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LcS Research | IMMUNE SYSTEM

Probiotic immune modulation is considered to be strain specific: i.e. an effect seen with one strain may not be the same for another strain, even if of the same genus or species.

A broad portfolio of in vitro and model studies have revealed at molecular and cellular levels, how Lactobacillus casei Shirota (LcS) is able to beneficially interact with the immune system. For example:

  • A recent review by Shida et al (2011) summarises data showing that the cell wall of LcS is responsible for induction of IL-12 (a cytokine important for anti-infection, stimulating T helper 1 cell development and activating natural killer cells)
  • L. casei Shirota differentially controls the inflammatory cytokine responses of macrophages and T cells in either Peyer's patches or the spleen (Chiba et al 2010; Habil et al 2012)
  • L. casei Shirota-induced IL-12 production by macrophages is modified when other bacteria or their cell components were also present (Kaji et al 2010)
  • Human intervention studies have also investigated if there are positive clinical outcomes associated with these immune modulatory effects (e.g. reduction of colds, benefit for IBD and necrotising enterocolitis)

Investigations in Japan, the UK and other countries continue to reveal more about these complex immune interactions.

Natural killer cell activity

Natural killer (NK) cells are large lymphocytes lacking antigen-specific receptors that are part of the innate immune system. Circulating in the blood, they target and kill abnormal cells such as certain tumour cells and viral-infected cells. For example, an 11-year retrospective study of a general population showed that medium and high cytotoxic activity of peripheral blood lymphocytes was associated with reduced cancer risk, whereas low activity was associated with increased cancer risk (Imai et al 2000). A more recent study found, among other changes, that there was reduced NK cytotoxic activity in cervical cancer and precursor lesions (Garcia-Inglesias et al 2009).

NK cell activity is one aspect of the immune response that may suffer transient depression as a result of lifestyle or other factors. A recent study showed obese subjects have impaired NK cell activity and are more susceptible to the detrimental effects of cigarette smoke compared to lean subjects; perhaps this is one explanation for the increase of cancer and infection seen for such people (O'Shea et al 2010; Hogan et al 2011).

Human studies with L. casei Shirota show that consumption of this strain is associated with maintenance of NK activity.

Reale M et al (2011)

Daily Lactobacillus casei Shirota intake increases natural killer cell activity in smokers. Br J Nutrition 108(2):308-314.

View the Study

METHOD

This double-blind, placebo-controlled, randomised study involved 72 healthy Italian blue collar male smokers: for three weeks, half the subjects were given L. casei Shirota, and the other half given a placebo. Baseline and post-consumption samples of peripheral blood mononuclear cells were taken in order to measure NK activity and CD16+ lymphocytes (the latter indicates induction of cytotoxic activity of NK and other immune cells). Before intake, NK cytotoxic activity had an inverse correlation with the number of cigarettes smoked.

RESULT

L. casei Shirota intake was associated with significant increase in NK cytotoxic activity as well as an increase in CD16+ cells (both P less than 0.001). These effects indicate that the probiotic helped to maintain NK activity, which would otherwise have been reduced due to cigarette smoking.

Salivary IgA

If the immune response is not functioning at maximum efficiency, this increases susceptibility to common infectious diseases. It is well known, for example, that the immune response becomes weakened in older people (Gomez et al 2008); chronic illness can also have a negative effect on the immune system. Psychological (Cohen et al 1991) and physical stress (Gleeson 2007) can cause transient immune depression, which has been linked to an increase in episodes of the common cold.

The mucosal antibody, salivary IgA, is important in protecting against upper respiratory tract infections. Athletes, for example, can have low levels of sIgA due to their intense level of exercise and this has been linked to their increased risk of respiratory illness (Gleeson et al 2000). Studies conducted with L. casei Shirota in athletes have shown that consumption of this probiotic can help maintain salivary IgA levels, and thus reduce incidence of colds.

Gleeson M et al (2011)

Daily probiotic's (Lactobacillus casei Shirota) reduction of infection incidence in athletes. Int J Sport Nutr Exercise Metab 21:55-64.

