The efficacy of the probiotic Symprove as assessed from randomised clinical trials - Ingvar Bjarnason, Department of Gastroenterology, King’s College Hospital

Bacteria emerged from hyperthermophiles about 3.5 billion years ago. They not only adapted to their environment but also changed it creating the oxygen enriched atmosphere that is the pre-requisite for much life on Earth. This apparently altruistic gesture is offset by their destructive nature, as bacteria cause more human deaths than any other single reason, including wars. Man has had to adapt to bacteria and nowhere is this in evidence better than in the gastrointestinal tract. There is a case for considering this interaction as mutualistically beneficial, but there is also a strong case for considering these bacteria as parasitic (1) with limited benefit to the host.

Nevertheless, humans have taken advantage of the properties of some bacteria, for example lactobacillus to preserve foods, mostly dairy products. This gathered momentum with the inclusion of Lactobacillus casei to yogurts in 1930 and this was successfully marketed as conferring a beneficial effect to humans. Most doctors were sceptical to such claims, until efficacy data emerged from randomised clinical trials (RCT). The early trials using lactobacillus and Bifidobacterium in Irritable Bowel Syndrome (IBS) (2, 3) were very convincing.

King’s College Hospital Gastroenterology has been actively involved in the clinical evaluation of Symprove, a non-dairy, liquid probiotic that contains four strains of naturally occurring bacteria: Lactobacillus rhamnosus NCIMB 30174, Lactobacillus plantarum NCIMB 30173, Lactobacillus acidophilus NCIMB 30175 and Enterococcus faecium NCIMB 30176. Here, I will provide an update on the research on its efficacy and highlight the more promising venues for future research.

CLINICAL STUDIES
IBS.

Dr Sisson conducted our first RCT assessing Symprove for management of IBS which is the most common gastrointestinal disorder in developed countries. He studied 186 symptomatic patients, half of whom took Symprove and the other half took a matching placebo (4). Symprove was associated with a significantly greater reductions in the IBS Symptom Severity Scores (SSS) after 12 weeks, mostly due to reduced abdominal pain and improvement in bowel action. Patients with moderate to severe symptoms (IBS- SSS > 175) reported complete resolution of symptoms with Symprove in 26.6% as compared to placebo 14.5% (p = 0.063). Of those who achieved a clinically important difference, defined as a drop of >95 points on the IBS-SSS, 39 (31.5%) vs. 9 (14.5%) achieved this in the probiotic and placebo groups, respectively (p = 0.013). There were no significant improvements in Quality of Life issues.

The fact that this trial was hospital-based means that we included a more severe, problematic or complex IBS cases than the General Practitioner manages. In order to capture the effect of Symprove in less severe cases an independent ‘real life situation’ study was commissioned (5). Participants (n=1246) were recruited through e-mail and social media advertising. These were mostly highly educated, non-smoking, health-conscious women with IBS. Over 90% reported improvements (‘completely resolved’ or ‘some positive difference’) in IBS or IBS-like symptoms, including abdominal pain (p<0.001), bloating (p<0.001), urgency to defecate (p<0.001) and bowel habit satisfaction (p<0.001). At face value this indicates, as is the case in many disease, that efficacy is markedly greater in milder disease.

Given this I now routinely advocate a holistic approach to treatment of IBS. This involves dietary assessment with implementation of a variety of food exclusions such as the low-FODMAP diet, the use of Symprove and an appropriate referral to a psychiatrist who is interested in the subject matter. About 70% of patients may be expected to gain significant benefit from this approach, which far greater than seen with traditional drug treatment.

DIVERTICULAR DISEASE

Colonic diverticular disease (DD) i.e. pouch-like bulging of the colonic, predominantly the sigmoid wall, is evident in approximately 40% and 70% of people aged over 60 and 80 years, respectively. About 25% experience an episode of acute diverticulitis. Acute diverticulitis is perceived to be a ‘surgical’ disease, but most patients recover without an operation. However, many such patients consequentially develop problematic IBS like symptoms.

Conventional treatment includes high fibre supplements, anti-diarrhoeals or anti-obstipants that lead to roller-coaster changes in bowel habits and anti-spasmotics. These patients are now share managed by colorectal surgeons and Gastroenterologists in dedicated “Diverticular Disease Clinics” at King’s College Hospital.

