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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


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.


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.

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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 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.

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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.


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.


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

Shida et al (2006) Essential roles of monocytes in stimulating human peripheral blood mononuclear cells with Lactobacillus casei to produce cytokines and augment natural killer cell activity

Hashimoto e al (1986 )The role of superoxide anion and lysosomal enzymes in anti-listerial activity of elicited peritoneal macrophages

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

Ho et al (2005). Intragastric administration of Lactobacillus casei expressing transmissible gastroenteritis coronavirus spike glycoprotein induced specific antibody production

Cross et al (2004). Patterns of cytokine induction by gram-positive and gram-negative probiotic bacteria

Miake et al (1985) Protective effect of Lactobacillus casei on Pseudomonas aeruginosa infection in mice

Nomoto et al (1985) Augmentation of host resistance to Listeria monocytogenes infection by Lactobacillus casei

Ezendam & van Loveren (2008) Lactobacillus casei Shirota administered during lactation increases the duration of autoimmunity in rats and enhances lung inflammation in mice

Nomoto et al (1992) Prevention of indigenous infection of mice with Escherichia coli by nonspecific immunostimulation

De Waard et al (2001) Enhanced antigen-specific delayed-type hypersensitivity and immunoglobulin G2b responses after oral administration of viable Lactobacillus casei YIT9029 in Wistar and Brown Norway Rats

Nomoto et al (1992). Prevention of 5-fluorouracil-induced infection with indigenous Escherichia coli in tumor-bearing mice by nonspecific immunostimulation

Furuse et al (1997) Acceleration of granulocytic cell recovery in irradiated mice by a single subcutaneous injection of a heat-killed Lactobacillus casei preparation

Setoyama et al (1985) Protective effect of lipoteichoic acid from Lactobacillus casei and Lactobacillus fermentum against Pseudomonas aeruginosa in mice

Nagao et al (2000) Effects of a fermented milk drink containing Lactobacillus casei strain Shirota on the immune system in healthy subjects.

Hashimoto et al (1984). Oxygen radical production by peritoneal macrophages and Kupffer cells elicited with Lactobacillus casei.

Hashimoto et al (1987) In vitro and in vivo release of cytostatic factors from Lactobacillus casei-elicited peritoneal macrophages after stimulation with tumor cells and immunostimulants.

Hayatsu & Hayatsu (1993) Suppressing effect of Lactobacillus casei administration on the urinary mutagenicity arising from ingestion of fried ground beef in the human

Hashimoto et al (1985) Cytotoxic factor production by Kupffer cells elicited with Lactobacillus casei and Corynebacterium parvum

Kato et al (1981) Antitumor activity of Lactobacillus casei in mice

Kato et al (1983) Macrophage activation by Lactobacillus casei in mice

Kato et al (1994) Effect of oral administration of Lactobacillus casei on antitumor responses induced by tumor resection in mice

Kato et al (1984) Augmentation of mouse natural killer cell activity by Lactobacillus casei and its surface antigens

Kato et al (1985) Induction of tumoricidal peritoneal exudate cells by administration of Lactobacillus casei.

Kato et al (1999) Lactic acid bacterium potently induces the production of interleukin-12 and interferon-gamma by mouse splenocytes

Kato et al (1999) Lactic acid bacterium potently induces the production of interleukin-12 and interferon-gamma by mouse splenocytes

Kato et al (1988) Correlation between increase in Ia-bearing macrophages and induction of T cell-dependent antitumour activity by Lactobacillus casei in mice

Matsuzaki et al (1996) Effects on antitumor activity and cytokine production in the thoracic cavity by intrapleural administration of Lactobacillus casei in tumor bearing mice

Kirjavainen et al (1999) The effect of orally administered viable probiotic and dairy lactobacillis on mouse lymphocyte proliferation

Matsuzaki et al (1997) Effect of oral administration of Lactobacillus casei on alloxan-induced diabetes in mice

Matsuzaki T (1998) Immunomodulation by treatment with Lactobacillus casei strain Shirota

Matsuzaki et al (1997) Prevention of onset in an insulin-dependent diabetes mellitus model, NOD mice, by oral feeding of Lactobacillus casei

Matsuzaki et al (1990) Augmentation of antimetastatic effect on Lewis lung carcinoma (3LL) in C57BL/6 mice by priming with Lactobacillus casei.

