The immune system is divided into 2 segments – the innate and the adaptive immune system. These 2 arms work together synergistically to protect the host from infectious disease. In mammals, the adaptive immune system includes both the systemic and local (mucosal) types, where cells and molecules interact to provide this protection in a complex and effective manner.Probiotics have long been used to improve gastrointestinal (GI) function; however, in recent years their beneficial systemic effects have taken front and center stage. The mechanisms of probiotic action include stimulating the secretion of antimicrobial substances, competitive adherence to the GI mucosa, strengthening of the intestinal epithelial barrier, and modulation of the immune system.1 Recent studies show that changes in the bacterial composition of the gut are linked to various metabolic and inflammatory diseases, including inflammatory bowel disease,2 obesity and type 2 diabetes,3 and allergies.4 Although most probiotics are known to affect the immune system, it’s been found that different strains may have rather discrete effects on immune function; the information on this topic is vast and growing at a rapid pace. This article will attempt to clarify some of the underlying mechanisms involved in the anti-inflammatory effects of selected probiotic strains.
The mucosal surface of the GI tract is an area where numerous encounters with antigens or infectious agents occur. The immune properties of the digestive mucosa are provided by the gut-associated lymphoid tissue (GALT). The epithelial cells of the intestine represent the primary physical barrier, now recognized as the main interface with the microbiome in the gut, where immune responses are initiated.5 The intestinal barrier protects the host from the external environment with a protective mucous layer, secretory IgA, and the tight junctions, which are sealed barriers between epithelial cells. Bacteria within the intestinal lumen can interact with intestinal epithelial and dendritic cells, macrophages, and lymphocytes.6
One of the most interesting effects of probiotics is their ability to modulate the immune system through the induction of cytokines. Probiotic bacteria induce the secretion of cytokines from epithelial cells; moreover, they do this in a strain-specific manner.7 This is a complex process – and, as such, studies have resulted in conflicting information, based on the state of the immune system at the time of probiotic administration, concomitant administration of other probiotic strains, inflammation or infection at time of administration, and a variety of other factors. Time will elucidate much more information on the effects of probiotic strains on the immune system in different situations for the host.
Inhibiting Inflammation at the Root: NF-ĸB
The key inflammatory signaling channel is nuclear factor-kappa B (NF-ĸB). This factor is present in an inactive form in the cytoplasm, bound to an inhibitory molecule – IĸB. When inflammatory stimuli trigger signaling pathways, this inhibitor molecule is broken down and NF-ĸB is released to activate the inflammatory cascade.7 Several probiotic strains can prevent the degradation of this inhibitory molecule, reducing the expression of proinflammatory cytokines.
For example, Lactobacillus rhamnosus GG has been found to decrease the degradation of IĸB and thereby minimize the production of the inflammatory cytokine, IL-8.8 Another example of this particular effect is the pretreatment of epithelial cells with Lactobacillus casei DN-114 001, resulting in inhibition of IĸB degradation and reduced NF-ĸB activation.9
Other studies have shown that administration of Lactobacillus casei CRL 431 can increase the cytokine IL-6, and increase IgA-secreting cells in mice, enhancing the production of the intestinal protector, IgA.10
Effects of Probiotics on Dendritic Cells
In addition to the above effects, probiotics can also affect the dendritic cells (DCs) that extend in between the epithelial cells into the intestinal lumen. DCs directly sample gut luminal contents and orchestrate T-lymphocyte responses in the systemic circulation. Certain strains of probiotics have been shown to regulate the maturation of DCs and polarize T-cell activity towards Th1, Th2, or T-regulatory responses.
