Probiotics and Disease: A Comprehensive Summary—Part 7, Immune Disorders

Abstract

This article series provides a literature review of the disease-specific probiotic strains associated with immune and autoimmune conditions that have been studied in published clinical trials in humans and animals. This is not an exhaustive review. The table design allows for quick access to supportive data and will be helpful as a guide for both researchers and clinicians. The goal of the probiotics and disease series is to provide clinically useful tools. The first article (part 1) focused on mental health and neurological conditions, and the second article (part 2) explored cultured and fermented foods that are commonly available in the United States. The third article (part 3) explored the relationship between bacterial strains and 2 of the most prevalent diseases we have in modern society: cardiometabolic disease and fatigue syndromes. The fourth article (part 4) elucidated the role of the microbiome in infectious diseases, and the fifth article (part 5) examined respiratory conditions of the ears, nose, and throat. The sixth article (part 6) explored the relationship between beneficial microbiota and skin disorders. This seventh article (part 7) reviews the relationship between beneficial microbiota and autoimmune diseases, allergies, asthma, and other immunity-related disorders. Future articles will review the relationship between probiotics and skin disorders, the influence of the microbiome on cancer development and prognosis, and gastrointestinal and genitourinary diseases associated with dysbiosis, followed by an article focused on probiotic supplements. This literature review is specific to disease condition, probiotic classification, and individual strain.

We investigated disease-specific probiotic strains associated with autoimmune diseases such as type 1 diabetes, connective tissue disease, and myasthenia gravis. This is not an exhaustive review.

The purpose of this summary is to provide nutritionists and other medical practitioners with a reference guide for recommending health-promoting commercially produced cultured and fermented food products to patients. There is considerable research on the gut microbiome and role of probiotics; however, this research has not been clearly connected with clinical practice. The authors undertook a review of current literature to explore which specific probiotics and probiotic strains have been utilized in clinical and laboratory studies.

To make this clinically valuable, product names of probiotics and fermented foods have been included. Finished products vary between manufacturers; thus, the researchers included brand listings to provide transparency and to facilitate a functional probiotics guide for clinicians. Exclusions of products meeting our criteria do not imply that these products are not effective—we simply were not aware of them.

Methodology

This literature review originated from a group project that was part of the requirements for a course in the doctoral program in functional and clinical nutrition at Maryland University of Integrative Health (Laurel, MD, USA). The student researchers had approximately 2 months to review the literature and synthesize the paper. The authors agreed on format, templates, and execution. Each author researched and wrote sections reviewing probiotics in relation to various health conditions with literature searches conducted in PubMed, Biomed Central, EBSCO Research Premier, PLoS One, Cochrane reviews, and topic-specific open-source journals.

The review of specific probiotic products in the professional marketplace and specific probiotics products was performed using Internet searches, primarily Shop Google, in addition to topic specific databases to search for specific probiotic species including the strains listed in the research. Novel strains were cross-referenced to determine whether the strain was available only for research purposes. If a probiotic combination was used in the research, formulas that closely matched the combination were included. Formulas that contain all or most of the specific probiotics and strains were also included. The food survey focused on bacterial strains in food and includes foods that are commercially produced and commonly available in the refrigerated sections of grocery stores in the United States. Information was gleaned from commercial Web sites, communications with food company personnel, and visiting grocery stores (primarily in California).

Understanding the Role of the Microbiome and Immune Function

Although supplementation with probiotics is extremely helpful in helping to prevent or mitigate the effects of immune disorders, the influence of diet on the microbiome should not be underestimated. Carbohydrates, proteins, fats, and fiber are essential dietary components and these macronutrient balances can be directly responsible for cell damage and the resulting inflammation that may trigger autoimmunity. Specifically, both fat and fiber intakes exert a strong influencer on the microbiome. Fiber intake is declining in Westernized societies. Higher fiber intakes not only help reduce the incidence of colon cancer, but the lack of fiber and its effects on the microbiome can also be partially responsible for the rise in allergy syndromes and autoimmunity.

Dietary fiber is consumed by various bacterial species in the microbiome, which then produce short-chain fatty acids (SCFAs; acetate, propionate, and butyrate).¹ This is important for colon health, because butyrate is the primary fuel for the colonocyte. Decreased production of SCFAs is highly correlated with intestinal permeability, which, in turn, leads to the destruction of immune tolerance and intestinal inflammation associated with diseases including celiac disease, colorectal cancer, allergies, asthma, chronic kidney diseases, and type 1 diabetes.¹ On the contrary, diets high in fiber generate ample SCFAs exerting anti-inflammatory and immunomodulatory effects via T-regulatory (Treg) cell generation. Tregs are responsible for actively inhibiting the immune system from overreaction during infections while also playing an important role in the prevention of autoimmune disease via self-recognition.² According to Smigiel,² “Excessive Treg activity can lead to immunodeficiency, chronic infection and cancer, (while) too little Treg activity results in autoimmunity and immunopathology, and impairs the quality of pathogen-specific responses.” Once bacteria have positively influenced the production of Treg cells, this helps to tip the cytokine production in the favor of anti-inflammatory cytokines such as interleukin (IL) 10.^2,3

The specific bacterial species present in the microbiome are also strong influencers of the immune response. There are several species such as Lactobacillus plantarum CCFM47, Lactobacillus acidophilus CCFM137, Lactobacillus casei LC2, Lactobacillus rhamnosus GG, Bifidobacterium lactis, Lactobacillus casei DN-114001, Lactobacillus salivarius, and Lactobacillus reuteri ATCC23272,^4,5 which stimulate the immune system to produce Treg cells, which is important in regulating the T-helper 1/T-helper 2 (T_h1/T_h2) balance:

T-helper 1 (T_h1) cells produce interferon (IFN)-gamma, IL-2 and tumor necrosis factor (TNF)-beta, (and) evoke cell-mediated immunity and phagocyte-dependent inflammation. T_h2 cells, which produce IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13, evoke strong antibody responses (including those of the IgE class) and eosinophil accumulation, but inhibit several functions of phagocytic cells (phagocyte-independent inflammation).⁶

These species, in the form of probiotics, also confer increased induction of tolerogenic antigen-presenting cells, which then generate Tregs. In this way, bacterial diversity has the potential to favorably regulate inflammatory diseases such as autoimmunity and allergies. In some cases, these bacterial species produce more potent Treg cells than were found before exposure to probiotics. Specifically, L reuteri was found to help prevent allergic inflammation of the airways. The influence exerted on Tregs by bacteria also affect nuclear factor kappa beta (NF-kB). L plantarum, for example, helps to stop NF-kB from breakdown by blocking proteasome function. Conversely, Bifidobacterium infantis appears to decrease NF-kB activation while increasing the amount of FOXP4 cells in both the mucosa and spleen. FOXP4 cells are responsible for cell type-specific gene transcription, and alterations in its function can increase the risk for certain cancers. This increase helps to provide protection against pathogenic species and favorable self-immunity.⁷

