LcS Research | GUT FUNCTION
A range of research studies (including human trials) have investigated the effects of Lactobacillus casei Shirota relating to constipation, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD).
It has been estimated that as many as 14 million people are affected by constipation in the UK; particularly at risk are children, pregnant women and people over 65. Older people, for example, are five times more likely to suffer compared to younger adults because of age-related issues such as inability to eat fibre because of dental problems, lack of exercise and use of medication.
Constipation is a disorder of the motor activity of the colon. Although GPs may focus on the infrequency of bowel movements, patients may not necessarily be bothered by this and complain instead of other symptoms. This is reflected in the Rome III diagnostic criteria for functional gastrointestinal disorders: diagnosis of constipation includes at least two of the following (*for at least 25% of defecations):
- Lumpy or hard stools*
- Sensation of incomplete evacuation*
- Sensation of anorectal obstruction/blockage*
- Manual manoeuvres to facilitate defecation (e.g., digital evacuation, support of the pelvic floor)*
In addition loose stools should rarely be present without use of laxatives, and there should be insufficient criteria for IBS-C.
The importance of the intestinal microbiota for bowel habit and gut function is highlighted by the fact that a large proportion of faecal bulk comprises bacteria (Stephen & Cummings 1980). The microbiota of constipated people may differ from those who are healthy: e.g. with lower levels of lactobacilli and bifidobacteria (Quigley 2011). Furthermore, microbial production of short chain fatty acids and metabolism of bile acids is important for lowering gut pH and stimulating its motility; this may also be influenced by microbial metabolic products that can act as neurotransmitters (Quigley 2007).
Constipation studies with L. casei Shirota include evidence from human trials (see examples) as well as indirect evidence from a range of mechanistic studies and other models. Also relevant are human trials that show consumption of this probiotic to be associated with increased levels of faecal lactobacilli and bifidobacteria, as well as studies showing positive effects on mood or anxiety (example studies Tuohy et al 2007; Rao et al 2009; Benton et al 2007).
Tilley et al (2014)
A probiotic fermented milk drink containing Lactobacillus casei strain Shirota improves stool consistency of subjects with hard stools. Int J Probiotics Prebiotics 9(1/2):23-30.
Objective To investigate earlier observations that ingestion of Lactobacillus casei Shirota (LcS) is associated with improved bowel habit, including improved stool consistency.
Methods:Double-blind, placebo-controlled, randomised trial involving 120 adult patients from Belgian GP surgeries, who were suffering from mild constipation. This was defined as four or less bowel movements per week, and hard or lumpy stools in at least 25% of times when stools were passed. The four-week intervention was with one bottle a day of LcS-fermented probiotic drink or placebo. Faecal samples from half the subjects were analysed after the two-week run-in period, post-intervention, and after the two-week follow-up. Stool consistency was analysed using a patient questionnaire based on the Bristol Stool Scale.
Results: Compared to the placebo group, the subjects taking the LcS-probiotic drink experienced a significant improvement in stool consistency; the stools became softer. This was associated with detection of viable LcS in the stools. Both groups showed improved defaecation frequency.
Conclusions: For people passing hard stools, ingestion of the probiotic fermented milk drink containing LcS was associated with significantly improvement of stool consistency, with their stools becoming softer (compared to the placebo group). This may well be due to a change in the intestinal microbiota.
B) Irritable bowel syndrome (IBS)
IBS is one of the most common gastrointestinal disorders experienced by the UK population, affecting up to 20% of people at some time during their life and twice as many women as men. It can be a debilitating condition, severely affecting quality of life.
Diagnosis of IBS is based on the presentation of one or more clinical symptoms that have no underlying pathological cause. The Rome III diagnostic criteria for functional gastrointestinal disorders, bases diagnosis on symptoms of recurrent abdominal pain or discomfort and a marked change in bowel habit for at least six months, with symptoms experienced on at least three days of at least three months (Spiegel et al 2010). Two or more of the following must apply:
- Pain is relieved by a bowel movement
- Onset of pain is related to a change in frequency of stool
- Onset of pain is related to a change in the appearance of stools
Symptoms vary from person to person. There is no cure but changes in diet or lifestyle may help considerably in reducing or preventing symptoms.
The aetiology of IBS is not fully understood but research has focussed on targeting two key areas of observed change: gut motility and visceral sensation. The intestinal microbiota influences both these aspects of gut function. Gut dysbiosis may occur in IBS sufferers: e.g. decreased levels of lactobacilli have been shown in patients (Kassinen et al 2007) and small intestinal bowel overgrowth (SIBO) occurs in up to 78% of cases (Lin 2004; Pimentel et al 2000). Development of IBS after disruption of the intestinal microbiota by antibiotic treatment or infection is further indication of the influence of the microbiota for this condition.