Lactobacillus paracasei CNCM I-4034 (and its supernatant) has been found to dramatically reduce the production of the Th1 cytokines, IL-6, IL-8, IL-12, and tumor necrosis factor-alpha (TNF-α) in human intestinal DCs challenged with Salmonella typhi.11
The combination probiotic VSL#3 has been found to induce anti-inflammatory IL-10 in DC culture supernatants.12 IL-10 is a Th2 cytokine that has been found to suppress IL-12 and other inflammatory cytokines, such TNF-α.13
Dendritic cells cultured with Lactobacillus casei have also been found to shift their cytokine profile in favor of IL-10, and are able to prevent type 1 diabetes development upon injection into non-obese diabetic mice – an animal model for type 1 (autoimmune) diabetes.14 Since a single injection of L casei-treated DCs is insufficient to mediate long-term protection, the mechanism in this case most likely involves the induction of regulatory cells.
Activation of Toll-like Receptors by Probiotics
Toll-like receptors are part of the innate immune system in the gut that recognize and respond to pathogens. These receptors are known to transmit signals in response to bacteria. It is therefore not surprising that probiotics which come into contact with immune cells in the gut can also elicit significant systemic immune responses.15 It is well established that the cells that interact most extensively with probiotics are the intestinal epithelial cells; however, probiotics also come into contact with DCs and other immune cells, as previously mentioned. Toll-like receptors (TLRs) are trans-membrane proteins that are expressed on both immune and non-immune cells ranging from intestinal epithelial cells to dendritic cells.
Activation of TLRs can signal immune responses in the intestinal epithelial cells, such as the major inflammatory pathway, NF-ĸB. TLR signaling can also control the maturation of dendritic cells in the gut.
Probiotic organisms in the gut can alter the immune state by affecting TLR expression on DCs, shifting the differentiation of T-helper cells into either Th1, Th2 or Th17.6 In fact, it’s now thought that specific types of TLRs create differing immune responses to probiotics.
An example of the action of a probiotic on TLRs is that of Lactobacillus casei Zhang – a probiotic strain found to increase the expression of TLR2 and TLR9, thereby reducing the production of TNF-α and IL-β in a rat model of acute hepatic inflammation.16
Probiotics can also act as negative regulators of TLRs. Lactobacillus plantarum genomic DNA has been found to inhibit NF-ĸB and TNF-α production.17 This inhibition was accompanied by the suppression of TLR2, TLR4, and TLR9, and an increase in IRAK M, a negative regulator of TLR.
The Effects of Probiotics on Cytokines & T-Cell Differentiation
Cytokines are produced by different types of immune cells, mainly the T-lymphocyte subsets. Typically, immune responses with cytokines that are classified as Th1 and Th17 are pro-inflammatory, whereas Th2 cytokines are typically anti-inflammatory, promote humoral immunity against extracellular pathogens, and are involved in allergic response. The Th1 cytokines include IFN-γ, IL-12, TNF-α, IL-2, and IL-17. The Th2 cytokines include IL-10, IL-4 and TGF-β.
Cytokines including IL-10 and TGF-β have been implicated in T-regulatory cell function, playing a role in suppressing and regulating immune responses. T-regulatory cells (Tregs) are the police of the immune system, active in suppressing the development of autoimmune disease in the ever-changing immune environment.
It is thought that the primary influence of probiotics on the immune system is on the intestinal epithelial cell. Firstly, probiotics can improve the integrity of epithelial cells, hence improving immune response through a secondary mechanism. As an example, Lactobacillus GG produces 2 proteins – p40 and p75 – which protect epithelial cells from apoptosis, thereby increasing the integrity of the gut barrier.18 Alternately, probiotics can act directly on immune responses by promoting cytokine release from the intestinal epithelial cells.