This positive influence of fiber on the immune system does not stop in the gut, as diet-derived microbial metabolites move across the mucosa to the lamina propria and then into systemic circulation via the portal vein. Although butyrate is primarily found in the colon, acetate is easily detectable in the periphery and appears to regulate the immune system both in and out of the gut.¹ In this way, SCFAs may protect against the development of autoimmune diseases. Even in utero, SCFAs pass through the placenta from the mother to the child, which may protect against inflammatory asthma via epigenetic influence. This is the result of gene transcription, specifically FOXP3 target genes, which are essential for tolerance/autoimmunity. FOXP3, like FOXP4, is important for Treg development and function and the 3 isoform is considered to be the master regulatory enzyme. It does so by generating Tregs and upregulating their function within the colon. FOXP3 is also responsible for exerting epigenetic effects required for extrathymic generation of Tregs.¹

Research Overview: Immune Conditions

There is a significant difference in beneficial bacteria levels in healthy children with a genetic predisposition to type 1 diabetes as compared with those who have type 1 diabetes. Healthy children have high levels of Lactobacillus and Firmicutes, whereas unhealthy children have higher levels of Bacteroides.⁸ Early probiotic supplementation may then play a protective role against the development of type 1 diabetes.

In one study, children with the DR3/4 genotype, a genotype that increases the risk of diabetes development, were provided early supplementation with probiotics from ages 0 to 27 days of life. This appeared to decrease the risk of type 1 diabetes compared with infants given probiotics after 17 days or when no probiotics were given at all. Supplements given to study participants included mixtures of various Lactobacillus and Bifidobacterium species. The authors speculated that the ineffectiveness of probiotics when given beyond 27 days of life is likely from the influence of diet on the microbiome.⁹

As part of the PRODIA Study, Ljungberg et al¹⁰ sought to determine whether probiotics given during the first 6 months of life could decrease the onset of type 1 diabetes in children at risk genetically for the disease. The initial pilot study assessed 200 subjects at 6, 12, and 24 months of age to look at the presence of autoantibodies. In addition, the authors were considering the feasibility of the protocol and whether it might be used in a subsequent study. Although there was a high dropout rate (between 15% and 25%) due to parents not wanting to participate, the authors believed that the PRODIA protocol was feasible. Probiotics used in this trial included L rhamnosus GG (5×109 CFU), L rhamnosus LC705 (5×109 CFU), Bifidobacterium breve BBI99 (2×108 CFU), and Propionibacterium freudenreichii subsp Shermanni (2×109 CFU). During the study, one subject developed diabetes at 6 months of age and 2 subjects at 24 months of age.

Systemic lupus erythematosus (SLE) appears to be influenced by a decreased ratio of Firmicutes to Bacteroidetes. In SLE, IFN-γ (T_h1 cytokine) levels were negatively associated with Bacteroidetes and positively associated with Firmicutes and the Firmicutes:Bacteroidetes ratio. The induction of Treg cells by species including Bifidobacterium bifidum LMG13195, Ruminococcus obeum DSM25238, and Blautia coccoides DSM935 help to balance the immune system, providing protection against SLE development. On the other hand, Synergistes were correlated in SLE with serum levels of proinflammatory and T_h17-promoting cytokine IL-6, which is associated with a humoral immune response. They may also promote immunoglobulin M antibodies, which could be decreased in SLE.¹¹

Unlike healthy controls, patients with rheumatoid arthritis (RA) have significantly less bifidobacteria, bacteria from the Bacteroides-Porphyromonas-Prevotella group, Bacteroides fragilis subgroup, and Eubacterium rectale-Clostridium coccoides group. Bacteria generally found in the oral cavity, including Porphyromonas gingivalis and Prevotella intermedia, can be found in the synovial fluid of patients with RA. Antigen-specific antibodies are also found against P gingivalis, P intermedia, and Bacteroides forsythus in these patients.¹² Species including L casei, Bacillus coagulans GBI-30 and 686, L rhamnosus GR-1, L reuteri R-14, Lactobacillus GG, Lactobacillus fermentum, Lactobacillus delbrueckii, and Lactobacillus acidophilus provide protection against RA by immunomodulation allowing a shift away from the T_h1 immune response that causes RA. For example, in a 12-week study, L casei decreased signs of arthritis infiltration of lymphocytes into the joint and cartilage breakdown in a rat model. Further, decreased levels of proinflammatory cytokines and decreased T-cell proliferation were found in combination with increased levels of the anti-inflammatory IL-10.¹³

Whereas beneficial microbiota decrease risk for autoimmunity by shifting cellular immunity toward T_h1, the opposite occurs to help prevent allergic response. For example, L casei Shirota helps to improve cellular immunity by modulating the T_h1/ T_h2 balance toward T_h1 improving the allergic response.¹⁴ Other similar species, found in autoimmunity, simply influence the generation of Treg cells. This includes L rhamnosus GG, B lactis, L casei DN-114001, L salivarius, and L reuteri ATCC23272.⁷ Alternately, probiotics may positively benefit the allergic response by inhibition of immunoglobulin E (IgE) production.¹⁵ Similarly, Lactobacillus GG and L rhamnosus LC705 suppress genes encoding FCER1A and FCER1G, which encode allergy-related high-affinity IgE receptor units α and γ, respectively, and also suppress the histamine H₄ receptor. They work by decreasing proinflammatory mediators such as IL-8 and tumor necrosis factor alpha (TNF-α), while upregulating the anti-inflammatory IL-10.¹⁶ Other strains, such as L casei DN-114-001, help stabilize mast cell degranulation and subsequent release of mediators including histamine and heparin, which prevent secretion of IL-5, IL-6, IL-13, TNF-α, MCP-1, and MIP-1α. These are the 4 cytokines and 2 chemokines that induce FCER1 aggregation.¹⁷

L reuteri DSM17938 has been found to be useful for those experiencing atopic dermatitis, gastrointestinal symptoms, and intestinal permeability. In a study by Randazzo et al,¹⁸ the authors investigated this strain to explore whether it would provide protection for those with systemic nickel allergy syndrome (SNAS) in which contact with nickel causes chronic and recurrent issues with inflammatory skin disease. Nickel is found in most food items and causes urticaria, angioedema, flares, itching, meteorism, colic, and diarrhea in patients with SNAS. Typically, patients with SNAS are advised to consume a low-nickel diet, which means severely limiting vegetable intake, which can contribute to additional health problems.¹⁸ In a preliminary double-blind randomized placebo-controlled study Randazzo et al,¹⁸ the authors determined that L reuteri DSM17938 could decrease symptoms of SNAS. Further, it may help restore diversity within the microbiome, which could also help to further calm the immune system.