IBS is difficult to research because of its heterogeneity, high placebo effect and different underlying causes. Despite this, the growing body of probiotic research has led to NICE and BDA guidelines including a recommendation that patients wanting to take probiotics, should try a product for at least four weeks and should monitor effects. This is sensible advice; patients can see for themselves if there is benefit but improvements may not be immediate.
IBS studies with L. casei Shirota include human trials (see example and citation list below) and mechanistic studies. Also relevant are human trials that show L. casei Shirota consumption to be associated with positive effects on mood or anxiety (example studies: Rao et al 2009; Benton et al 2007), and studies demonstrating downregulation of inflammation.
Barrett JS et al (2008)
Probiotic effects on intestinal fermentation patterns in patients with irritable bowel syndrome World J Gastroenterol 14:5020-5024.
Small intestinal bacterial overgrowth (SIBO) occurs in up to 78% of IBS patients and may cause symptoms to develop. SIBO can be revealed by detection of an early rise in breath hydrogen after drinking a solution of lactulose (ERBHAL), indicating that there may be bacterial fermentation in the small intestine due to bacterial overgrowth. The question addressed in this small study was whether a probiotic (L. casei Shirota) could reverse SIBO, and if so, whether this would help IBS symptoms.
Eighteen ERBHAL-positive patients with IBS (Rome II criteria) consumed a daily fermented milk drink containing L. casei Shirota before breakfast for six weeks and kept a daily symptom diary.
Of the fourteen patients completing the study, 9 (64%) showed reversal of ERBHAL; one symptom (wind) was significantly improved. Greater improvement in overall symptom score was seen in subjects who had at least moderate symptoms at baseline and who became ERBHAL-negative after the probiotic intervention, compared to those who remained ERHBAL-positive.
The researchers concluded that the L. casei Shirota drink was effective in altering fermentation patterns in the small bowel, consistent with reducing SIBO. Reversal of ERHBAL was associated with improvement in symptoms.
Thijssen AY et al (2011)
A randomized, placebo-controlled double blind study to assess the efficacy of a probiotic dairy product containing Lactobacillus casei Shirota on symptoms of irritable bowel syndrome. Gastroenterology 140 (5) Suppl 1: S609
This randomised, double-blind, placebo-controlled trial of 80 IBS patients, assessed the effect of eight weeks of taking a probiotic (with a fermented milk drink containing a minimum of 6.5 x 109 live cells of L. casei Shirota) on symptoms as recorded in a daily diary (i.e. discomfort, pain, constipation, diarrhoea, bloating). An improvement >30% was predefined as clinically relevant.
When symptoms before and after intervention were compared, in the probiotic group an improvement of >30% improvement was seen for all symptoms apart from bloating, but there was no such improvement of symptoms observed in the placebo group. The improvement was significantly higher in the probiotic group compared to placebo for discomfort, flatulence and total symptom score, and a non-significant improvement for pain and mean symptom scores. Logistic regression indicated benefits may have been much greater for males compared to women.
C) Inflammatory bowel disease (IBD)
The range of IBD conditions includes:
Ulcerative colitis, which affects 1 in 500 – 1,000 people worldwide, with onset often between the age of 15 and 30 years. Acute and chronic inflammation affects the mucosa of all or part of the colon (always the rectum), which may become ulcerated. This commonly results in symptoms such as diarrhoea, bleeding from the back passage and abdominal pain. Sufferers may also experience wind, constipation, passing of mucus and tiredness. Symptoms are often worse in the morning.
Crohn's disease, which affects up to 1 in 500 people in Western countries. Any part of the gastrointestinal tract can be affected – from mouth to anus – but inflammation is most common in the ileum and colon and can be transmural. Symptoms are non-specific abdominal pain and diarrhoea, often with blood and mucus.
Pouchitis Some patients with serious ulcerative colitis undergo surgical resection of the diseased colon. The bowel is reconnected and an internal pouch created from the small intestine, to hold waste before elimination. Inflammation of the lining of this pouch occurs in up to 50% of the patients who have this operation. Symptoms include abdominal pain, more frequent bowel activity and rectal bleeding, as well as malaise and fever.
These are very debilitating chronic diseases and there is a strong need to find ways to help sufferers.