Probiotic Strains and Cytokines
Certain probiotic strains appear to promote the production of specific cytokines, including IFN-γ, IL-12, IL-2, TNF-α, and IL-6 from Th1/Th17 cells, while some of other probiotic strains may promote the production of regulatory cytokines, including IL-10 and TGF-β from Tregs7:
L rhamnosus Lc705 has been found to have a strong downregulating effect on several proinflammatory genes, such as IL-8 and TNF-α, while upregulating genes that encode anti-inflammatory cytokines, such as IL-1019
L plantarum 2142 has been found to significantly decrease IL-8 and TNF-α mRNA levels, decreasing Th1 inflammatory responses20
Bacillus coagulans GB-30 has been found to increase the population of another intestinal bacteria, F prausnitzii,21 possibly due to the production of lactic acid by B coagulans.2 F prausnitzii has been shown to potently induce production of anti-inflammatory cytokines, specifically IL-10.21
Similarly, a previous study showed that Bacillus coagulans was able to stimulate the production of major anti-inflammatory cytokines such as IL-1022
Administration of the probiotic yeast, Saccharomyces boulardii, to a group of 37 patients was found to reduce systemic and local proinflammatory cytokines IL-8 and TNF-α, increase anti-inflammatory IL-10 levels, and increase the tissue IL-10/IL-12 ratio23
Patients receiving Lactobacillus casei 01 revealed a significant difference between IL-10, IL-12, and TNF-α changes over the course of the study, with a shift towards anti-inflammatory Th2 cytokine release24
Lactobacillus casei DN-114001 has been found to increase the number of CD4 Fox P3 Tregs in the mesenteric lymph nodes, and decrease the production of the proinflammatory cytokines TNF-α and IFN-γ25
In terms of combination products, the probiotic strains found in VSL#3 have been shown to be protective in several animal models of colitis, including IL-10-deficient mouse models of colitis, and were found to mediate their effect through the induction of Tregs26
Th17 & Autoimmunity
Th17 cells represent a population of T cells that are not only important for fighting bacterial infection, but are also involved in the pathogenesis of a number of inflammatory and autoimmune diseases.
Th17 cell responses appear to be induced by a restricted number of microbial species, such as the segmented filamentous bacteria (SFB) – gram-positive bacteria within the Firmicutesphylum.27 SFB are thought to play a key role in the maturation of the adaptive mucosal immune response in the gut. A microbiota favoring SFB could therefore have an impact on immune response and, consequently, on the development of Th17-mediated inflammatory/autoimmune diseases in the gut and at distant sites in predisposed individuals.
Lactobacillus plantarum has been found to decrease the colonization and survival of SFB in mice, restoring SFB-dominant GI tracts to a healthy level.28 As such, it may be inferred that this strain may be beneficial in reducing some of the stimulus for Th17 and autoimmunity.
In another recent report, colonization of germ-free mice with the human commensal, Bacteroides fragilis, was shown to induce IL-10 production and Foxp3 expression, decrease Th17 cells, and prevent colitis development. B fragilis is not yet available as a commercial probiotic, however.
Finally, oral administration of different probiotic species has been shown to protect against development of various Th17-mediated autoimmune diseases, such as type 1 diabetes (L casei),29 experimental autoimmune encephalomyelitis (L paracasei DSM 13434, L plantarumDSM 15312 and DSM 15313),30 and experimental rheumatoid arthritis (L casei24,31) via induction of IL-10-producing Tregs and attenuation of Th1 and Th17 cytokines.
It’s well known that there is a central inflammatory component to metabolic disease and that the microbiome is significantly altered in metabolic disorders.32 Treatment of metabolic disorders with drugs such as metformin, or natural products such as berberine, can shift the microbiome, increasing the production of anti-inflammatory short-chain fatty acids; this may be a major mechanism through which these agents improve metabolism.33 Specific probiotic strains have been found to affect metabolic inflammation. For example, Lactobacillus casei CRL 431 administration decreased inflammatory cytokines in a diet-induced obese mouse model, including TNF-α, IL-6, and IL-17.