View the Study

METHOD

This double-blind, placebo-controlled study conducted at Loughborough University, randomised 84 healthy adults engaged in regular sports training (mainly running, cycling, swimming, triathlons, team games and racquet sports) to take a probiotic fermented milk drink (L. casei Shirota) or placebo for 16 weeks. At baseline, 8 and 16 weeks, resting blood and saliva samples were tested for a range of immune parameters: immunoglobulins, cell counts and cytokines. The subjects kept weekly records of their training and any illness, and were required to maintain a minimum level of training.

RESULTS The main finding from the immune analysis, was that after 8 and 16 weeks of intervention, salivary IgA concentrations were higher in the probiotic group compared to the placebo group (P = 0.03). Associated with this was evidence of health benefit.

Analysis of those completing the full 16 weeks of the study (n = 58):

Endpoint LcS group Placebo group P (less than)
Mean number URTI episodes 1.2 ± 1.0 2.1 ± 1.2 l0.01
Mean number of URTI symptom weeks 1.9 ± 1.5 3.5 ± 2.0 l0.01
Proportion of weeks with URTI episodes 0.12 0.23 0.001
Proportion of weeks taking medication 0.10 0.17 0.01
Proportion/ training impaired during URTI 0.54 0.81 0.036

Allergy

Allergy affects approximately 25% of the UK population at some time of their lives, with children representing up to 50% of those affected. Numbers of sufferers are increasing each year. Reduced exposure to microbial allergens in early childhood (the hygiene hypothesis) has been proposed as one factor to explain this.

The allergic response results from an imbalance of Th1:Th2 cells, causing an overreaction to normally harmless substances resulting in symptoms such as rhinitis, eczema, asthma etc. An aberrant intestinal microbiota has been shown for infants with allergies, with higher numbers of clostridia, fewer bifidobacteria and with species more typical of those in adults.

There has been probiotic research in this area, with many studies focussing on modulation of the immune system in early childhood. Studies have been conducted with Lactobacillus casei Shirota, investigating effects on adults with allergic rhinitis, mainly investigating downregulation of the immune response, as shown in the UK study conducted by Ivory et al (2008) below.

It is important to note that benefits associated with immune changes can only be properly determined by studies that also look at clinical changes. One study  with L. casei Shirota investigated its effect on symptoms of people with allergic rhinitis induced by Japanese cedar pollen. No benefit was shown overall but a sub-group of people with moderate to severe nasal symptom scores did show a tendency for alleviation of symptoms that was associated with the L. casei Shirota intervention (Tamura et al 2007).

Ivory K et al (2008)

Oral delivery of Lactobacillus casei Shirota modifies allergen-induced immune responses in allergic rhinitis. Clinical & Experimental Allergy 38(8):1282-9.

View the Study

METHOD

In a double-blind, placebo-controlled pilot study, healthy seasonal allergic rhinitis sufferers (SAR; n=20) consumed a daily probiotic drink containing a minimum of 6.5 x 109 L. casei Shirota (LcS) or a placebo drink for five months. Fasting blood samples were taken pre-, peak- and post- grass pollen season for analysis of total plasma IgE, and levels of IgE and IgG specific for grass pollen antigens (GX1 and GX2). In addition, cytokine expression was analysed in the presence or absence of the same grass pollen antigens.

RESULTS

Oral administration of LcS resulted in modification of the allergen-specific response in SAR. Significantly lower levels of allergen-induced cytokines (IL-5, IL-6 and IFN-γ) were found in the probiotic group compared with the control group (P less than 0.05). In addition, levels of specific IgG increased and IgE decreased in the LcS.

CONCLUSIONS

The authors concluded that L. casei Shirota supplementation was associated with a down-regulation of both Th1- and Th2-type cytokines induced by seasonal allergic rhinitis, and a shift in the balance of pollen-specific IgG and IgE levels.

Available Papers

Gleeson et al (2011) Daily probiotic’s (Lactobacillus casei Shirota) reduction of infection incidence in athletes


Shida et al (2011) Flexible cytokine production by macrophages and T cells in response to probiotic bacteria


Reale et al (2011) Daily intake of Lactobacillus casei Shirota increases natural killer cell activity in smokers


Stadlbauer et al (2008) Effect of probiotic treatment on deranged neutrophil function and cytokine responses in patients with compensated alcoholic cirrhosis


Habil et al (2012) Lactobacillus casei strain Shirota selectively modulates macrophage subset cytokine production


Gleeson (2008) The effect of 14 days supplementation with Yakult probiotic on circulating hormonal, leukocyte, and cytokine responses to prolonged cycling in man


Dong et al (2010) Selective effects of Lactobacillus casei Shirota on T cell activation, natural killer cell activity and cytokine production


Chiba et al (2010) Well-controlled proinflammatory cytokine responses of Peyer’s patch cells to probiotic Lactobacillus casei.


