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune disease that affects the central nervous system (CNS) and is characterized by immune reactions against myelin proteins and gangliosides. Susceptible HLA alleles and environmental factors, such as virus infection, a hypercaloric diet, vitamin D deficiency, and intestinal dysbiosis, have been implicated in triggering MS . MS promotes disability in young adults and affects twice more women than men. According to the Multiple Sclerosis International Federation and World Health Organization, the prevalence of MS increased from 2.1 million in 2008 to 2.3 million in 2013 .
Studies have shown that gut microbiota can affect the development of MS, and these works implicated intestinal dysbiosis as one of the possible causes of extraintestinal disease development . The colonization of germ-free mice with segmented filamentous bacteria promotes an increase in the number of Th17 cells in the lamina propria and CNS, worsening disease severity in experimental autoimmune encephalomyelitis (EAE), a MS animal model . Likewise, the colonization of the same mice with
3.2.1. Probiotics in experimental autoimmune encephalomyelitis
Several studies in experimental autoimmune encephalomyelitis (EAE) mice reported the immunomodulatory functions of probiotic administration. Treatment with
In previous studies, performed in National Institute for Public Health and the Environment, in the Netherlands, in 2008, Ezendam and colleagues evaluated the effect of the probiotic
Two years later, Lavasani and colleagues, from Lund University, in Sweden, evaluated the effect of five daily-administered
In 2010, Kobayashi and colleagues, from Yakult Central Institute for Microbiological Research, in Japan, evaluated the safety of two probiotic bacterial strains,
Two years later, Kobayashi and colleagues investigated the safety use of
In 2013, Kwon and colleagues, from School of Life Sciences and Immune Synapse Research Center, in Republic of Korea, evaluated the prophylactic and therapeutic actions of a mixture of five probiotics (IRT5) in EAE mice. IRT5 includes
Three years later, Abdurasulova and coworkers, from Institute of Experimental Medicine, in St. Petersburg, Russian Federation, evaluated the effect of probiotic
The Goudarzvand group , from School of Medicine, in Karaj, Iran, investigated the effect of
A recent study, performed by Secher and colleagues , from the University of Toulouse, in France, evaluated the effects of the probiotic
Another recent study, performed in Immunology Research Center, in Mashhad, Iran, Salehipour and colleagues , evaluated the therapeutic effect of probiotic strains,
3.2.2. Probiotic applications in MS patients
Probiotic applications based on the hygiene hypothesis, such as administration of the eggs from nonpathogenic helminth
Two years later, Rosche and colleagues, from the Department of Neurology and Experimental Neurology, in Berlin, Germany, evaluated the administration of 2500
In a recent study, Kouchaki and colleagues , from School of Medicine from Kashan, in Islamic Republic of Iran, reported improved Expanded Disability Status Score (EDSS), insulin resistance, and a decrease in inflammatory markers in MS patients treated with probiotic supplementation containing
Another recent randomized, double-blind, placebo-controlled clinical trial, performed in Islamic Republic of Iran, by Tamtaji and colleagues , evaluated the role of probiotic administration on gene expression associated to inflammatory, glucose, and lipid signaling pathways in MS patients. The study included 40 patients with MS. Participants were randomly assigned into two groups to receive either a probiotic capsule containing
3.3. Rheumatoid arthritis
Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by chronic inflammation of multiple joints, bone erosion, and cartilage destruction. Moreover, RA can affect internal organs such as the lungs, heart, and kidneys. Anti-cyclic citrullinated peptide and rheumatoid factor are the most important autoantibodies in RA and can be found before disease onset . The disease is three times more common in women, and according to the World Health Organization, the worldwide prevalence, which is between 0.3 and 1%, ranks the disease among the most common autoimmune disorders. The triggering of RA involves the interaction of HLA genes and environmental factors, such as smoking and infections . Among environmental factors, dysbiosis has been identified as a possible trigger factor for autoimmunity and RA development .
