LcS Research | INFECTIONS
Medical and scientific experts acknowledge the importance of the commensal intestinal microbiota for the body's defences against infection. This internal microbial population is a key factor in maintaining colonisation resistance, and is equally important in educating and supporting the immune system.
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Since their first development, there has been interest in using probiotics against gut infections, particularly diarrhoeal illness. Scientific evidence supports this: Cochrane reviews in 2010 concluded that, used alongside rehydration therapy, probiotics are safe and have clear benefits in shortening duration and reducing stool frequency in acute infectious diarrhoea although there was limited evidence for children (Allen et al 2010; Aponte et al 2010).
Research with Lactobacillus casei Shirota has investigated diarrhoea of undetermined aetiology as well as infection with a range of pathogens: bacterial (Clostridium difficile; Helicobacter pylori), viral (rotavirus, norovirus) and parasitic (Trichinella spiralis). In human studies target groups have included children, adults and older patients in hospitals or care homes. Supporting evidence also comes from extensive mechanistic and model studies.
a) Antibiotic-associated diarrhoea (AAD) & Clostridium difficile infection (CDI)
It has been reported that 1% - 44% of people taking antibiotics develop diarrhoea, either during or within 2-3 weeks after the course finishes. Risk factors include extremes of age, co-morbidity and broad spectrum antibiotics (particularly clindamycin, β-lactams and third generation cephalosporins). Up to 25% of these cases are caused by C. difficile. This spore-forming pathogen is present in up to 3% of healthy adults, but its growth is prevented by the normal bacterial population in the intestine. If antibiotics have disrupted this microbial protection, then C. difficile can grow unchecked, producing toxins that cause illness of differing severity, ranging from diarrhoea to pseudomembranous colitis, a potentially fatal disease. The group most at risk are older hospital patients: over 80% of reported C. difficile cases are in people aged over 65 years. Illness can be recurrent.
C. difficile spores can survive for long periods in the environment so they can be spread easily on the hands of anyone who has picked them up, perhaps from infected patients or surfaces. Good hygienic practices, including rigorous cleaning and hand washing as well as strict antibiotic prescribing regimes, are the best way to prevent this infection in hospitals or care homes. UK guidance on infection control procedures for C. difficile is available on the UK's Health Protection Agency and NHS websites. Irish guidance on infection control procedures for C. difficile is available on the Health Protection Surveillance Centre and HSE websites.
Probiotics are known to address one of the underlying risks for CDI, namely gut dysbiosis, thus there has been considerable research in this area, particularly investigating whether risk of CDI can be reduced by taking a probiotic before, during and/or after antibiotics. Studies with L. casei Shirota (as Yakult) have been conducted (see LcS Topic: Gut-related infection).
Pirker et al (2012)
Effects of antibiotic therapy on the gastrointestinal microbiota and the influence of Lactobacillus casei. Food & Agric Immunol DOI:10.1080/09540105.2012.689816.
This study involved 678 hospital patients (mean age 71) who were on a range of single or multiple antibiotic regimes. One group (n=340) consumed a daily fermented milk drink containing L. casei Shirota during the antibiotic treatment and for three days after this ceased. (At the time of probiotic intervention, all patients and staff on the ward received probiotic.) A control group of patients also on antibiotics (n=338), did not receive the probiotic; these patients were matched to the probiotic group in terms of age, sex, antibiotics, disease severity, length of hospital stay, use of proton pump inhibitors.
There was no exclusion of any particular antibiotic. Antibiotics taken included penicillins, cephalosporins, quinolones, clindamycin, vancomycin, and were multiple as well as single antibiotic regimes.
During probiotic intake, all patients on the ward were offered probiotic, as well as the staff. During periods on the wards of no probiotic intake, neither staff nor patients took probiotic.
AAD:* 17/340 (5%) in LcS group vs 63/338 (18.6%) control group (P less than 0.001)
CDI*: 1/340 (0.3%) in LcS group vs 21/338 (6.2%) control group (P less than 0.001)
Faecal analysis showed that antibiotic therapy decreased abundance of total bacteria, Bifidobacterium spp, Clostridium clusters IV and XI whereas Enterobacteriaceae increased. LcS intervention reduced the observed antibiotic-induced decrease in abundance of total bacteria and Bifidobacterium. LcS intervention also increased Lactobacillus abundance.
*Antibiotic-associated diarrhoea = AAD; C. difficile infection = CDI
b) Paediatric diarrhoea
Enteric infections affect many infants and young children, particularly in developing countries. Even in the UK and Ireland, probably almost every infant suffers at least one episode of rotavirus before they are five. Many studies have shown probiotic benefit in this area, either for reduction of the duration of diarrhoea or reducing risk of illness; research has been conducted with L. casei Shirota.
