THE IMPACTS OF PROBIOTICS, PREBIOTICS AND SYNBIOTICS ON THE IMMUNE SYSTEM
There are many opportunities to support the immune system and promote health. A healthy immune system allows the body’s defense system to reduce the risk and impacts of infections due to viruses and bacteria. Health conditions such as stress (1, 2), obesity (3), and aging (4) will diminish immune responses.
Severe respiratory tract infections may be caused by bacteria and viruses such as influenza (2). Nonetheless, the risk and severity of enteritis and ventilator-associated pneumonia are reduced with beneficial changes to the gut microbiota, while probiotics can also reduce side-effects of antibiotics that may be used to treat respiratory infections (5). Azad et al. (6) noted that modulation of gut microbiota by probiotics and synbiotics may enhance immune responses. Nishihira et al. (2) stated that “Among various potential candidates, the use of probiotics is one possible way to prevent influenza virus”. Other studies suggest a role for probiotics and prebiotics for modulation of the microbial community, supporting the digestive and immune systems.
Over 70% of the immune system is located within the digestive tract. The mucosal system protects the gastrointestinal tract, urogenital tract respiratory tract, and oral-pharyngeal cavity, and has similar features and structures within these different regions of the body (6). The mucosal epithelial layer, coupled with innate and adaptive immune responses, helps to protect against pathogenic bacteria and viruses. The gut-associated lymphoid tissue (GALT) responds to antigens within the lumen, and GALT histology and function are affected by diet (7).
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Cytokines control the growth and activity of immune cells and affect the growth of blood cells that support immune and inflammatory responses within the body. Chemokines are a particular type of cytokine that direct immune cells towards a target. Examples of chemokines include growth factors, interferons, interleukins (ILs) and tumor necrosis factors (TNF). These may mediate immune responses, and may also play a role in inflammation, which may have beneficial or adverse effects.
Antibodies such as immunoglobulins play an important role in protecting against disease and infection. Antibodies will bind to particular antigens, triggering a response by other immune cells.
Immunoglobulin A (IgA) is mainly found in and secreted by mucosal tissues. IgA thus plays an important role in immune function within the intestine and respiratory tract. Release of IgA targets bacterial pathogens and viruses, preventing their binding to the epithelium and/or neutralizing toxins produced by pathogens (2, 7, 8).
Immunoglobulin G (IgG) accounts for about 75% of the antibodies in the body, and is an important biomarker supporting immune function and response. Other immunoglobulins include IgM, IgE and IgD. IgM responds quickly to infections, triggering other antibodies and immune cells such as IgG into action.
Other cells that influence immune and inflammatory responses to pathogens include Natural Killer (NK) cells and Natural Killer T (NKT) cells (8), along with up-regulation of IL-10 (anti-inflammatory) and TNF-alpha (proinflammatory) cells (6). infections and injuries to tissue cause IL-6 to be produced by monocytes and macrophages. Hepatocytes and immune competent cells are activated by IL6 to promote healing and removal of infectious agents. However, overexpression of IL-6 can lead to chronic inflammation and acute complications (9).
KEY ANTIBODIES, CYTOKINES AND CHEMOKINES
Probiotics and prebiotics can modify the gut microbial community, affecting the immune response within the body, supporting innate immunity and antipathogenic activity. Orally administered probiotics support immune function by directly or indirectly interacting with the host immune system (10, 11). However, the ability to modulate the human immune system is not universal. Impacts on the immune system, if present, are dependent upon the strain of probiotic, and metabolites produced by the probiotic or microbes induced by the probiotic (12, 13). Several probiotics have been reported to decrease proinflammatory chemokine responses in epithelial cells. However, the strain of probiotic may affect chemokine responses; the expression of certain chemokines may be reduced while others may be promoted, depending upon the strain (8). Lymphocytes are affected by short chain fatty acids produced by microbial metabolism (either from probiotics or commensal microbes induced by prebiotic consumption) (8).
Some species of probiotics improve mucosal barrier function (14). Lacticaseibacillus casei and Bifidobacterium adolescentis produce metabolites that limit expression of viral and bacterial toxins that disrupt the function and structure of tight barrier junctions during infection. Consequently, these probiotics maintain barrier function and permeability.
Probiotics can trigger the release of cytokines and chemokines, e.g. interleukins (IL), lymphocytes, tumor necrosis factor (TNF), transforming growth factor (TGF), interferons, mast cells, dendritic cells and macrophages (2, 6). For example, type 1 interferon (IFN) production and NK cell activity can be stimulated following consumption of lactic acid bacteria (LAB) (15, 16, 17). Lehtoranta et al. (18) noted improved antibody responses and antiviral cytokine responses from IL-2, IL-12, IL-18 and IFN-γ following probiotic administration. Similarly, increased natural killer cell activity and cytotoxic activity has been observed following consumption of select probiotics (19). A review of six randomized placebo-controlled clinical trials by Gui et al. (20) concluded that probiotics significantly increased NK cell activity in healthy elderly participants, although the results may be affected by the strain, dose, and heterogeneity of the studies and study participants.