Although studies examining probiotics given to young children to prevent IgE allergies have failed to show validity in the general population, they may confer protection to children delivered by cesarean section.¹⁹ A double-blind, placebo-controlled study consisting of 1223 mothers pregnant with infants thought to have substantial risk for allergy were given, during their final month of pregnancy, a probiotic mixture containing a probiotic mixture containing 2 lactobacilli, bifidobacteria, and propionibacteria, or a placebo. The children born to these mothers were also given probiotics from birth through 6 months of age, as well as the prebiotic galactooligosaccharide or placebo. The children were then evaluated at the age of 5 years for allergic conditions such as eczema, food allergy, allergic rhinitis, and asthma. Although again this study showed that there was no difference in general between the active and placebo groups, it was found that there was a decreased rate of IgE-associated allergies in children who were delivered by cesarean section (24.3% vs 40.5%; OR, 0.47; 95% CI, 0.23% to 0.96%; P = .035).¹⁹ There did seem to be a significant decrease in IgE-associated allergies in all infants in the study at 2 years of age. The authors believed that this protection was provided by mediators such as IL-6 produced by toll-like receptors that could then induce IgA differentiation for naïve B cells, a common occurrence in infants with eczema after being given probiotics.¹⁹ Infants in this 2009 study were found at 6 months of age to have elevated levels of serum C-reactive protein, IL-10, and IgE at 6 months of age.

Although there is a wealth of information regarding the effect of various microbial species on the immune system and the implications for autoimmunity and allergy, one should be aware that the vast majority of these studies have been conducted on rat and mouse populations and not on humans. Human randomized controlled trials are greatly needed to help expand clinical knowledge of probiotics so that practitioners may better use probiotics effectively with patients. Further, although research has been conducted for autoimmune diseases such as SLE, RA, type 1 diabetes, and myasthenia gravis, there is a lack of information regarding other autoimmune diseases such as Hashimoto’s thyroiditis, Graves’ disease, pernicious anemia, alopecia areata, vitiligo, and others. The question of how much one should extrapolate information regarding probiotic’s effect on one autoimmune disease to another is another issue that requires addressing in the expanding knowledge base of the microbiome’s effect on the immune system.

Nutritional Supplements Overview

Professional and commercial dietary supplements containing probiotics are widely available.²⁰ In 2002, it was estimated that more than 100 companies in the United States marketed probiotic supplements and nearly 2 million adults consumed them regularly.²¹ In 2012, probiotic or prebiotic use was the third most commonly used nonvitamin, nonmineral dietary supplement, and global sales are projected to reach to $42 billion by the end of 2016.²² Using probiotics for general health versus targeting a specific health concern is more complex, because the properties of probiotic species are strain specific.²³ Unfortunately, research models lack consistency in naming therapeutic strains while, in addition, specific strains are often not listed on supplement labels. This challenge prevents the practitioner from distinguishing the researched strain from the supplemental product and is a limitation of these tables. If the researched strain was not readily available on the label or marketing material, the brand, potentially containing the strain, was not included in the table.

The Joint Food and Agriculture Organization of the United Nations/World Health Organization Expert Consultation on Evaluation of Health and Nutritional Properties of Probiotics developed guidelines for evaluating probiotics in food.²⁴ A combination of phenotypic and genotypic tests must be performed to determine the strain; however, regulations on species identification is not in place and supplement companies are not required to list this information on labels. In this multiseries review, it was identified that 30 species were specifically isolated for research purposes and were unavailable, and another 56 strains were not commercially available. Due to the wide variety of formulations on the market, lack of knowledge, and poor labeling, it is difficult for practitioners and consumers to determine which brand contains specific strains researched to address a particular health concern.

Table 2 is designed to be a resource to see what is available “at-a-glance.” The brands were chosen by searching the probiotic strain and strain species using Google, several supplement companies, Probiotics Advisor,²⁵ and the Clinical Guide to Probiotic Products.²⁶ Based on the results and to determine what was commercially available, the search was refined using Google Shopping. In some instances, the supplement company was called to determine whether the formula contains a specific species.

Table 2.

