Introduction
The human intestine contains a large number of microbes, mainly located within the colon. It is estimated that the colon of an adult human contains over 40 trillion bacteria cells!.
Many factors influence the composition of the intestinal flora including age, dietary composition, immune status, susceptibility to infection, stress, and gastro-intestinal pH and transit time. The idea that dietary manipulation can be used to change the gastro-intestinal microbial flora and improve health has led to the concept of probiotic and prebiotic therapy.
There has been an increasing interest about the potential benefits of taking probiotic and prebiotic supplements. Pharmacists have responded by stocking these supplements, as a consequence, patients are asking for more information about these products. In order to provide accurate advice it is important that pharmacy professionals and their teams understand the differences between probiotic and prebiotic supplements. Pharmacists, as healthcare professionals, are often placed in a difficult position when asked about which supplement would be compatible with specific medical conditions or medication along with situations where their use would be clinically inappropriate.
Probiotics are defined as “Live microorganisms that, when administered in adequate amounts, confer a health benefit on the host”[1]. This contrasts to prebiotics that are defined as “a selectively fermented ingredient that results in specific changes in the composition and/or activity of the gastrointestinal microbiota, thus conferring benefits on host health”1 in order words prebiotics constitute the media for probiotics to flourish.1 Synbiotics are single products that contain both probiotic and prebiotic ingredients.
Probiotics
Probiotics are live microbial food supplements that beneficially affect the host by improving its intestinal microbial balance. For humans, probiotics could be considered as fermented milk products and over–the-counter supplements including powders, tablets and capsules that contain lyophilised bacteria.
Probiotic supplements can contain a wide variety of micro-organisms although the most commonly used are producers of lactic acid, such as lactobacilli or bifidobacteria. These are commonly referred to as “good” or “friendly” bacteria. However yeasts, usually saccharomyces strains, are also included in some probiotic supplements.
Probiotic strains - the micro-organisms most widely used in probiotic supplements are lactic acid producers such as lactobacilli and bifidobacteria. Specific strains commonly used include[2]:
Lactobacilli
- Lactobacillus acidophilus
- L Casei
- L delbrueckii subsp bulgaricus
- L reuteri
Streptococci
- Streptococci salivarius subs thermophile
- S diacetylactis
- S intermedius
- Bifidobacteria
- Bifidobacterium bifidum
- B adloescentis
- B animalis
Yeasts
- Saccharomyces boulardii
- S cerevisiae
Mechanism of action - The key benefit of a probiotic is to increase the gastro-intestinal levels of beneficial bacteria and reduce the population of potentially pathogenic microorganisms.
Probiotics can:
- antagonise potential pathogens,
- improve the intestinal environment,
- strengthen the intestinal barrier, reduce inflammation
- stimulate the host immune response to potential antigenic challenges.
Probiotics can exert these effects by several different mechanisms including altering the gastro-intestinal pH to make it a less favourable environment for pathogenic survival, production of bacteriocins that inhibit the growth of pathogens, competing with pathogens for available nutrients, stimulating host immune response through activation of macrophages or secretion of immunoglobulin A and increasing epithelial mucin production and promoting the strength of the intestinal barrier.
These actions are thought to be responsible for most of the beneficial effects of probiotics including the reduction in incidence and severity of diarrhoea, which is a widely recognised use of probiotics.
Clinical use
Probiotics have been proposed as being potentially useful in a wide range of clinical conditions including:
- Treatment and/or prevention of diarrhoea of differing causes
- Eradication of Helicobacter
- Liver disease including:
- hepatic encephalopathy
- non-alcoholic fatty liver disease
- Gastrointestinal conditions including:
- Ulcerative colitis
- Crohn’s disease
- Irritable bowel syndrome
- Colic
- Lactose malabsorption
- Necrotizing enterocolitis
- Pouchitis
- Boosting the immune system
- Prevention of systemic infection
- The strength of the evidence base for probiotic use differs for each proposed clinical use. The World Gastroenterology Probiotic and prebiotic guideline1 provides the following overview of the possible clinical uses and associated evidence base for probiotics.
Colorectal cancer - diet is a recognised contributory factor in the development of colorectal cancer. Probiotics and prebiotics have shown improvement in biomarkers for colorectal cancer but available data is limited regarding potential benefits in disease prevention.