Sur D et al (2010)
Role of probiotic in preventing acute diarrhoea in children:a community-based, randomized, double-blind placebo-controlled field trial in an urban slum. Epidem Infect 139(6):919-26
This double-blind, placebo-controlled, randomised study investigated 3,758 children aged one to five years old living in an urban slum in India. Every day for 12 weeks, the children drank one daily probiotic fermented milk drink (L. casei Shirota, minimum 6.5 x 109) or a placebo drink of similar nutrient content, taste and appearance. The effects of these interventions were assessed during the drinking period and for a further 12 weeks.
After 24 weeks, the incidence of diarrhoea in the probiotic group was 608 (i.e. 0.88 cases/child per year) compared to 674 for the placebo group (1.029 cases/child per year). This was equivalent to a reduction of risk of diarrhoea associated with probiotic of 14% (95% confidence interval 4-23, P < 0.01 in adjusted model).
Microbial analysis found a range of pathogens in the stools making it difficult for probiotic effect to be attributed to any particular aetiology. Species of Aeromonas and Cryptosporidium, however, were found at a lower rate in faeces of those drinking probiotic compared to the placebo.
Norovirus (also known as Norwark virus or small round structured viruses) is the most common cause of infectious gastroenteritis in England and Wales (costing the NHS over £100 million per annum in bad years) and in Ireland. It is aptly called the winter vomiting disease because of its symptoms (vomiting and diarrhoea) and its seasonality, although it can strike any time of the year. It is highly contagious; outbreaks can occur in hospitals, nursing homes, schools and cruise ships.
The illness can be quite unpleasant but should only last a few days; advice is to rest, keep hydrated and try not to infect anyone else. Prevention, as always, is better than cure so good hygiene is important: pay attention to hand washing, washing of towels and bed clothes, disinfecting surfaces, cleaning toilets – and only eat oysters from a reliable source!
There is very little probiotic research on norovirus but one trial has been conducted with L. casei Shirota.
Nagata S et al (2011)
Effect of the continuous intake of probiotic-fermented milk containing Lactobacillus casei strain Shirota on fever in a mass outbreak of norovirus gastroenteritis and the faecal microflora in a health service facility for the aged. Br J Nutr 106(4):549-56
This was an open label study of seventy-seven persons (mean age 84 years) in a residential home for older people in Japan. The intervention was over a winter period, and involved an L. casei Shirota fermented milk drink given to 39 residents; a control group of 38 did not receive the probiotic. Probiotic effect was assessed by looking at records of illness for the month of December.
The mean duration of fever >37 °C after onset of illness was 1.5 d (SD 1.7) in the probiotic group compared to 2.9 d (SD 2.3) in the control group, which was a significant reduction (P less than 0.05). There was, however, no significant difference in incidence of norovirus gastroenteritis during the same month.
Faecal analysis of a sub-group of subjects found that there was a significant increase in numbers of Bifidobacterium (P less than 0.05) and Lactobacillus (P less than 0.01) after one month on the probiotic. After two months there was a significant decrease in levels of Enterobacteriaceae and Pseudomonas (P less than 0.05). Whilst probiotic was being consumed, no methicillin-resistant Staphylococcus aureus or methicillin-resistant coagulase-negative Staphylococcus was detected.
d) Helicobacter pylori
In the UK it is estimated that about 40% of people are infected with H. pylori, rising to over 50% in people aged 50 years or over. It is a Gram-negative helical bacterium that is able to colonise the gastric mucosal surface. Often picked up in childhood from other people, it will remain in the stomach unless particular antibiotics are given.
In the majority of cases (nearly 90%) this does not cause any problems but H. pylori is considered a pathogen because it can cause chronic inflammation of the inner stomach lining. It is the most common cause of ulcers: about 15% of infected people develop ulcers in the stomach or duodenum.
Treatment is with a combination of antibiotics but there has been research investigating the benefit of probiotic either with or without the antibiotics. A meta-analysis by Zou et al (2009), for instance, concluded supplementation with lactobacilli could be effective in increasing eradication rates of anti-H. pylori therapy for patients treated for the first time, and also had a positive effect on some of the therapy-related side effects.
Studies have been conducted with L. casei Shirota, examining both its effects alone or in combination with antibiotic therapy..
Sahagún-Flores JE et al (2007)
Eradication of Helicobacter pylori: triple treatment scheme plus Lactobacillus vs triple treatment alone. Cirug Ciruj 75(5): 333-336.
This was a randomised comparative trial investigating if there was any benefit in including the probiotic L. casei Shirota with conventional triple antibiotic treatment (clarithromycin, amoxicillin and omeprazole) for H. pylori infection.
Based on breath test measurements, eradication of H. pylori was achieved in 29/31 of subjects given the probiotic (94%) compared to 25/33 of the control group (76%) (P less than 0.05).
Due to their ability to influence the body via multiple mechanisms of activity, effects of probiotics can be seen beyond the gut. In terms of infectious disease, the primary mechanism is modulation and support of the immune response to pathogens.
Human studies have shown positive results with L. casei Shirota in terms of reducing upper respiratory tract infections in athletes, benefit for HTLV-1 myelopathy and human papillomavirus (linked to development of cervical cancer).