Summary of Nutritional Supplements by Health Concern

Health Concern	Professional and Commercial Products	Strains
Allergy	Advanced Acidophilus Plus (Solgar)	B lactis (BB-12)
Allergy	Advanced Acidophilus Plus (Solgar)	B lactis (BB-12)
Allergy	Advanced Multi-Billion Dophilus (Solgar)	Lactobacillus GG
Allergy	Bifido GI Balance (Life Extension)	B longum BB-536
Allergy	Bifilon (Quality of Life Herbs)	B longum BB-536
Allergy	BioDoph-7 Plus (Biotics Research)	S thermophilus, L paracasei
Allergy	Dr. Formulated Probiotics and Primal Defense (Garden of Life)	L salivarius
Allergy	Flora products (Innate Response)	L salivarius
Allergy	Gr8-Dophilus (NOW Foods)	L salivarius
Allergy	ImmuProbio (Health Aid)	L acidophilus, L bulgaricus, B bifidum, B longum
Allergy	Innate Flora 5-14 (Complete Care)	B longum
Allergy	Jarr-Dophilus EPS 25 Billion (Jarrow Formulas)	L lactis
Allergy	Jarro-Dophilus EPS and Baby’s Jarro-Dophilus+FOS Powder (Jarrow Formulas)	B longum BB536
Allergy	Lactobacillus Gasseri 3 Billon CFU (Swanson )	L gasseri
Allergy	Mega Flora (Mega Foods)	B longum
Allergy	Mutaflor (Tribute Pharmaceuticals); contains the Nissle 1917 strain	E coli
Allergy	Not available	L casei Shirota, DN-114 001 and YIT9029
Allergy	Not available	L rhamnosus GG (ATCC53103), JB-1
Allergy	Not available	L reuteri (ATCC23272)
Allergy	Not available	L casei DN-114001
Allergy	Not available	L reuteri DSM 122460
Allergy	Not available	L rhamnosus 19070-2, LC705
Allergy	Not available	L brevis HY7401
Allergy	Not available	L plantarum HY20301
Allergy	Not available	L salivarius LS01
Allergy	Not available	B fragilis
Allergy	One-A-Day TruBiotics (Bayer)	B lactis (BB-12)
Allergy	One-A-Day TruBiotics (Bayer)	B lactis (BB-12)
Allergy	Perfect Biotics (Probiotic America)	L lactis
Allergy	ProSynbiotic (Standard Process)	B lactis (BB-12)
Allergy	ProSynbiotic (Standard Process)	B lactis (BB-12)
Allergy	RAW Probiotics Women 85 Billion CFU (Garden of Life)	L lactis
Allergy	SymBiotics with FOS Description (Nutricology)	S thermophilus
Allergy	Tribif (Valeas)	B longum BB536
Allergy	Ultra Strength Probiotic 10 (Nature’s Bounty)	L salivarius
Allergy	UltraFlora Spectrum (Metagenics)	L salivarius
Allergy	Walgreens Probiotic Lactobacillus GG	Lactobacillus GG
Autoimmune Encephalomyelitis	Not available	L paracasei DSM-13434
Autoimmune Encephalomyelitis	Not available	L plantarum DSM-15312 and DSM15313
General Immune/Autoimmune	Biotics Research Biodolph 7-Plus	L plantarum
General Immune/Autoimmune	Fem-Dophilus (Jarrow Formulas)	L rhamnosus GR-1, L reuteri RC-14
General Immune/Autoimmune	Klaire Labs Ther-Biotic Complete	L casei, L plantarum
General Immune/Autoimmune	Not available	B fragilis
General Immune/Autoimmune	PerioBiotic (Toothpaste-Designs for Health)	L casei
General Immune/Autoimmune	UltraFlora Women’s	L rhamnosus GR-1, L reuteri RC-14
Multiple Sclerosis	Flora 50-14 and Flora 20-14 (Innate Response)	L casei, L acidophilus, L reuteri, B bifidum, S thermophiles combined
Multiple Sclerosis	IRT5 probiotic powder	L casei, L acidophilus, L reuteri, B bifidum, S thermophiles combined
Multiple Sclerosis	Isolated for research purpose; not commercially available.	T suis ova
Multiple Sclerosis	Mega Flora Plus (Mega Food)	L casei, L acidophilus, L reuteri, B bifidum, S thermophiles combined
Myasthenia Gravis	Flora 50-14 and Flora 20-14 (Innate Response)	IRT5 probiotics
Myasthenia Gravis	Mega Flora Plus (Mega Food)	IRT5 probiotics
Rheumatoid Arthritis	Advanced Multi-Billion Dophilus (Solgar)	Lactobacillus GG
Rheumatoid Arthritis	Flora 50-14 and Flora 20-14 (Innate Response)	IRT5 probiotics
Rheumatoid Arthritis	Klaire Labs Ther-Biotic Complete	IRT5 probiotics
Rheumatoid Arthritis	Mega Flora Plus (Mega Food)	IRT5 probiotics
Rheumatoid Arthritis	Walgreens Probiotic Lactobacillus GG	Lactobacillus GG
Systemic Lupus Erythematosus	Isolated and cultured for research purposes.	B bifidum LMG13195 (Bb)
Systemic Lupus Erythematosus	Not available	R obeum DSM25238, B coccoides DSM935
Type 1 Diabetes	Dophilus EPS (Jarrow Formulas)	L casei
Type 1 Diabetes	Gr8-Dophilus (Now Foods)	L casei
Type 1 Diabetes	Isolated from BB-DR rats for research purposes and not available commercially.	L johnsonii N62
Type 1 Diabetes	Primal Defense HSO (Garden of Life)	L casei
Type 1 Diabetes	Ther-Biotic Factor 4 (Bifidobacterium Complex) 60c by Klaire Labs	B breve
Type 1 Diabetes	Udo’s Choice Super 5 Probiotic Flora	L casei
Type 1 Diabetes	Ultra Jarro-Dophilus (Jarro-Dophilus + FOS, Jarro Formulas)	L casei
Type 1 Diabetes	VSL#3 (Sigma-tau Pharmaceuticals, Inc): B longum, B infantis, B breve, L acidophilus, L casei, L delbrueckii subsp, L bulgaricus, L plantarum, and S salivarius subsp Thermophiles	B breve

Table 1.