O'Connell et al (2010) A pilot study investigating the effects of yakult fermented milk drink (L. casei Shirota) on salivary IFN-gamma, sIgA, IgA1 and IgA2 in healthy volunteers.


Mitsuyama et al (2008) Beneficial effects of Lactobacillus casei in ulcerative colitis: a pilot study


Kobayashi et al (2010) Oral administration of probiotic bacteria, Lactobacillus casei and Bifidobacterium breve, does not exacerbate neurological symptoms in experimental autoimmune encephalomyelitis. I


Shida et al (2009) Induction of interleukin-12 by Lactobacillus strains having a rigid cell wall resistant to intracellular digestion.


Ivory et al (2008) Oral delivery of Lactobacillus casei Shirota modifies allergen-induced immune responses in allergic rhinitis


Yasuda et al (2011) Lectin microarray reveals binding profiles of Lactobacillus casei strains in a comprehensive analysis of bacterial cell wall polysaccharides


Zarfeshan et al (2011) Effect of Lactobacillus casei on the production of pro-inflammatory markers in streptozotocin-induced diabetic rats


Van Puyenbroeck et al (2012) Efficacy of daily intake of Lactobacillus casei Shirota on respiratory symptoms and influenza vaccination immune response: a randomized double-blind, placebo-controlled trial in healthy elderly nursing home residents


Dong et al (2011) Comparative effects of six probiotic strains on immune function in vivo.


Matsumoto et al (2009) A component of polysaccharide peptidoglycan complex on Lactobacillus induced an improvement of murine model of inflammatory bowel disease and colitis-associated cancer


Kaji et al (2010) Bacterial teichoic acids reverse predominant IL-12 production induced by certain Lactobacillus strains into predominant IL-10 production via TLR2-dependent ERK activation in macrophages


Martinez-Gomez et al (2009) Effect of Lactobacillus casei Shirota strain intraperitoneal administration in CD1 mice on the establishment of Trichinella spiralis adult worms and on IgA anti-T. spiralis production


Thomas & Versalovic (2010) Probiotics-host communication. Modulation of signaling pathways in the intestine


Staab et al (2009) The influence of a probiotic milk drink on the development of gingivitis: a pilot study


Matsumoto (2008) Anti-inflammatory effects of probiotic Lactobacillus casei strain Shirota in chronic intestinal inflammatory disorders


Fujimori et al (2007) High dose probiotic and prebiotic co-therapy for remission induction of active Crohn’s disease


Seifert et al (2011) Probiotic Lactobacillus casei Shirota supplementation does not modulate immunity in healthy men with reduced natural killer cell activity


Lim et al (2009) The effects of heat-killed wild-type Lactobacillus casei Shirota on allergic immune responses in an allergy mouse model


De Jonge et al (2008) Lactobacillus casei Shirota does not decrease the food allergic response to peanut extract in Brown Norway rats


Snel et al (2011) Strain-specific immunomodulatory effects of Lactobacillus plantarum strains on birch-pollen-allergic subjects out of season


Massen & Claassen (2008) Strain-dependent effects of probiotic lactobacilli on EAE autoimmunity


Shida & Nanno (2008) Probiotics and immunology: separating the wheat from the chaff


De Waard et al (2003) Enhanced immunological memory responses to Listeria monocytogenes in rodents, as measured by delayed-type hypersensitivity (DTH), adoptive transfer of DTH, and protective immunity, following Lactobacillus casei Shirota ingestion


Takagi et al (2008) The relationship between the in vitro response of dendritic cells to Lactobacillus and prevention of tumourigenesis in the mouse


De Waard et al (2002) Antagonistic activity of Lactobacillus casei strain Shirota against gastrointestinal Listeria monocytogenes infection in rats


Yasuda et al (2008) Suppressive effect on activation of macrophages by Lactobacillus casei strain Shirota genes determining the synthesis of cell wall-associated polysaccharides