Two example trials are shown below. Reprints are available on request, please contact the Science Team:
A) Human papillomavirus infection (cervical cancer risk)
Cervical cancer is the the most common cancer in women younger than 35 in the UK, which is why cervical screening (also known as PAP smear test) is available in the UK for women aged between 25 and 65 years old. Cervical cancer is associated with infection by a member of the family of human papillomaviruses (HPVs) - in fact, HPV-DNA can be found in 99.7% of all cervical cancers. Low-grade squamous intraepithelial lesions are closely associated with infection with certain high risk HPV; the clearance of both shows a close temporal relationship (Szryjanen review, 2007).
Verhoeven V et al (2012)
Probiotics enhance the clearance of human papilloma virus-related lesions: a prospective controlled pilot study. EurJ Cancer 22(1):46-51.
This open- label, controlled study investigated whether Lactobacillus casei Shirota (LcS) could influence the clearance of HPV infection and associated pre-cancerous abnormalities (low-grade squamous intraepithelial lesions; LSIL). For six months, the researchers followed 54 women diagnosed with HPV+ LSIL in their PAP smear, who were allocated to take either a daily LcS probiotic drink, or no intervention. Probiotic efficacy was assessed by comparing their PAP smear and HPV status at baseline with the same tests after six months.
The women who were taking the daily LcS had twice the likelihood of clearance of cytological abnormalities (60% vs. 31%; P=0.05). The probiotic group also had a higher HPV clearance rate (29% vs. 19%; P=0.41).
The authors concluded that this pilot study indicates that LcS promotes clearance of HPV-related cytological abnormalities, which could be a novel way of managing cervical cancer precursors.
B) Upper respiratory tract infections
Low levels of salivary IgA have been linked to elite athletes' increased susceptibility to upper respiratory tract infections. This may be the mechanism behind the LcS-associated reduction of common colds observed in this trial.
Gleeson et al (2011)
Daily probiotic's (Lactobacillus casei Shirota) reduction of infection incidence in athletes. Int J Sport Nutr Exercise Metab 21: 55-64
To investigate the effect of the probiotic Lactobacillus casei Shirota (LcS) on immune markers and incidence of upper respiratory tract infections (URTI), in sports people during four months of endurance-based sports activities in winter.
The 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 (LcS) or placebo for 16 weeks. At baseline, 8 and 16 weeks, resting blood and saliva samples were taken and tested for a broad range of immune parameters: immunoglobulins, cell counts and cytokines. The subjects also kept weekly records of their training and any illness. Subjects were required to maintain a minimum level of training.
Analysis of the subjects who completed the full 16 weeks of the study (n = 58), showed that the proportion of those who had one or more weeks of URTI symptoms was 27% lower in the LcS group compared to placebo (P = 0.021).
The average number of URTI episodes was 50% lower in the LcS group compared to placebo (P less than 0.01). There was no difference in the severity and duration of symptoms. The proportion of weeks that subjects took medication was significantly higher in the placebo group compared to those taking probiotic (P less than 0.01).
The main finding from the immune analysis, was that salivary IgA concentrations were higher in the LcS group compared to the placebo group (P = 0.03).
The probiotic group also experienced significantly fewer days with GI discomfort symptoms (P = 0.008).
Subject dropout was mainly due to air travel to competitions, injury or persistent illness. These prevented the subjects either being able to take the drinks or undertake the minimum level of training required for the study. Blinding was shown to be effective.
The authors concluded that regular ingestion of the probiotic LcS appeared to be beneficial in reducing the frequency of URTI in this group of athletes.
Gleeson et al (2011) Daily probiotic’s (Lactobacillus casei Shirota) reduction of infection incidence in athletes
Sur et al (2010) Role of probiotic in preventing acute diarrhoea in children: a community-based, randomized, double-blind placebo-controlled field trial in an urban slum
Nagata et al (2011) Effect of the continuous intake of probiotic-fermented milk containing Lactobacillus casei strain Shirota on fever in a mass outbreak of norovirus gastroenteritis and the faecal microflora in a health service facility for the aged
Pirker et al (2013) Effects of antibiotic therapy on the gastrointestinal microbiota and the influence of Lactobacillus casei
Verhoeven et al (2012) Probiotics enhance the clearance of human papillomavirus-related lesions: a prospective controlled pilot study
Eguchi et al (2010) Perioperative synbiotic treatment to prevent infectious complications in patients after elective living donor liver transplantation. A prospective randomised study
Lewis et al (2009) The potential of probiotic fermented milk products in reducing risk of antibiotic-associated diarrhoea and Clostridium difficile disease
Bian et al (2011) Effects of the continuous intake of Lactobacillus casei strain Shirota-fermented milk on risk management of long-term inpatients at health service facilities for the elderly
Sahagün-Flore et al (2007) Eradication of Helicobacter pylori: triple treatment scheme plus Lactobacillus vs. triple treatment alone.
Tiengrim & Thamlikitkul (2012) Inhibitory activity of fermented milk with Lactobacillus casei strain Shirota against common multidrug-resistant bacteria causing hospital acquired infection
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