Selected Immune Conditions

Immune Conditions	Strains	Overview	Professional and Commercial Products	Foods
Type 1 Diabetes
Kingma et al27 (2011)	L johnsonii N62	L johnsonii N62 reduced the rate of type 1 diabetes in BioBreeding diabetes-prone rats by decreasing proinflammatory cytokines, IFN-γ, and TNF-α. This probiotic activates the innate immune response via an increased expression of CCL20 (MIP3A), CXCL8 (IL-8), and CXCL10 (IP10).	L johnsonii N62 isolated from BB-DR rats for research purposes and not available commercially.	L johnsonii N62: None identified.
Davis-Richardson et al8 (2015)	Lactobacillus and Firmicutes	There is a significant difference in the microbiome of healthy children with genetic predisposition to type 1 diabetes than in those who have type 1 diabetes. Healthy children have high levels of Lactobacillus and Firmicutes, whereas unhealthy children have higher levels of Bacteroides.	Lactobacillus found in most commercially available probiotic supplements.	Lactobacillus commonly found in fermented foods and beverages.
Calcinaro et al28 (2005)	VSL#3 (B longum, B infantis, B breve, L acidophilus, L casei, L delbrueckii subsp, L bulgaricus, L plantarum, and S salivarius subsp Thermophilus)	VSL#3 helped prevent diabetes development in NOD mice with decreased insulitis and rate of b-cell destruction via an increased in IL-10. In mice and humans, GALT is involved in islet-specific autoimmunity in diabetes-prone individuals. VSL#3 administration in mice works to induce IL-10-producing cells in GALT.	VSL#3: Sigma-tau Pharmaceuticals, Inc (B longum, B infantis, B breve, L acidophilus, L casei, L delbrueckii subsp, L bulgaricus, L plantarum, and S salivarius subsp Thermophiles) Sibiotica (Apex Energetics)	VSL#3: None
Uusitalo et al9 (2016)	Lactobacillus and Bifidobacterium species	In children with the DR3/4 genotype, early supplementation with probiotics from the ages of 0 to 27 d decreased the risk of type 1 diabetes compared with use of probiotics after 27 d or no probiotics at all. Typical probiotic supplements used by study participants included mixtures of various Lactobacillus and Bifidobacterium species. The lack of protection provided in infants after 27 d of life may be linked to the influence of diet on the microbiome. Antibiotic use was positively associated with type 1 diabetes development.	Lactobacillus and bifidobacteria found in most commercially available probiotic supplements.	Cultured dairy and dairy alternatives; fermented vegetables.
Dolpady et al29 (2016)	Lactobacillus species	VSL#3 with and without retinoic acid decreases risk for type 1 diabetes in NOD mice by influencing both the gut and immune system. This occurs by increasing levels of Lactobacillus species and improving various protolerogenic species such as Clostridia species in the Firmicutes phylum, which induce FOXP3+ Treg cell differentiation.	Lactobacillus found in most commercially available probiotic supplements.	Cultured dairy and dairy alternatives; fermented vegetables.
Kverka et al30 (2012)	L johnsonii	Lactobacteria appear to be good candidates for protecting against type 1 diabetes. L johnsonii appears to inhibit disease development by immunomodulation, changes in the metabolism of eicosanoids, and improvement of the function of the gut barrier.	L johnsonii N62 isolated from BB-DR rats for research purposes and not available commercially.	L johnsonii N62: None identified.
Ljungberg et al10 (2006)	L rhamnosus GG, L rhamnosus, B breve BBI99, P freudenreichii subsp Shermanii	In a pilot study to the PRODIA Study, infants who were genetically at risk for type 1 diabetes were given a mixture of L rhamnosus GG (5 × 109 CFU), L rhamnosus LC705 (5 × 109 CFU), B breve BBI99 (2 × 108 CFU), and P freudenreichii subsp Shermanii (2 × 109 CFU). The study found that the use of these probiotics was safe and feasible but did not significantly change prevalence of autoantibodies.	L rhamnosus GG: Walgreens Probiotic Lactobacillus GG Advanced Multi-Billion Dophilus (Solgar)	None
Systemic Lupus Erythematosus
Lopez et al11 (2015)	B bifidum LMG13195 (Bb), R obeum DSM25238, B coccoides DSM935, Synergistetes	Decreased Firmicutes to Bacteroidetes ratio. In SLE, IFN-γ (Th1 cytokine) levels were negatively associated with Bacteroidetes and positively associated with Firmicutes and the Firmicutes:Bacteroidetes ratio. Bifidobacterium and Clostridium spp help to induce Treg cells, which help to balance the immune system. B bifidum LMG13195 (Bb) helps induce FOXP3 expression. R obeum DSM25238 and B coccoides DSM935 help induce Treg cells. Synergistetes were correlated in SLE with serum levels of proinflammatory and Th17-promoting cytokine IL-6, which is associated with a humoral immune response. May also promote IgM antibodies, which could be decreased in SLE.	B bifidum LMG13195 (Bb): Cultured for research purposes. Robeum DSM25238 & B coccoides DSM935: Not available.	None
Richards et al1 (2016)		“In a mouse model of lupus, treatment with butyrate and synthetic HDAC inhibitors led to the suppression of mechanisms that promote hypermutated antibody responses and class-switching, which culminate in the generation of high-affinity autoantibodies.”
Allergy
Kobayashi et al14 (2010)	L casei Shirota DN-114 001 and YIT9029	L casei Shirota helps to improve cellular immunity by modulating the Th1/Th2 balance toward Th1, improving the allergic response.	L casei Shirota DN-114 001 and YIT9029: Not available.	L casei Shirota: Yakult
Issazadeh-Navikas et al5 (2012)	L rhamnosus GG (ATCC53103), B lactis (BB-12), L salivarius, L reuteri (ATCC23272), L casei DN-114001	L rhamnosus GG (ATCC53103) and B lactis (BB-12) increase FOXP3 and consequently Treg cells, allowing for decreased airway reactivity in ovalbumin-induced asthma models. L salivarius and L reuteri (ATCC23272) increase FOXP3 and, therefore, Treg cells by decreasing airway reactivity in ovalbumin-induced asthma models. Improved FOXP3 levels and Treg cells and decreased delayed-type hypersensitivity by causing an increase in IL-10 in ovalbumin and 2-4-dinitroflurobenzene-sensitized mice.	L rhamnosus GG (ATCC 53103), JB-1: Not available. B lactis (BB-12): One-A-Day TruBiotics (Bayer) ProSynbiotic (Standard Process) Advanced Acidophilus Plus (Solgar) L reuteri (ATCC23272): Not available. L salivarius: Gr8-Dophilus (NOW Foods) Dr. Formulated Probiotics and Primal Defense (Garden of Life) UltraFlora Spectrum (Metagenics) Flora products (Innate Response) Ultra-Strength Probiotic 10 (Nature’s Bounty)	L rhamnosus GG (ATCC 53103), JB-1: None B lactis (BB-12): Nancy’s Organic Low-fat Kefir L salivarius: None L reuteri (ATCC 23272): None L casei: Kefir, kvass, lassi, yogurt
Vaarala31 (2003)	Lactobacilli, enterococci, bifidobacteria, Lactobacillus GG, B lactis BB-12, L reuteri DSM122460, L rhamnosus 19070-2	Increased levels of Lactobacilli are more commonly found in the microbiome of infants in Estonia than those in Sweden, providing protection against allergy. Decreased levels of Enterococci and Bifidobacteria are found in the first year of life in children who developed allergies while they had higher levels of Clostridia and staphylococci. Decreased Bifidobacterium levels and increased Clostridia levels were found in Finnish children with atopic sensitization. Oral probiotics used in infancy may help prevent food allergies by affecting T cells in Peyer’s patches. This is particularly influenced by Gram-positive or Gram-negative bacteria, including bifidobacteria or E coli. Lactobacillus GG was used in a study on children at risk for atopic disease and was given in capsules to mothers for the 2 to 4 wk before delivery and after delivery to either the breastfeeding mother or the child for 6 mo. The frequency of atopic eczema in the probiotic group was found to be half that of the placebo group. Both B lactis BB-12 and Lactobacillus GG decreased the number of infants with atopic eczema in comparison with infants given hydrolyzed formula and no probiotics. L reuteri DSM122460 and L rhamnosus 19070-2 helped to decrease eczema in children aged 1 to 13 y and decreased eosinophil cationic protein levels.	B lactis Bb-12: One-A-Day TruBiotics (Bayer) ProSynbiotic (Standard Process) Advanced Acidophilus Plus (Solgar) L reuteri DSM-122460: Not available. L rhamnosus 19070-2, LC705: Not available.	B lactis (BB-12): Nancy’s Organic Low-fat Kefir L reuteri DSM 122460, L rhamnosus 19070-2, LC705: None
Furchiaroni et al32 (2013)	Lactobacilli, bifidobacteria	Decreased amounts of both lactobacilli and bifidobacteria are closely associated with allergies.	Lactobacillus found in most commercially available probiotic supplements.	Cultured dairy and dairy alternatives; fermented vegetables.