Different lines of evidence suggest the intestinal microbiota may be involved in the pathogenesis of IBD thus there might be benefit in manipulating the intestinal microbiota, perhaps with probiotics.
- Germ-free animals do not develop IBD
- Diversion of the faecal stream (with the highest concentration of bacteria) can be beneficial
- Antibiotic treatment can be beneficial
- The mucosal response is similar to that seen with bacterial infection
- Sufferers have been shown to have an altered microbiota
In terms of probiotic research and IBD, there is limited evidence of benefit for only a few strains: strongest with ulcerative colitis and weak for Crohn's disease. Studies have investigated probiotics +/- conventional therapy, and examined either maintenance of remission or treatment of active disease.
There are several lines of research in this area with L. casei Shirota but the studies are mostly mechanistic or animal models. One human study is described below.
Mitsuyama K et al (2008)
Beneficial effects of Lactobacillus casei in ulcerative colitis: a pilot study. J Clin Biochem Nutr 43(Suppl 1): 78-81.
In an open-label trial, ten patients with mild to moderately active ulcerative colitis (UC) consumed a daily fermented milk drink containing 8 x 1010 L. casei Shirota for eight weeks in conjunction with conventional therapy (aminosalicylates and/or prednisolone). Changes in their clinical status were measured by a clinical activity index score at baseline and at two week intervals, which recorded several aspects of disease (episodes of diarrhoea, nocturnal diarrhoea, visible faecal blood, abdominal pain or cramping, general wellbeing, abdominal tenderness, need for anti-diarrhoeal medication). The control group were nine previously treated patients with active UC, whose baseline characteristics were similar to the study group and who had previously received conventional therapy but not a probiotic.
Compared to the control group, probiotic consumption was associated with significantly improved clinical activity index scores after four weeks (P = 0.033), six weeks (P = 0.026) and eight weeks (P = 0.012). When compared to pre-treatment clinical activity index scores, a trend for improved clinical status was observed in the probiotic group but not in the control group, at six weeks (P = 0.010) and eight weeks (P = 0.035). There were indications that the mechanism of activity may involve inhibition of IL-6 signalling.
Barrett et al (2008) Probiotic effects on intestinal fermentation patterns in patients with irritable bowel syndrome
Ishikawa et al (2005) Randomized trial of dietary fibre and Lactobacillus casei administration for prevention of colorectal tumours
Almeida et al (2012) Beneficial effects of long-term consumption of a probiotic combination of Lactobacillus casei Shirota and Bifidobacterium breve Yakult may persist after suspension of therapy in lactose-intolerant patients.
Krammer et al (2011) Effect of Lactobacillus casei Shirota on colonic transit time in patients with chronic constipation
Matsumoto et al (2010) Effects of a probiotic fermented milk beverage containing Lactobacillus casei strain Shirota on defecation frequency, intestinal microbiota, and the intestinal environment of healthy individuals with soft stools.
Mitsuyama et al (2008) Beneficial effects of Lactobacillus casei in ulcerative colitis: a pilot study
Endo et al (2011) Efficacy of Lactobacillus casei treatment on small bowel injury in chronic low-dose aspirin users: a pilot randomized controlled study
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
Shioiri et al (2006) The effects of a synbiotic fermented milk beverage containing Lactobacillus casei strain Shirota and transgalactosylated oligosaccharides on defecation frequency, intestinal microflora, organic acid concentrations, and putrefactive metabolites of sub-optimal health state volunteers: a randomized placebo-controlled cross-over study
Candy et al (2001) Effect of administration of Lactobacillus casei Shirota on sodium balance in an infant with short bowel syndrome
Quigley (2011) The enteric microbiota in the pathogenesis and management of constipation
Nakabayashi et al (2011) Effects of synbiotic treatment on serum level of p-cresol in haemodialysis patients: a preliminary study
Botschinsky et al (2011) A review of the evidence available for the use and effectiveness of probiotic drinks and supplements for the treatment of irritable bowel syndrome.