Certain metabolites can stimulate the release of pro- and anti-inflammatory cytokines and molecules recognized by toll-like receptors in the intestine and by the immune system (21, 22, 23). The reduction in pH by organic acid metabolites from Lactobacilli and primary metabolites such as hydrogen peroxide may lead to direct virucidal effects (24). Metabolites produced by probiotics and commensal bacteria stimulated by prebiotics may thus have an important role in the immune response to infections.
Some probiotics may have a more direct effect on the immune response. Lactobacillus spp. that express CD4 receptors in their cell walls are suggested to directly bind to the HIV-1 pseudovirus, reducing attachment to and infection of CD4+ cells (25).
Impacts of Specific Probiotics
Various strains of Lactobacillus, Lactocaseibacillus, and Bifidobacteria have the potential to initiate expression of IL-10, IL-6 and TGF-beta, and stimulate production of immunoglobulins such as IgA.
L. acidophilus, L. plantarum , L. casei, L. lactis, L. rhamnosus, and L. bulgaricus increased the quantity of cells producing IgA within the mucosa (6). Metabolites produced by several strains of L. gasseri act on human monocytes (21), while proliferation of mononuclear cells was inhibited by B. lactis, L. acidophilus L. rhamnosus GG, and S. thermophilus (6). NK cell activity was stimulated by L. casei Shirota (LcS) and L. bulgaricus OLL1073R-1 (2).
Viral defense genes induced by L. acidophilus NCFM increased expression of interferon and induced interleukin 12 and TLR-3 (26). Stimulation of dendritic cells by a probiotic mixture consisting of S. thermophilus, L. reuteri, L. acidophilus, B. bifidium, and L. casei led to increased expression of IL-10, TGF beta, and COX-2, which combined to promote generation of CD4+FOXp3+ regulatory T-cells. Reduced expression of CD16-Cd56 NKT cells and IL-10 secretion were observed after consumption of a combination of xylo-oligosaccharide (XOS) with B. animalis. L. gasseri SBT2055 (LG2055) induced IgA production and increased the number of IgA+ cells (8). Patients with psoriasis or ulcerative colitis that consumed B. infantis 35624 saw higher levels of T-reg cells and reduced levels of proinflammatory C-reactive protein. Kynurenine is an anti-inflammatory and immunosuppressant molecule derived from tryptophan. The microbiota can modulate the tryptophan-kynurenine pathway thus affecting immune function (27, 28). L. plantarum DR7 reduced the expression of the tryptophan-kynurenine pathway in humans, while increasing the expression of the competing tryptophan-serotonin pathway (29).
L. rhamnosus GG produces Msp2 protein that sends a signal to epithelial cells in the digestive tract to produce IgA antibodies following stimulation of B cells (30).
IMPACT OF PROBIOTICS ON IMMUNITY
Several clinical trials have been conducted with probiotics and synbiotics (probiotic + prebiotic combination) to assess their effect upon respiratory tract infections, influenza, the common cold, and more recently, COVID-19.
A 12-week randomized placebo-controlled study with 272 subjects concluded that subjects consuming 1 billion CFU/d of L. plantarum HEAL9 and L. paracasei 8700:2 had a lower incidence of colds, fewer days with cold symptoms, less severe symptoms and a reduction in pharyngeal symptoms (31). This combination of probiotics can induce IL-10 and TGF-. A reduction in the number of upper respiratory tract infections and nasal symptoms was also observed in a similar 12-week randomized study conducted in 109 subjects administered 1 billion CFUs of L. plantarum DR7 or a placebo (32). L. plantarum DR7 is able to stimulate kynurenine production via the tryptophan-kynurenine pathway in humans.
The immune response of the influenza vaccine against Influenza A/H1N1 and Influenza B, was enhanced in trial subjects consuming yogurt containing L. gasseri SBT2055 (LG2055), with significantly higher antibody titers, IgG levels and IgA levels in subjects that consumed the yogurt containing LG2055 versus a control group (2).
Children consuming 5 billion CFUs/d each of B. lactis Bi-07 and L. acidophilus NCFM had less severe and shorter acute flu-like symptoms, including a 73% reduction in fever, a 62% reduction in coughing, and a 59% reduction in rhinorrhea (33). Treatment with L. acidophilus NCFM (10 billion CFUs per day) alone was also beneficial; however the combination probiotic was more effective. The benefits of the single or combination probiotic were attributed to their interactions with toll-like receptors that affect the immune response.
A combination of B. bifidum NF20-5, L. gasseri PA16-8, and B. longum SP07-3 reduced the duration and severity of respiratory tract infections in a randomized placebo controlled clinical trial in 479 healthy adults. However, the overall likelihood of acquiring an infection was not affected (21). The group that consumed probiotics had significantly higher levels of CD8+ and CD4+ cells that enhance the response of the immune system against viral infections.