Jeongmin et al33 (2013)	L acidophilus, L bulgaricus, B bifidum, B longum, L casei YIT9029, L casei HY7201, L brevis HY7401, L plantarum HY20301	L acidophilus, L bulgaricus, B bifidum, and B longum help promote cellular immune responses by activating Th1 cells helping to reduce total or OVA-specific IgE production as well as changing cytokine patterns in a strain-dependent manner. Mice given L casei YIT9029, L casei HY7201, L brevis HY7401, or L plantarum HY20301 every 2 d for 3 wk had decreased total IgE levels and OVA-specific IgE levels. L casei HY7201 induced an allergic response, whereas L casei YIT9029 induced higher Th1 cytokines with a decrease in Th2 cytokines, thus decreasing the allergic response.	L acidophilus, L bulgaricus, B bifidum, and B longum: Combined in ImmuProbio (Health Aid) Strengtia (Apex Energetics) B longum: Mega Flora; Innate Flora 50-14 Complete Care (Mega Foods) L plantarum HY20301: Not available. L brevis HY7401: Not available.	L acidophilus: Kefir, lassi, yogurt L bulgaricus, B bifidum: Kefir, all yogurt containing “live and active cultures” B longum, L brevis HY7401, L plantarum HY20301, L salivarius LS01: None L bulgaricus, S thermophilus: Kefir, all yogurt containing “live and active cultures”
Castellazzi et al34 (2013)	L rhamnosus, L casei, L salivarius LS01	L rhamnosus used in children with atopic dermatitis decreased dermatitis, as well as TNF-a and a1-AT in feces. L casei DN-114001 helped to reduce by 33% the occurrence of yearly rhinitis. L salivarius LS01 decreased skin manifestations after 16 wk in adult atopic patients with a reduced level of Staphylococcus in feces and improvements in the Th1/Th2 cytokine profile.	L rhamnosus: Walgreens Probiotic Lactobacillus GG Advanced Multi-Billion Dophilus (Solgar) L salivarius LS01: Not available. L salivarius: Gr8-Dophilus (NOW Foods) Dr. Formulated Probiotics and Primal Defense (Garden of Life) UltraFlora Spectrum (Metagenics) Flora products (Innate Response) Ultra-Strength Probiotic 10 (Nature’s Bounty)	L rhamnosus GG (ATCC 53103), JB-1: None L casei: Kefir, kvass, lassi, yogurt L salivarius: None
Das et al35 (2013)	L rhamnosus JB-1, L gasseri A5, B longum BB536, L paracasei, L casei Shirota, L bulgaricus, S thermophilus	L bulgaricus, S thermophilus, and L casei supplemented at 100 mL/d for 12 mo decreased episodes of asthma and rhinitis. Four capsules/day for 5.5 mo of L rhamnosus decreased total symptoms scores in allergic nose, eye, and lung symptoms. L casei Shirota provided at 80 mL/d for 8 wk changed the symptom medication score in children with allergies. L paracasei given at 2 capsules/day for 30 d decreased rhino-conjunctivitis in children and improved the quality of life score. B longum BB536 at 200 g/d 14 wk decreased subjective symptoms score in allergic adults. L gasseri A5 capsule provided to 105 children aged 6 to 12 y with asthma improved peak expiratory flow rates, symptoms of asthma, and allergy relief scores of the patients, as well as immunological parameters. L rhamnosus JB-1 provides significant inhibition of mast cell degranulation to a range of stimuli (ie, IgE-mediated activation) in rat models. Therefore, this strain may be effective as a mast cell stabilizer. In fact, this strain can downregulate FCER1 expression on mast cells.	L rhamnosus GG (ATCC 53103), JB-1: Not available. L gasseri: Kyo-Dophilus 9 Probiotic Formula for Intestinal Balance and Immune Support L Gasseri 3 Billion CFU (Swanson) PurFem Probiotic WITH APPLICATOR 10 Vaginal Suppositories B longum BB536: Bifilon (Quality of Life Herbs) Bifido GI Balance (Life Extension) Jarro-Dophilus EPS and Baby’s Jarro-Dophilus+FOS Powder (Jarrow Formulas) Tribif (Valeas) S thermophilus and L paracasei: BioDoph-7 Plus (Biotics Research) S thermophilus: SymBiotics with FOS Description (Nutricology)	L rhamnosus GG (ATCC 53103), JB-1: None L bulgaricus, S thermophilus: Kefir, all yogurt containing “live and active cultures” L paracasei: Kevita Probiotic Drinks B longum BB536, L gasseri, B fragilis: None
Hendaus et al36 (2016)	Bifidobacterium spp, B fragilis, Lactobacillus GG, B lactis, L plantarum, L reuteri, L gasseri, B longum	Whereas in breastfed infants Bifidobacterium spp predominate the microbiome (60% to 70%), formula-fed infants had more Bacteroides and Clostridium spp. This may lead to an increased risk of allergies and other diseases. B fragilis given to germ-free mice helped improve Th1 response and balanced Th1/Th2. In a murine model, Lactobacillus GG decreased allergic airway response and peribronchial inflammation in mouse offspring. Lactobacillus GG or B lactis BB12 in a murine model decreased pulmonary eosinophilia, airway reactivity, and antigen-specific IgE production. The addition of L plantarum helped decrease airway eosinophilia following aerosolized allergen exposure. Giving L plantarum and L lactis helped to reduce allergen-induced basophil degranulation upon exposure to birch pollen. L reuteri decreased allergy response to methacholine, airway eosinophilia, and local response of cytokines. Lactobacillus GG may be helpful in infant eczema and dermatitis symptoms in IgE-sensitized infants, but not in non-IgE-sensitized infants. Use of yogurt containing L gasseri, Lactobacillus GG, and B longum may help with nasal blockage in seasonal allergic rhinitis.	B fragilis: Not available. B longum: Mega Flora; Innate Flora 50-14 Complete Care (Mega Foods) L lactis: Goat Milk Kefir (Activia)	B longum BB536, L gasseri, B fragilis: None
Magerl et al37 (2008)	E coli (nonpathogenic)	In a murine model, colonization with very high doses of live, unfimbriated, nonpathogenic E coli bacteria strongly reduced mast cell degranulation.	E coli: Mutaflor (Tribute Pharmaceuticals); contains the Nissle 1917 strain	None
Oksaharju et al16 (2011)	Lactobacillus GG, L rhamnosus LC705	Lactobacillus GG and L rhamnosus LC705 suppressed genes encoding FCER1A and FCER1G, which encode allergy-related high-affinity IgE receptor subunits α and ■, respectively, and also suppressed the histamine H4 receptor. They worked by decreasing proinflammatory mediators such as IL-8 and TNF-a, while upregulating the anti-inflammatory IL-10.	Lactobacillus GG: Walgreens Probiotic Lactobacillus GG Advanced Multi-Billion Dophilus (Solgar)	None
Schiffer et al17 (2011)	L casei DN-114-001	L casei DN-114-001 provided protection from IgE- and IgG-induced mouse mast cell activation and ex vivo on IgE-dependent human basophil activation. It appears that this strain can inhibit mast cell degranulation and the secretion of IL-5, IL-6, IL-13, TNF-α, MCP-1, and MIP-1α. These are the 4 cytokines and 2 chemokines that induce FCER1 aggregation. Further, L casei inhibited β-hexosaminidase release via IgG immune complexes.	L casei DN-114001: Not available.	None
Forsythe et al38 (2012)	Lactobacillus GG	Lactobacillus GG may be effective as a mast cell stabilizer. In fact, this strain is able to down regulate FCER1 (IgE receptor) expression on mast cells.	Lactobacillus GG: Walgreens Probiotic Lactobacillus GG Advanced Multi-Billion Dophilus (Solgar)	None
Zhang et al39 (2016)	L salivarius, L paracasei, B animalis, B bifidum, L rhamnosus, L rhamnosus GG, B longum, B lactis, L acidophilus, L lactis, L reuteri, L paracasei	In a systematic review and meta-analysis, it was found that pre-and postnatal administration of probiotics could reduce the risk of atopy and food hypersensitivity. The mechanism is thought to be a shift of immune balance toward a Th1 response and therefore decreased production of Th12 cytokines such as IL-4, IL-5, and IL-13. In addition, there is decreased IgE and increased production of C-reactive protein and IgA. Probiotics protective against atopy include L salivarius, L paracasei, B animalis, B bifidum, L rhamnosus, L rhamnosus GG, B longum, B lactis, L acidophilus, L lactis, L reuteri, and L paracasei. Probiotics protective against food sensitization include L rhamnosus, B animalis, L rhamnosus GG, B bifidum, B lactis, L acidophilus, L lactis, and L reuteri.	L salivarius: Gr8-Dophilus (NOW Foods) Dr. Formulated Probiotics and Primal Defense (Garden of Life) UltraFlora Spectrum (Metagenics) Flora products (Innate Response) Ultra-Strength Probiotic 10 (Nature’s Bounty) B longum: Mega Flora; Innate Flora 50-14 Complete Care (Mega Foods) L acidophilus, L bulgaricus, B bifidum, and B longum: Combined in ImmuProbio (Health Aid) Strengtia (Apex Energetics) L lactis: RAW Probiotics Women 85 Billion CFU (Garden of Life) Perfect Biotics (Probiotic America) Jarr-Dophilus EPS 25 Billion (Jarrow Formulas) S thermophilus and L paracasei: BioDoph-7 Plus (Biotics Research)	L paracasei: Kevita Probiotic Drinks L rhamnosus GG: None
Zajac et al40 (2015)	L paracasei 33	L paracasei 33 helps protect against grass pollen allergy.	None	L paracasei 33: None
Johansson et al41 (2011)	Bifidobacterium	For children with parents who have allergies, there are lower levels of endotoxin in house dust, which decrease infant exposure to bifidobacteria species. S aureus was found more frequently in children with allergies.	Bifidobacteria: Klaire Factor 4	Cultured dairy and dairy alternatives; fermented vegetables.
Randazzo et al18 (2014)	L reuteri DSM17938	L reuteri DSM-17938 was found to help improve both clinical symptoms and microbiome diversity in patients with SNAS.	L reuteri DSM-17938: BioGaia (Gastrus)
Kuitunen et al19 (2009)	Probiotic mix including 2 lactobacilli, bifidobacteria, and propionibacteria	A probiotic mixture given to pregnant mothers during their final month of pregnancy and to infants during their first 6 m along with the prebiotic galactooligosaccharide, was found to prevent IgE-associated allergy until the age of 5 y, but only in children delivered by cesarean section.	Various	Cultured dairy and dairy alternatives; fermented vegetables.
