An Innate Immune Shield Against Colds and Flu

If ever there were a perfect name for a malady, it’s the ‘common cold.’ Common indeed—upper respiratory tract infections are the most common infectious illness in the US, and the leading reason for missing work or school.¹ Acute bronchitis—is close behind.² About 5% of adults and 6% of children have at least one episode of acute bronchitis each year.³ The diagnosis of acute bronchitis should be made only when there is no clinical or radiographic evidence of pneumonia, and the common cold, acute asthma, or an exacerbation of COPD have been ruled out as the cause of cough.  Finally, add influenza, which can afflict up to 20% of the population in a given year and you can see that many people suffer.⁴

Usually, where colds are concerned, one just has to tough it out for a week or ten days, until the immune system has crafted exquisitely specific antibodies to lock firmly onto and vanquish that particular virus. Acute bronchitis can last several weeks. Flu can be so severe it leads to hospitalization and death.⁵ Preventing colds and flus is an ideal approach, and an impressive body of new research on the beneficial organism, Lactobacillus plantarum, suggests that one strain in particular, L-137, can be surprisingly protective against these viruses. In fact, effective strains don’t even need to be alive. Beneficial bacteria can transfer health benefits simply by virtue of the signaling molecules on their surface. These molecules “cross talk,” or communicate with pattern recognition receptors (PRRs) on the mucosal cells of our digestive tract. It is the signaling back and forth that regulates our immune system, and the molecules themselves carry the signal, whether they are part of a living organism or not.⁶

A lactobacillus-mediated innate immune shield…may ultimately serve as critical and long-term protection against infection in the absence of specific antiviral vaccines.

Beneficial bacteria or probiotics that have been heat-shocked or broken up are often referred to as immunobiotics.⁷ The term was first coined in 2003, by Australian immunologist Robert Clancy, a pioneer in the field of mucosal immunology. Clancy and his team’s groundbreaking work discovered a powerful correlation between the gut and the lung, and showed that one could create immunity against infection in the respiratory tract by stimulating the gut immune system.⁸ Immunobiotics, says Clancy, have both local and distant effects. A local effect might be reducing recurrent ear infections in children via intranasal application of specific strains of bacteria.⁹ A distant effect might be protection against bronchial infection through oral administration of particular strains of lactobacilli.¹⁰

In a series of studies beginning nearly thirty years ago, lead scientist Yasunobo Yoshikai and his colleagues at the Research Center for Infectious Diseases and the Medical Institute of Bioregulation at Kyushu University in Fukuoka, Japan, began investigating the immune boosting effects of heat-killed Lactobacillus plantarum L-137 (henceforth HK-LP-137). This is a strain of lactic acid bacteria isolated from a traditional Asian fermented fish and rice dish.

When treated with a proprietary heat process, the live bacteria are killed and their broken cell wall actually potentiates their immune characteristics, because the molecules on the lipid surface layers of the bacteria are freed to be exposed to the immune system. A study of HK-LP-137 found that it was more potent than live L-137. In simulated digestive juices in the laboratory, HK-LP-137 stimulated mouse spleen cells to produce more Interleukin-12 (IL-12) than unheated L-137. HK-LP-137 was also more protective than its unheated, live counterpart in a mouse model of colitis.¹¹ In addition, HK-LP-137 is stable, and does not lose potency the way live probiotics may.

Heat killed Lactobacillus plantarum was more protective than its unheated, live counterpart.

Both randomized and targeted studies have shown that HK-LP-137 can both prevent upper respiratory tract infections and ameliorate symptoms when they do occur.

The teams’ research began in mice. Yoshikai’s team showed that HK-LP-137 was a potent inducer of IL-12 production, which leads to a T helper (Th) 1-type immune response and subsequent anti-allergic or anti-tumor effects. The researchers fed a special strain of mice a casein diet, which resulted in the mice producing anti-casein IgE antibodies. When they were then treated with HK-LP-137, their IgE antibodies decreased and their interleukin 12 increased.¹² IL-12 is a molecule produced mostly by the immune system mainly in response to bacteria and parasites.¹³ It suppresses IgE production, and IgE specific for dietary protein plays an important role in modulating tolerance.