Lactobacillus gasseri SBT 2055, Lactobacillus rhamnosus ATCC 53103, and the combination of L rhamnosus ATCC 53102 and Bifidobacterium lactis Bb12 may improve short-chain fatty acid production and reduce the low-grade inflammation that is central in obesity and metabolic disorders.34
Saccharomyces boulardii has also been found to attenuate the markers of metabolic inflammation in mice, reducing body weight, fat mass, hepatic steatosis, and overall inflammatory tone.35
Comparing Immune Effects of Lactobacilli & Bifidobacteria
Another interesting study compared the cytokine profiles of different strains, examining the ratios of key cytokines, IL-10/IL-12, and TNF-α/IL-10.36 In this study, distinct patterns emerged for Lactobacilli and Bifidobacteria strains: Bifidobacteria, in particular, produced a high ratio of IL-10/IL-12 (Th2 dominance), whereas Lactobacillus strains tended to produce a high ratio of TNF-α/IL-10 (Th1 dominance).36 Although this is of interest, there are clearly Lactobacilli that have potent anti-inflammatory effects, so this should not be taken as a generalization
Care should also be taken to not view Th1 patterns as negative when it comes to inflammation. In fact, the Th1 branch of the immune system is protective against cancer, allergy, and infection – as such, its activation is exceptionally beneficial for the appropriate patient population.
In terms of anti-inflammatory Bifidobacteria species, Bifidobacterium breve has been found to increase Th2- and Treg-associated cytokines in the distal colon, leading to increases of Treg and decreases of Th17 cell subsets in Peyer’s patches of mice with intestinal inflammation.37
Bifidobacterium infantis is a well-researched probiotic that has been shown to adhere to GI epithelial cell lines without inducing NF-ĸB activation or the secretion of chemokines.38 B infantishas been found to reduce Th1- and Th17-related cytokines and increase Treg-related molecules in mice with colitis.39
The effects of B infantis also go beyond the gut mucosa and into the periphery: B infantis 35624 feeding reduced inflammatory markers in patients with ulcerative colitis, chronic fatigue syndrome, and psoriasis when compared with placebo.40 Interestingly, plasma TNF-α was reduced in chronic fatigue syndrome (CFS) and psoriasis, while IL-6 was reduced in ulcerative colitis and CFS.
Furthermore, in healthy subjects, LPS-stimulated TNF-α and IL-6 secretion by peripheral blood mononuclear cells (PBMCs) was significantly reduced in B infantis 35624-treated groups compared with placebo following 8 weeks of treatment.
Th1 Inducers – Benefits for Allergic Inflammation
We have talked about inducing Th2 with probiotics, which would produce anti-inflammatory effects for both metabolic and autoimmune-mediated inflammation. However, allergy is another important inflammatory disease, mediated by high levels of Th2 cytokines. As an example of a Th1-inducing effect in a probiotic strain, L acidophilus (ATCC4356) has been found to increase the production of IFN-γ and decrease the production of IL-4 (a Th2 cytokine) in spleen cell culture.41
B bifidum PRL2010 enhances production of IL-6 and IL-8 cytokines, presumably through NF-κB activation, resulting in a Th1 response.42
L acidophilus AD031, Bifidobacterium lactis AD011, and the combination of L acidophilus AD031 and B lactis AD011, have also been found to induce a Th1 response, thereby reducing mast cells and eosinophils.43 These strains are thus likely indicated for those with allergic conditions that are Th2-dominant; however, more research is needed to determine if these strains may have unwanted effects in Th1-dominant immune conditions.
Other Factors & Important Considerations
It’s important to note that other factors may impact the effect of probiotics on the immune system.
Dosing of probiotics may be impactful; for example, low-dose L acidophilus NCFM has been found to significantly increase IFN-γ (a Th1 cytokine) and downregulate T-regulatory cell responses, when compared with high doses of the same probiotic and control groups.44 High doses of the same strain have also been shown to increase the production of Tregs. Unfortunately, there is currently little information on the dose-dependent effects of probiotic strains, but this remains an area of interest for further research.
As seen above, the combination of different probiotic strains also impacts the effect of a probiotic, as does the baseline inflammatory state of the host.
Dietary factors also likely play a profound role in the immunological effects of probiotics – clearly another area for further investigation.
Although the effects of probiotics on the immune system are fascinating, the mechanisms and connections of their actions are still emerging. More research will help to clarify better probiotic and nutritional treatment strategies to benefit patients with a variety of immune and inflammatory conditions.
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