Rheumatoid Arthritis
Vitetta et al12 (2013)	Bifidobacteria, B fragilis, L casei, B coagulans GBI-30, 6086, L rhamnosus GR-1, L reuteri RC-14	Compared with individuals without RA, RA patients have significantly less bifidobacteria, bacteria from the Bacteroides-Porphyromonas-Prevotella group, B fragilis subgroup, and E rectal-C coccoides group. Bacteria normally found in the oral cavity, including P gingivalis and P intermedia, is found in the synovial fluid of patients with RA. Antigen-specific antibodies are also found against P gingivalis, P intermedia, and B forsythus in these patients. L casei was shown to prevent RA progression in rat models by suppressing collagen-induced arthritis, decreasing paw swelling, decreased lymphocyte infiltration, and reduced destruction of cartilage. It works by decreasing proinflammatory cytokines and upregulating IL-10 levels and suppressing the Th1 immune response that causes RA. “Compared with placebo, Bacillus coagulans GBI-30, 6086 treatment resulted in greater improvement in patient global assessment and self-assessed disability; reduction in CRP; as well as the ability to walk 2 miles, reach, and participate in daily activities.” L rhamnosus GR-1 and L reuteri R-14 helped to functionally improve those with RA in a double-blind RCT of 29 RA patients.	Bifidobacteria: Klaire Factor 4 Klaire Labs Ther-Biotic Complete (L rhamnosus, L acidophilus, L casei, L plantarum, L salivarius, B longum, L bulgaricus, L paracasei, B lactis, B breve, B bifidum) L rhamnosus GR-1, L reuteri RC-14: UltraFlora Women’s (Metagenics) Women’s Fem Dophilus (Jarrow Formulas)	Bifidobacteria: Cultured dairy and dairy alternatives; fermented vegetables. B fragilis: None L casei: Kefir, kvass, lassi, yogurt B coagulans GBI-30, 6086, L rhamnosus GR-1, L reuteri RC-14, Lactobacillus GG, L fermentum: None
Mandel et al13 (2010)	B coagulans, Lactobacillus GG, L casei	B coagulans showed borderline statistical significance in a double-blind RCT of 45 patients with RA in decreasing pain when included in a protocol that also included green tea extract; MSM; vitamins A, B, C, D, E and folic acid; and selenium. Lactobacillus GG decreased inflammation in rats as compared with rats fed yogurt. L casei in a 12-wk study decreased signs of arthritis, infiltration of lymphocytes into the joint, and cartilage breakdown in a rat model. Decreased levels of proinflammatory cytokines and decreased T-cell proliferation was found in combination with increased levels of the anti-inflammatory IL-10.	Lactobacillus GG: Walgreens Probiotic Lactobacillus GG Advanced Multi-Billion Dophilus (Solgar) Klaire Labs Ther-Biotic Complete (L rhamnosus, L acidophilus, L casei, L plantarum, L salivarius, B longum, L bulgaricus, L paracasei, B lactis, B breve, B bifidum)	B coagulans: None Lactobacillus GG: None L casei: Kefir, kvass, lassi, yogurt
Scofield42 (2014)		Oral bacteria may be implicated in the pathogenesis of RA via molecular mimicry. In particular, P gingivalis may be the culprit because it is the only bacterium that contains the enzyme peptidylarginine deiminase used to convert arginine to citrulline allowing for generation of antibodies to binding citrullinated peptides in RA.
Kwon et al43 (2010)	L casei, L acidophilus, IRT5 probiotic (L acidophilus, L casei, B bifidum, L reuteri, and S thermophiles)	L casei decreases the proinflammatory responses via an increase in levels of IL-10. L acidophilus increases Th1 cytokines. IRT5 helps to decrease autoimmunity via increasing the level of CD4+FOXP3+Tregs.	IRT5 probiotics: Mega Flora Plus (Mega Food) Flora 50-14 and Flora 20-14 (Innate Response) Klaire Labs Ther-Biotic Complete (L rhamnosus, L acidophilus, L casei, L plantarum, L salivarius, B longum, L bulgaricus, L paracasei, B lactis, B breve, B bifidum) Strengtia (Apex Energetics; (L acidophilus, B coagulans)	L casei: Kefir, kvass, lassi, yogurt L acidophilus: Kefir, lassi, yogurt RT5 probiotic: Similar to many mixtures used in kefir and yogurts.
Vaghef-Mehrabany et al44 (2014)	L casei 01	L casei 01 significantly reduced disease activity in patients with RA helping to decrease TNF-α, IL-6, and IL-12. It also increased the anti-inflammatory IL-10.	L casei 01: None.	L casei 01: None
Myasthenia Gravis
Chae et al45 (2012)	IRT5 probiotics (S thermophiles, L reuteri, B bifidum, L acidophilus, L casei)	IRT5 decreases symptoms of myasthenia gravis by “inhibiting the infiltration of complement component and loss of AChR contents at NMJ. Treatment with IRT5 probiotics further suppressed AChR reactive immune responses and down-regulated the levels of pro-inflammatory cytokines (IFN-γ, TNF-α, IL-6 and IL-17).”45 Further, this probiotic blend decreased autoantibody levels. IRT5 probiotics (S thermophiles, L reuteri, B bifidum, L acidophilus, L casei) suppress immune disorders by creation of CD4+FOXP3+ Tregs.	IRT5 probiotics: Mega Flora Plus (Mega Food) Flora 50-14 and Flora 20-14 (Innate Response) Strengtia (Apex Energetics)	IRT5 probiotics: Similar to mixtures used in many kefirs and yogurts.
Autoimmune Encephalomyelitis
Lavasani et al46 (2010)	L paracasei DSM 13434, L plantarum DSM 15312 and 15313	L paracasei DSM-13434, L plantarum DSM-15312, and DSM-15313 decreased inflammation in the central nervous system. L paracasei and L plantarum DSM-15312 caused CD4+CD25+FOXP3+ regulatory T cells to be induced and also increased production of serum TGF-β1. Serum IL-27 was increased with use of L plantarum DSM-15313. Use of L paracasei DSM-13434, and L plantarum DSM-15312 and DSM-15313 appeared to decrease signs and symptoms of autoimmune encephalomyelitis. “Our data revealed that the suppressed activity was associated with reduced inflammation in CNS, down-regulation of MOG-induced T cell responses and a shift in production of pro-inflammatory cytokines toward the beneficial Th2 type response including IL-4, IL-10 and TGF-β1.”	L paracasei DSM-13434: Not available. L plantarum DSM 15312 and 15313: Not available.	None
General Immune/Autoimmune
Issazadeh-Navikas et al7 (2012)	L plantarum, L reuteri, L casei	L plantarum blocks proteasome function blocking the breakdown of NF-kB, which influences Treg cells. L plantarum, L reuteri, and L casei activate dendritic cells allowing for conversion of T cells to Treg cells.	L plantarum: Biotics Research Biodolph 7-Plus Sibiotica (Apex Energetics) L rhamnosus GR-1 and L reuteri RC-14: UltraFlora Women’s Fem-Dophilus (Jarrow Formulas) L casei: PerioBiotic Toothpaste (Designs for Health) L casei and L plantarum: Klaire Labs Ther-Biotic Complete Sibiotica (Apex Energetics)	L plantarum: Fermented vegetables, Kevita probiotic drinks, olives (green) L reuteri: None L casei: Kefir, kvass, lassi, yogurt
Chervonsky3 (2011)	B fragilis	B fragilis contains a bacterial polysaccharide (polysaccharide A) that stimulates immune response and can suppress reaction of the immune system. Various bacteria strains exert effects on anti-inflammatory cytokines such as IL-10 and suppressive Treg cells. Segmented filamentous bacteria induce Th17 in mice models, a proinflammatory T-helper cell. Microbiota serve as a means of “colonization resistance,” preventing various infections such as S typhimurium.	B fragilis: Not available.	B fragilis: None
Richards et al1 (2016)	SCFA	Production of SCFA provides health benefits such as decreasing inflammation and improving homeostasis of the metabolism. SCFAs exert influence on immune cells located near the lymphoid compartments of the gut and can move systemically to influence tissues in the periphery. High-fiber foods positively affect the immune system and microbiota by providing an energy source for microbial communities, which then influence the immune and metabolic homeostasis. The SCFA acetate appears to provide immune benefits and protection from pathogens helping to prevent intestinal permeability associated with autoimmune disease. SCFAs are anti-inflammatory and immunomodulatory, because they promote Treg cells allowing for better immune tolerance. The Treg cells then produce IL-10 after TGF-β cytokine exposure in the periphery from naive CD4+ T cells. SCFAs influence autoreactive cells, such as B cells related to inflammatory disease, such as lupus and type 1 diabetes via their production of autoantibodies.	Probiotics that contain prebiotics.	High-fiber foods
Kverka et al30 (2012)		Probiotics can influence the microbiome by influencing production of antimicrobial peptides in the hosts and improving barrier function, and they have immunomodulatory properties at most levels of regulation such as downregulation of PRRs expression, NF-kB signaling, and proinflammatory cytokine production.
Reynolds et al47 (2016)	B fragilis, B infantis, Clostridium spp, Lactobacillus spp	B fragilis, B infantis, Clostridium spp, and Lactobacillus spp induce production of suppressive Tregs.	Lactobacillus found in most commercially available probiotic supplements. B infantis: Mega Flora (Mega Food) Innate Flora 5-14 Complete Care	Lactobacillus commonly found in fermented foods and beverages. B infantis: None