3.3.1. Probiotics in animal models of RA
Experiments in animal models suggest that gut microbiota influences local and systemic immunity and might trigger joint inflammation . Studies in collagen-induced arthritic (CIA) mice showed that the administration of antibiotics exacerbates the disease and increases the level of IL-6, IFN-γ, and IL-17 pro-inflammatory cytokines. Further study showed differences in the gut microbiota composition between CIA-susceptible and CIA-resistant mice, with a prevalence of
The study performed by Abhari and colleagues , in Shiraz University, in Iran, investigated the possible role of probiotic
Another work, performed in the Department of Probiotics Immunology, Sapporo University, in Japan, Yamashita and colleagues , evaluated the effect of the oral administration of
Intestinal dysbiosis has been previously identified in patients with RA, and the administration of certain probiotics showed an improvement in RA. Study from Gohil and colleagues , from the Institute of Pharmaceutical Education and Research, in Gujarat, India, was designed to find out the antiarthritic activity of cell wall content of
3.3.2. Probiotic applications in RA patients
Some performed studies evaluating the effect of probiotics as an adjuvant therapy for RA treatment have shown no significant results, and some of these conducted studies have smaller number of patients and a short period of evaluation [63, 64].
The earliest study to evaluate the efficacy of probiotics in RA was performed in Rheumatism Foundation Hospital, in Finland, and was published in 2003. In a pilot study, Hatakka and colleagues evaluated 25 non-treated RA patients that were randomized to receive either two capsules of a
A double-blind, placebo-controlled clinical trial, performed in the University of Western Ontario, Canada, by Pineda and colleagues , evaluated the effect of the oral administration of
Another randomized, double-blind placebo-controlled trial, performed in Tabriz University of Medical Sciences, in Iran, by Vaghef-Mehrabany and colleagues , investigated the role of
Another clinical trial, with the same study design, performed by Zamani and colleagues , in Kashan University of Medical Sciences, Iran, evaluated the effect of probiotic administration on clinical and metabolic parameters in RA patients. Sixty patients aged 25–70 years were enrolled into two groups to receive either probiotic or placebo. Probiotic group received a daily capsule containing three strains:
3.4. Systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is an autoimmune and heterogeneous disease characterized by damage to the skin, kidneys, lungs, joints, heart, and brain . The disease affects mainly females, and its worldwide prevalence varies from 30 to 60 per 100,000 in the United Kingdom and the United States . SLE pathogenesis may involve genetic and environmental factors, such as viral infections, defective apoptosis, elevated oxidative stress, and solar exposure to ultraviolet-B waves. Regarding immune response, it is known that autoantibodies bind mainly with nuclear and cytoplasmic antigens . Moreover, increased evidence has emerged in a recent year that suggests the role of intestinal dysbiosis in SLE development .
3.4.1. Probiotics in animal models of SLE
In female lupus-prone mice, Zhang and colleagues  reported a decrease in the relative abundance of
In a lupus-like animal model, the administration of retinoic acid restored
In a recent study, performed by Tzang and colleagues , in Chung Shan Medical University, in Taiwan, scientists investigated the effects of oral administration of
Although some studies in SLE animal models showed promising results using probiotic supplementation, currently, there are no clinical trials reported at clinicaltrials.gov investigating the role of probiotics as an adjuvant therapy in the treatment of SLE patients.
Evidences associate intestinal dysbiosis with autoimmune disease pathogenesis. Impaired gut microbiota function and diversity could represent a trigger site of autoimmunity by neo-antigen generation under dysbiotic conditions. Emerging findings point to the use of probiotics as a preventive functional food and as adjuvant treatment of autoimmune diseases. However, further clinical trials, with large cohorts, to evaluate the security and efficacy of the probiotic administration in patients with autoimmune diseases are needed.
Thanks for the School of Health Sciences Dr. Paulo Prata, Barretos, Sao Paulo, Brazil.
Conflict of interest
The author reports no conflict of interest.
Appendices and nomenclature
|Treg||T regulatory cells|
|T1D||Type 1 diabetes|
|NOD mice||Nonobese diabetic mice|
|TNF-α||Tumor necrosis factor-alpha|
|TGF-β||Transforming growth factor-beta|
|MCP-1||Macrophage chemoattractant protein-1|
|NOR mice||Resistant NOD mice|
|TEDDY||The Environmental Determinants of Diabetes in the Young|
|CNS||Central nervous system|
|EAE||Experimental autoimmune encephalomyelitis|
|MOG||Myelin oligodendrocyte glycoprotein|
|TSO||Trichuris suis ova|
|MRI||Magnetic resonance imaging|
|EDSS||Expanded Disability Status Score|
|CIA mice||Collagen-induced arthritic mice|
|CII||Type II collagen-specific antibodies|
|NZB||New Zealand black mice|