The group then looked at HK-LP-137 for its anti-tumor effect in mice. Daily injection of L. plantarum L-137 from the 7th day after tumor inoculation exerted a marked antitumor effect, but not if given on the first day, and not if given only twice a week. The researchers concluded that HK-LP-137 exerts an anti-tumor effect at the late stages of tumor development, when IL-12 production is considerably impaired.¹⁴

Armed with these animal studies—and their proof of concept—the scientists moved on to humans. In 2006, they published evidence that ingesting HK-LP-137 daily improved immunity in healthy adults. Sixty healthy men and women were randomly assigned a capsule daily containing either 10 mg of HK-LP-137 daily, or a placebo. Natural killer cells, neutrophil activity, the proliferative response of T-cells,the activity of monocytes and other biomarkers of inante immunity were measured at the outset and every four weeks for twelve weeks. At the same time, biomarkers for acquired immunity such as Th1:Th2 ratio and the serum IgG4:IgG ratio, were measured. evidence of acquired immunity was also measured. Many of the immune markers improved, suggesting that daily intake of HK-LP-137 enhanced immunity. The proliferative response of T cells was considerably augmented by HK-LP-137. The specificity of this strain’s effect—greater than other strains of Lactobacillus plantarum—may be due to the expression of Lipoteichoic acid (LTA) on its cell surface. LTA is a major immunostimulatory component of Gram-positive bacteria, and induces IL-12.¹⁵ The researchers concluded, “Our results suggest that intake of HK-LP-137 may be useful for prevention and treatment of infectious and some allergic diseases induced by a weak Th1-type immune response.”¹⁶

Zeroing in on Colds and Flu

With strong evidence in mice and humans that HK-LP-137 boosts immunity in measurable and recognizable ways, the researchers zeroed in on colds and flus. Following a rigorous and precise research protocol, they first went back to mice and gave them HK-LP-137 while infecting them intranasally with an influenza virus strain adapted to mice. Survival time was significantly prolonged in treated mice, and viral titers in the lung were significantly lower. An appreciable level of interferon (IFN)-β was detected in the serum of mice treated with HK-LP, while no IFN-β was detected in controls after influenza infection.

Yoshikai and his team then examined the effect of HK-LP-137 on IFN-β in humans. Sixteen individuals were randomly assigned to receive a capsule of either 10 mg of HK-LP-137 or a placebo for eight weeks. An inactivated influenza vaccine was then given in two doses, and both groups had similar antibody responses and titers. However, levels of IFN-β were significantly higher in the HK-LP-137 group than in the control group. The group also looked at IFN-β in the blood cells of pigs fed HK-LP-137; their levels of IFN-β were also higher.¹⁷

The incidence of upper respiratory tract infections was significantly lower in the group taking heat-killed Lactobacillus platarum 137 than in the control group.

Finally, they demonstrated efficacy against colds and flus in humans. In a 2012 study, they found that HK-LP-137 protected against upper respiratory tract infections in healthy individuals under high psychological stress. Psychological stress is strongly correlated with an increased risk of acute infectious respiratory illness.^18,19 A randomized, double-blind, placebo-controlled, study was conducted in seventy-eight healthy adults (thirty-three men and forty-five women) with high scores on eighteen-item subscales of psychological distress in the Brief Job Stress Questionnaire. They received either HK-LP-137 or a placebo for 12 weeks. Their upper respiratory symptoms were rated daily on the Wisconsin Upper Respiratory Symptom Survey-21. Every four weeks their blood was drawn and serum IFN-β, IL-4 and other markers of immune function were measured. The incidence of upper respiratory tract infections (URTI) was significantly lower in the HK-LP-137 group than in the control group. URTI incidence, duration and severity, and duration of medication were also significantly lower in those receiving HK-LP-137.²⁰

Recent research by Helene F. Rosenberg and her team at the National Institutes of Health complements the Yoshikai team’s thirty years of fine-tuned and meticulous work. “The inflammatory response to respiratory virus infection can be complex and refractory to standard therapy,” writes Rosenberg in a 2011 study. “Lactobacilli, when targeted to the respiratory epithelium, are highly effective at suppressing virus-induced inflammation and protecting against lethal disease…[they function] as an effective Lactobacillus-mediated innate immune shield, which may ultimately serve as critical and long-term protection against infection in the absence of specific antiviral vaccines.”²¹

References:

1. Cherry DK, Hing E, Woodwell DA, Rechtsteiner EA. National Ambulatory Medical Care Survey: 2006 Summary. Hyattsville, MD: National Center for Health Statistics; 2008. Natl Health Stat Report 2008Aug 6;(3):1-39. PMID: 18972720 View Abstract
2. Braman, SS (January 2006). “Chronic cough due to acute bronchitis: ACCP evidence-based clinical practice guidelines.”. Chest 129 (1 Suppl): 95S–103S. PMID: 16428698 View Abstract
3. Wenzel, RP; Fowler AA, 3rd (16 November 2006). “Clinical practice. Acute bronchitis.” N Engl J Med. 2006 Nov 16;355(20):2125-30. PMID: 17108344 View Abstract
4. http://www.webmd.com/cold-and-flu/flu-statistics
5. https://www.cdc.gov/flu/about/burden/index.html 
6. Lebeer S, Vanderleyden J, De Keersmaecker SCJ. Host interactions of probiotic bacterial surface molecules: comparison with commensals and pathogens. Nature Reviews Microbiology 2010 Mar 8;(3), 171-84 . PMID: 20157338 View Abstract
7. Clancy R. Immunobiotics and the probiotic evolution. FEMS Immunol Med Microbiol. 2003 Aug 18;38(1):9-12. PMID: 12900049 View Abstract
8. Clancy, R. L. (2012), Towards a vaccine for chronic obstructive pulmonary disease. Internal Medicine Journal, 42: 607–13. PMID: 22372964 View Abstract
9. Roos K., Hakansson E.G., Holm S. (2001) Effect of recolonization with ‘interfering’α streptococci on recurrences of acute and secretory otitis media in children: randomised placebo controlled trial. Br. Med. J. 2001 Jan 27;322(7280):1210-2. PMID: 11159619 View Abstract
10. Kalliomäki M., Salminen S., Arvilommi H., et al. (2001) Probiotics in primary prevention of atopic disease: a randomized placebo-controlled trial. Lancet 2001 Apr 7;357(9262); 1076–9. PMID: 11297958 View Abstract
11. Fujiki T, Hirose Y, Yamamoto Y, Murosaki S. Enhanced immunomodulatory activity and stability in simulated digestive juices of Lactobacillus plantarum L-137 by heat treatment.Biosci Biotechnol Biochem. 2012;76(5):918-22. PMID: 22738959 View Abstract
12. Murosaki S, Yamamoto Y, Ito K, Inokuchi T, Kusaka H, Ikeda H, Yoshikai Y. Heat-killed Lactobacillus plantarum L-137 suppresses naturally fed antigen-specific IgE production by stimulation of IL-12 production in mice. J Allergy Clin Immunol. 1998 Jul;102(1):57-64. PMID: 9679848 View Abstract
13. Trinchieri G Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol. 1995;13:251-76. PMID: 7612223 View Abstract
14. Murosaki S, Muroyama K, Yamamoto Y, Yoshikai Y. Antitumor effect of heat-killed Lactobacillus plantarum L-137 through restoration of impaired interleukin-12 production in tumor-bearing mice. Cancer Immunol Immunother. 2000 Jun;49(3):157-64. PMID: 10881695 View Abstract
15. Hirose Y, Murosaki S, Fujiki T, Yamamoto Y, Yoshikai Y, Yamashita M. Lipoteichoic acids on Lactobacillus plantarum cell surfaces correlate with induction of interleukin-12p40 production.Microbiol Immunol. 2010 Mar;54(3):143-51. PMID: 2023642 View Abstract
16. Hirose Y, Murosaki S, Yamamoto Y, Yoshikai Y, Tsuru T. Daily intake of heat-killed Lactobacillus plantarum L-137 augments acquired immunity in healthy adults. J Nutr. 2006 Dec;136(12):3069-73. PMID: 17116721 View Abstract
17. Arimori Y, Nakamura R, Hirose Y, Murosaki S, Yamamoto Y, Shidara O, Ichikawa H, Yoshikai Y. Daily intake of heat-killed Lactobacillus plantarum L-137 enhances type I interferon production in healthy humans and pigs. Immunopharmacol Immunotoxicol. 2012 Dec;34(6):937-43. PMID: 22468623 View Abstract
18. Cohen S, Tyrrell DA & Smith AP (1991) Psychological stress and susceptibility to the common cold. N Engl J Med. 1991 Aug 29;325(9): 606–12. PMID: 1713648 View Abstract
19. Cohen S, Frank E, Doyle WJ, et al. (1998) Types of stressors that increase susceptibility to the common cold in healthy adults. Health Psychol 1998 May;17(3):214–23. PMID: 9619470 View Abstract
20. Hirose Y, Yamamoto Y, Yoshikai Y, Murosaki S.Oral intake of heat-killed Lactobacillus plantarum L-137 decreases the incidence of upper respiratory tract infection in healthy subjects with high levels of psychological stress. J Nutr Sci. 2013 Dec 6;2:e39. PMID: 25191589 View Abstract
21. Gabryszewski SJ1, Bachar O, Dyer KD, Percopo CM, Killoran KE, Domachowske JB, Rosenberg HF Lactobacillus-mediated priming of the respiratory mucosa protects against lethal pneumovirus infection. J Immunol. 2011 Jan 15;186(2):1151-61. doi: 10.4049/jimmunol.1001751. Epub 2010 Dec 17. PMID: 21169550 View Abstract