Note: Several other conditions are autoimmune in nature; however, they have been covered extensively in other portions of this comprehensive review. Please see the additional articles of this series for specific conditions, as outlined in the abstract.

Abbreviations: GALT, galactose-1-phosphate uridylyltransferase; IFN-γ, interferon gamma; IgA, immunoglobulin A; IgE, immunoglobulin E; IgM, immunoglobulin M; IL, interleukin; NF-kB, nuclear factor kappa B; NOD, nonobese diabetic; OVA, ovalbumin; PRRs, pattern recognition receptors; RA, rheumatoid arthritis; RCT, randomized clinical trial; SCFA, short-chain fatty acid; SLE, systemic lupus erythematosus; SNAS, systemic nickel allergy syndrome; TGF, transforming growth factor; T_h1, T-helper 1; T_h2, T-helper 2; TNF-α, tumor necrosis factor alpha; Treg, T-regulatory.

Biographies

Jessica M. Pizano, MS, CNS

Christy B. Williamson, MS, CNS

Keren E. Dolan, MS

Crystal M. Gossard, MS, CNS

Cathleen M. Burns, MS, RD

Margaret G. Gasta, MS, RDN, CCN

Heather J. Finley, MS, RD, LD, CEDRD

Emily C. Parker, MS, RD, are doctoral students in the doctor of clinical nutrition program

Elizabeth A. Lipski, PhD, CNS, CCN, BCHN, IFMCP, is a professor.