We assessed the efficacy of Symprove by itself (without other specific treatments) in a RCT involving 120 adult patients with moderate-to-severe chronic, non-acute symptomatic diverticular disease (6).

Symprove taken over 12 weeks was associated with significant improvements in diarrhoea, constipation mucorrhoea and back pain. Patients abdominal pain decreased in both groups, but did not reach a statistical significance (p = 0.11).

Three patients on Symprove and eitght on placebo developed diverticulitis during the study (p = 0.19). Given this we now advocate Symprove for these patients, but there is clearly the potential to consider further studies.

INFLAMMATORY BOWEL DISEASE (IBD)

There was a hint from the above studies that Symprove had subtle anti-inflammatory properties. We designed a study assessing faecal calprotectin, a quantitative marker of intestinal inflammation, before and after four weeks of Symprove v placebo in asymptomatic patients with ulcerative colitis (n=81) and Crohn’s disease on minimal medical treatment (7). This represents a small group of patients with IBD who have a more benign course of disease than most. In short calprotectin levels were significantly (p < 0.015) reduced in the patients with ulcerative colitis receiving the probiotic as opposed to placebo, demonstrating an anti-inflammatory effect. No significant differences were seen in Crohn’s Disease. This was not a clinical outcome trial, but suggests that some patients with ulcerative colitis may benefit from taking Symprove.

POTENTIAL BENEFITS
COVID-19

The pan-epidemic due to COVID-19 has affected millions of people and accounts for about 160, 000 premature deaths in the UK at present. The most severe disease requires intensive care treatment. About 50% of such patients die and many of the survivors have a delayed recovery, requiring intensive prolonged rehabilitation with symptoms reminiscent of the chronic fatigue syndrome (8).

The gastrointestinal tract has been the focus of some research during this epidemic. 30- 50% infected patients shed the virus in stool (9-11) and many have a ‘gastroenteritis’ like illness (12, 13). It has been suggested that the gastrointestinal involvement plays an important role in increasing the severity of complications of the infection (14-16).

There has been one open uncontrolled study of a probiotic in COVID-19 patients. D’Ettorre et al (17)assessed the effect of Sivomixx, a multistrain freeze-dried formulation of lactic acid- and bifido-bacteria, in 28 patients with COVID-19 receiving the probiotic as compared with 42 control patients. The probiotic was associated with resolution of diarrhoea within three days (94%) as compared with 30% for those not on probiotics p < 0.001. There was a significantly more rapid resolution of composite symptoms (tiredness, headache, myalgia and dyspnoea) in the probiotic treatment evident within 48 and 72 hours (p<0.001). On day seven 98% of the probiotic group had improvements in the symptom severity as compared to 40% in the patients not receiving the probiotic supplement (p < 0.001). Furthermore, on day seven there was an eightfold decrease in the requirement of respiratory support in the probiotic group (p = 0.01).

If similar results were evident in RCT then this treatment would revolutionise the management of severe Covid.

PARKINSON’S DISEASE.

Twenty years ago there was a neurological consensus that Parkinson’s Disease was a localised brain disease with a prominent genetic disease basis with some environmental triggers in the minority of cases. Then the idea that it was a more generalised disease emerged (18) and the Dobbs’ team launched an integrated research program into a gut – CNS association (19-21). To make a long story short, they found that eradication of H pylori not only halted but reversed brady/hypokinesia while treatment failure led to further deterioration (22-24). This work even suggested an importance for H suis (25, 26). However, H pylori treatment success was associated with small intestinal bacterial overgrowth (SIBO) (27, 28) with deterioration of symptoms. Introduction of a maintenance laxative in these cases shows plateauing of year-on-year increase in rigidity (29, 30). These findings conform to the idea that intestinal dysbiosis contributes to certain facets of Parkinson’s disease. Symprove has been suggested as an adjunct treatment for Parkinson’s disease and some trials are completed but the results are unknown and further funding has been sought for multi-centre trials.

FURTHER POTENTIAL

It is increasingly recognised that the intestinal microbiome is variously disturbed in several clinical conditions and disease. Such findings do not establish a cause and effect relationship. Indeed there is no certainty that probiotics will be of benefit in these conditions and it will be necessary to demonstrate efficacy in adequately designed clinical trials.

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Content provided by Professor Ingvar Bjarnason, Department of Gastroenterology, King’s College Hospital, Denmark Hill, London SE5 9PJ
Tel: 07784 589003
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