Gibson & Barrett (2010) The concept of small intestinal bacterial overgrowth in relation to functional gastrointestinal disorders
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
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
Uchida K et al (2007) Immunonutritional effects during synbiotics therapy in pediatric patients with short bowel syndrome
Bongaerts et al (2006) Lactobacillus fermentum bacteremia in a seriously ill premature short small bowel patient during probiotic Lactobacillus casei therapy
Kanamori et al (2006) Abnormal intestinal microbiota in pediatric surgical patients and the effects of a newly designed symbiotic therapy
Matsumoto et al (2006) The effect of a probiotic milk product containing Lactobacillus casei strain Shirota on the defecation frequency and the intestinal microflora of sub-optimal health state volunteers: a randomized placebo-controlled cross-over study
Banaszkiewicz A & Szajewska H (2005) Probiotics in the treatment of constipation: a systematic review of randomized controlled trials
Takagi et al (2008) The relationship between the in vitro response of dendritic cells to Lactobacillus and prevention of tumourigenesis in the mouse
Kanamori et al (2002) A novel synbiotic therapy dramatically improved the intestinal function of a pediatric patient with laryngotracheo-esophageal cleft (LTEC) in the intensive care unit
Kanamori et al (2001) Combination therapy with Bifidobacterium breve, Lactobacillus casei, and galactooligosaccharides dramatically improved the intestinal function in a girl with short bowel syndrome: a novel synbiotics therapy for intestinal failure
Ohashi et al (2001) Strain gauge force transducer and its application in a pig model to evaluate the effect of probiotic on colonic motility
Kawamura et al (1981) Clinical study on a Lactobacillus casei preparation (BLG-01) in patients with chronic irregular bowel movement and abdominal discomfort
Morita M (1973) Clinical use of a high-concentration Lactobacillus casei preparation
Numata K (1973) Clinical effect of a high concentrate lactobacilli preparation on chronic constipation
Ogawa et al (1974) Clinical experience with the use of high concentration lactic acid preparation LP-201 to treat habitual constipation: double-blind crossover study
Ohta Z (1974) Treatments of SMON abdominal syndromes by high-concentration preparation of Lactobacillus - Its clinical effect and variation of intestinal flora and fecal organic acids
Chmielewsak A & Szajewska H (2010) Systematic review of randomised controlled trials: Probiotics for functional constipation
Shimizu & Shibamoto (1964) Clinical observation of the effects of a strain of acidophilic lactic acid bacteria (Yakult strain) on the intestinal gas production
Herias et al (2005). Probiotic effects of Lactobacillus casei on DSS-induced ulcerative colitis in mice
Cassani et al (2011) Use of probiotics for the treatment of constipation in Parkinson’s disease patients
Sawamura et al (1994) The enhancing effect of oral Lactobacillus casei on the immunologic activity of colon cancer patients
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
Mazlyn MM et al (2013) Effects of a probiotic fermented milk drink on functional constipation: A randomized, double-blind, placebo-controlled study.
Takahashi K, Terashima H, Kohno K, Ohkohchi N (2013) A stand-alone synbiotic treatment for the prevention of d-lactic acidosis in short bowel syndrome
Aoki T et al (2014) Effects of the continuous intake of a milk drink containing Lactobacillus casei strain Shirota on abdominal symptoms, fecal microbiota, and metabolites in gastrectomized subjects
Tilley L et al (2014) A probiotic fermented milk drink containing Lactobacillus casei strain Shirota improves stool consistency of subjects with hard stools
Tsuji H et al (2014) Maintenance of healthy intestinal microbiota in women who regularly consume probiotics
Ford AC et al (2014) Efficacy of prebiotics, probiotics, and synbiotics in irritable bowel syndrome and chronic idiopathic constipation: systematic review and meta-analysis
Sakai T et al (2014) Effect of fermented milk containing Lactobacillus casei strain Shirota on constipation-related symptoms and haemorrhoids in women during puerperium
Dimidi E et al (2014) The effects of probiotics on functional constipation in adults: a systematic review and meta-analysis of randomized controlled trials
Vignati F et al (2014) Effects of the use of a fermented milk with Lactobacillus casei Shirota in elderly people with chronic constipation
Van den Nieuwboer M (2015) Improving the bowel habit of elderly residents in a nursing home using probiotic fermented milk drink.
Thijssen et al (2015) Efficacy of Lactobacillus casei Shirota for patients with irritable bowel syndrome
Sakai T et al (2011) Fermented milk containing Lactobacillus casei strain Shirota reduces incidence of hard or lumpy stools in healthy population.
Miller et al (2016) Contemporary meta-analysis of short-term probiotic consumption on gastrointestinal transit.
Kanazawa et al (2005) Synbiotics reduce postoperative infectious complications: a randomized controlled trial in biliary cancer patients undergoing hepatectomy
Ohashi et al (2004) Transition of the probiotic bacteria, Lactobacillus casei strain Shirota, in the gastrointestinal tract of a pig
Spanhaak et al(1998) The effect of consumption of milk fermented by Lactobacillus casei strain Shirota on the intestinal microflora and immune parameters in humans