Takeda & Okumura (2007) Effects of a fermented milk drink containing Lactobacillus casei strain Shirota on the human NK-cell activity


Matsuzaki et al (2004) Antitumour activity and action mechanisms of Lactobacillus casei through the regulation of immune responses


Tamura et al (2007) Effects of probiotics on allergic rhinitis induced by Japanese cedar pollen: randomized double-blind, placebo-controlled clinical trial


Morimoto et al (2005) Modulation of natural killer cell activity by supplementation of fermented milk containing Lactobacillus casei in smokers


Kobayashi et al (2012) Probiotic upregulation of peripheral IL-17 responses does not exacerbate neurological symptoms in experimental autoimmune encephalomyelitis mouse models.


Meijerink et al (2012) Immunmodulatory effects of potential probiotics in a mouse peanut sensitization model


Ogawa et al (2001) Inhibition of in vitro growth of Shiga toxin-producing Escherichia coli O157: H7 by probiotic Lactobacillus strains due to production of lactic acid


Ogawa et al (2001) Protective effect of Lactobacillus casei strain Shirota on Shiga toxin-producing Escherichia coli O157: H7 infection in infant rabbits


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Takeda et al (2006) Interleukin-12 is involved in the enhancement of human natural killer cell activity by Lactobacillus casei Shirota


Herias et al (2005). Probiotic effects of Lactobacillus casei on DSS-induced ulcerative colitis in mice


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Mann ER et al (2013) Dysregulated circulating dendritic cell function in ulcerative colitis is partially restored by probiotic strain Lactobacillus casei Shirota


Ivory K, et al (2013) Oral delivery of a probiotic induced changes at the nasal mucosa of seasonal allergic rhinitis subjects after local allergen challenge: A randomised clinical trial


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Yasutake et al (1985). Anti-tumour effect of humoral and cellular immunities mediated by a bacterial immunopotentiator, Lactobacillus casei, in mice


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Mann ER et al (2014) Human gut dendritic cells drive aberrant gut-specific T-cell responses in ulcerative colitis, characterized by increased IL-4 production and loss of IL-22 and IFN-gamma.


Pang & Shaopeng (2013) Immune modulatory mechanisms of Yakult in prevention of colitis-associated colorectal cancer


Kaya MS et al (2014) In case of obesity, longevity-related mechanisms lead to anti-inflammation


Kawakami et al (2009) p-Cresol inhibits IL-12 production by murine macrophages stimulated with bacterial immunostimulant


Falasca K et al (2015) Effect of probiotic supplement on cytokine levels in HIV-infected individuals: a preliminary study.


Shida K et al (2015) Daily fermented milk with Lactobacillus casei strain Shirota reduces the incidence and duration of upper respiratory tract infections in healthy middle-aged office workers


Yokoyama Y et al (2014) Randomized clinical trial of the effect of perioperative synbiotics versus no synbiotics on bacterial translocation after oesophagectomy.


Nissen et al (2009) Gut health promoting activity of new putative probiotic/protective Lactobacillus spp. strains: A functional study in the small intestinal cell model.


Gleeson et al (2016) Effects of Lactobacillus casei Shirota ingestion on common cold infection and herpes virus antibodies in endurance athletes: a placebo-controlled, randomized trial.


Kato-Katoaka et al (2016) Fermented milk containing Lactobacillus casei strain Shirota prevents the onset of physical symptoms in medical students under academic examination stress


Nanno et al (2008) Effect of oral administration Lactobacillus casei Shirota on experimental autoimmune encephalomyelitis in rats


Sugawara et al (2006) Perioperative synbiotic treatment to prevent postoperative infectious complications in biliary cancer surgery: A randomized controlled trial


Asahara et al (2003) Assessment of safety of Lactobacillus strains based on resistance to host innate defense


Matsuguchi et al (2003) Lipoteichoic acid from Lactobacillus strains elicit strong tumor necrosis factor alpha-inducing activities in macrophages through Toll-like receptor 2


Hashimoto et al (1989) Role of culture supernatant of cytotoxic/cytostatic macrophages in activation of murine resident peritoneal macrophages


Kato et al (1998) Suppressive effects of the oral administration of Lactobacillus casei on type II collagen-induced arthritis in DBA/1 mice


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