Matsuzaki et al (1997) Antidiabetic effects of an oral administration of Lactobacillus casei in a non-insulin-dependent diabetes mellitus (NIDDM) model using KK-Ay mice.

Matsuzaki et al (1998) The effect of oral feeding of Lactobacillus casei strain Shirota on immunoglobulin E production in mice

Matsuzaki et al (1987) Antimetastatic effect of Lactobacillus casei YIT9018 (LC9018) on a highly metastatic variant of B16 melanoma in C57BL/6J mice

Matsuzaki et al (1988) Antitumor effect of intrapleural administration of Lactobacillus casei in mice.

Nanno et al (1988). Role of macrophages in serum colony-stimulating factor induction by Lactobacillus casei in mice

Matsuzaki et al (1988) The role of lymph node cells in the inhibition of metastasis by subcutaneous injection of Lactobacillus casei in mice

Nanno et al (1989) Increased production of cytotoxic macrophage progenitors by Lactobacillus casei in mice

Matsuzaki et al (1985) Anti-tumour activity of Lactobacillus casei on Lewis lung carcinoma and line-10 hepatoma in syngenic mice and guinea pigs

Paubert-Braquet et al (1995) Enhancement of host resistance against Salmonella typhimurium in mice fed a diet supplemented with yogurt or milks fermented with various Lactobacillus casei strains

Pouwels et al (1996) The potential of Lactobacillus as a carrier for oral immunization: Development and preliminary characterization of vector systems for targeted delivery of antigens

Sakagami et al (1992) Distribution of TNF endogenously induced by various immunopotentiators and Lactobacillus casei in mice

Sawamura et al (1994) The enhancing effect of oral Lactobacillus casei on the immunologic activity of colon cancer patients

Shimizu et al (1988) Usefulness of priming of hosts with LC 9018 in the LC 9018 immunotherapy system

Okawa et al (1989) Phase II randomized clinical trial of LC9018 concurrently used with radiation in the treatment of carcinoma of the uterine cervix: Its effect on tumor reduction and histology

Shinomiya N & Kuratsuji T (1989) The reinforcement of host defense mechanisms by Lactobacillus casei YIT9018 (LC9018) part 1: augmentation of immunological reaction on human mononuclear cells

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

Yokokura et al (1986) Enhancement of hematopoietic response of mice by subcutaneous administration of Lactobacillus casei

Takagi al (1999) Inhibitory effect of oral administration of Lactobacillus casei on 3-methylcholanthren-induced carcinogenesis in mice

You & Yaqoob (2012) Evidence of immunomodulatory effects of a novel probiotic, Bifidobacterium longum bv. infantis CCUG 524866

Paszti-Gere (2012) Metabolites of Lactobacillus plantarum 2142 prevent oxidative stress-induced overexpression of proinflammatory cytokines in IPEC-J2 cell line

Dong H et al (2013) Immunomodulatory effects of a probiotic drink containing Lactobacillus casei Shirota in healthy older volunteers

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

Hailesalassie Y et al (2013) Lactobacilli regulate Staphylococcus aureus 161:2-induced pro-inflammatory T-cell responses in vitro.

Widuri & Suryani (2013) Effect of probiotic Lactobacillus casei L. shirota strain in patients with allergic rhinitis symptoms

You J et al (2014) Probiotic modulation of dendritic cell function is influenced by ageing.

Yasutake et al (1984) Host-mediated antitumor activity of Lactobacillus casei in mice

Jeon SG et al (2012) Probiotic Bifidobacterium breve induces IL-10-producing Tr1 cells in the colon.

Yasutake et al (1984) Comparison of antitumor activity of Lactobacillus casei with other bacterial immunopotentiators

Habil N et al (2014) Heat-killed probiotic bacteria differentially regulate colonic epithelial cell production of human beta-defensin-2: dependence on inflammatory cytokines

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

Yokokura T (1994) Antitumor and immuno-stimulating activities of Lactobacillus casei

Braga TD et al (2011) Efficacy of Bifidobacterium breve and Lactobacillus casei oral supplementation on necrotizing enterocolitis in very-low-birth-weight preterm infants: a double-blind, randomized, controlled trial

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.

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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