A multi-year study was conducted to investigate potential benefits of synbiotic combinations on respiratory infections and influenza-like illnesses (34). In the first and second stages of the trial, subjects consuming a combination of B. lactis (Probial BS01), L. rhamnosus (Probial LR04), and L. plantarum (Probial LP02), (10 billion CFU each) plus 3 grams short chain-FOS had fewer, shorter and less severe acute and upper respiratory tract infections compared to the control group. In the third stage of the trial, similar outcomes were obtained in the group receiving B. lactis (Probial BS01), L. rhamnosus (Probial LR04), L. plantarum (Probial LP01), L. rhamnosus (Probial LR05), and L. plantarum (Probial LP02), (5 billion CFU each) plus either 2.5 g GOS (galactooligosaccharide) or 3 g short chain-FOS (fructooligosaccharide).
In a randomized 60-day study of 4,556 infants in rural India, a significant reduction in lower respiratory tract infections and cases of sepsis was observed in infants that received L. plantarum ATCC-202195 plus 150 mg of fructooligosacharide (FOS) compared to a placebo (35).
A Cochrane meta-analysis of 3,720 participants in 12 randomized trials concluded that “Probiotics were better than placebo in reducing the number of participants experiencing episodes of acute URTI, the mean duration of an episode of acute URTI, antibiotic use and cold-related school absence” (36).
Collectively, these results indicate an opportunity to reduce the incidence, severity, and duration of viral respiratory tract infections using probiotics, prebiotics and synbiotics that support the immune system.
CLINICAL STUDIES TO EVALUATE PROBIOTICS FOR RESPIRATORY TRACT INFECTIONS
COVID-19 binds to angiotensin-converting enzyme 2 (ACE2) receptors found in the lungs and small intestinal epithelial cells. (5, 37). Furthermore, Gao et al. (and others) (5) report some incidence of digestive symptoms in people with COVID-19, and detection of nucleic acids from COVID-19 in the stool suggests respiratory and gastrointestinal crosstalk (37).
Thevarajan et al. (38) reported that activation of CD4+ and CD8+ Tcells and IgM and IgG antibodies in a patient hospitalized with COVID19 preceded resolution of symptoms. These immune parameters may be key to disease outcome and evaluation of interventions to minimize disease severity.
Recent clinical trials have provided promising evidence of benefits from use of probiotics with COVID-19. Gutierrez-Castrellon et al. (39) completed a randomized, quadruple-blinded RCT in adult symptomatic COVID-19 outpatients. Patients received with either a placebo or a 2 x 109 CFU mixture of probiotic strains (L. plantarum strains KABP022, KABP023 and KABP033, plus Pediococcus acidilactici KABP021). Compared to the placebo, probiotic supplementation reduced nasopharyngeal viral load, lung infiltrates, and the duration of digestive and non-digestive symptoms. Probiotic supplementation increased specific IgM and IgG antibodies against SARS-COV2, but there was no apparent change in the composition of the fecal microbiota. These observations suggest that the probiotic formula acts by supporting the immune system, rather than modification of the microbial community.
Wischmeyer et al. (40) conducted a study to assess if L. rhamnosus GG (LGG), taken prophylactically, could prevent, delay, or reduce the severity of COVID-19 in individuals that were exposed to the virus via a household contact. The study results indicate that individuals consuming LGG were less likely to develop symptoms compared to those receiving the placebo. Furthermore, there was a statistically significant reduction in COVID-19 infection via a time-to-event analysis. Individuals consuming the probiotic had greater levels of L. rhamnosus GG in their stool, and the b-diversity of the stool microbiota was also affected by probiotic consumption.
Researchers have thus shown that specific probiotic strains can specifically enhance immune system components that support the immune response against COVID-19, reducing the incidence and severity of symptoms, while also reducing the viral load. Furthermore, probiotics may reduce the risk for secondary infections and the side effects of treatment (5).
LINK TO COVID-19
Sandra Saville is the Director of Education and Communication for the International Probiotics Association (IPA), liaising with health care professionals, and educating about the benefits of probiotics.
As a Registered Dietitian, Sandra has diverse expertise in food, nutrition and health. Sandra has been extensively involved in research and education about the microbiome, prebiotics, and probiotics to health care professionals, consumers and industry. Sandra is also the co-founder of two prebiotic companies, Prenexus Health and Greensage Prebiotics, and is the President of Microbiome Experts Inc. and Saville Nutrition Consulting.
About IPA: The International Probiotics Association (IPA) is a global non-profit organization that promotes the safe and efficacious use of probiotics throughout the world. Holding NGO status before Codex Alimentarius, the IPA is also recognized as the unified Global Voice of Probiotics® around the world. To learn more about IPA, visit https://internationalprobiotics.org/.
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