Treatment of acute diarrhoea - there is evidence that some probiotic strains can shorten the duration and reduce the severity of infectious diarrhoea in children. Oral administration has been shown to reduce symptom duration by approximately one day. Currently available evidence suggests the mechanism of action may be strain specific.
Prevention of acute diarrhoea - In specific settings there is some evidence that probiotics prevent diarrhoea in both adults and children.
Prevention of antibiotic-associated diarrhoea - there is strong evidence of efficacy for the use of probiotics in preventing antibiotic associated diarrhoea in adults and children.
Prevention of Clostridium difficile diarrhoea - a 2016 meta-analysis concluded that the risk of developing C. difficile-associated diarrhoea in patients receiving antibiotics can be reduced by the use of probiotics although further studies are required to confirm optimum dosage and microbial strain.
Helicobacter eradication - research has shown that prebiotic and probiotics are useful in reducing side effects associated with H pylori eradication regimes, although the quality of the evidence was low.
Hepatic encephalopathy - prebiotics such as lactulose are already used, and licensed, for prevention and treatment of hepatic encephalopathy. There is also an evidence base that suggests one probiotic mixture can reverse minimal hepatic encephalopathy.
Immune response - there is evidence suggesting that some probiotic strains and the prebiotic oligofructose can improve the human immune response. Studies aimed at preventing acute infections, such as nosocomial diarrhoea in children and influenza in winter, along with the antibody response to vaccines have shown an enhanced immune response following prebiotic and probiotic administration.
Pouchitis - this is an inflammation of the ileal pouch or artificial rectum surgically created out of ileal gut tissue in patients who have undergone a colectomy. Certain probiotics have been shown to be useful in preventing an initial attack of pouchitis and in preventing further relapse after antibiotic induced remission. Probiotics can be recommended to patients with mild pouchitis or as maintenance therapy once in remission.
Ulcerative colitis - certain probiotics have been shown to be as effective as conventional therapy in achieving a higher response and remission rate in mild to moderately active ulcerative colitis in both adults and children
Crohn’s disease - studies have not shown any beneficial effect of probiotics in maintaining remission in Crohn’s disease.
Irritable bowel syndrome - probiotic studies have consistently shown reduced abdominal bloating and flatulence, some studies have also shown that certain strains reduce pain and provide symptom relief.
Colic - certain probiotic strains have been shown to reduce crying time in breastfed infants suffering from colic.
Lactose malabsorption - lactose digestion and symptoms associated with lactose intolerance have been shown to improve following administration of Streptococcus thermophilus and Lactobacillus delbrueckii subsp. bulgaricus.
Necrotizing enterocolitis - probiotic supplementation has been shown to reduce the risk of necrotizing enterocolitis in preterm babies.
Non-alcoholic fatty liver disease - certain probiotics have been shown to be useful treatment options in steatohepatitis in both adults and children.
Prevention of systemic infections - there is insufficient evidence to support the use of probiotics and synbiotics in seriously ill patients.
Prebiotics
The concept of prebiotics is more recent than that of probiotics. Prebiotics are dietary substances that support the growth and/or activity of beneficial bacteria in preference to harmful ones. Lactobacilli and Bifidobacterium are the most common target organisms for prebiotics.
The key difference between prebiotics and probiotics is that prebiotics contain no live microbes. Prebiotics are not digested by intestinal enzymes which means they pass unchanged through the upper GI tract to the colon where they are selectively used as fuel by beneficial bacteria. The clinical benefit of the prebiotic is consequently dependent on the health promoting effect of the beneficial bacteria.
All prebiotics are classed as non-digestible dietary fibre although all fibre cannot be classified as being a prebiotic.
In order to classify a food ingredient as prebiotic it must be shown to[3]:
- Resist gastric acidity, hydrolysis by mammalian enzymes and absorption in the upper gastro-intestinal tract
- Be fermented by intestinal microflora
- Selectively stimulate the growth and/or activity of intestinal bacteria potentially associated with health and well-being
Commonly used prebiotics are:
- Fructooligosaccharide (FOS)
- Inulin
- Galactooligosaccharides (GOS)
- Lactulose
- Breast milk oligosaccharides
Fructooligosaccharide (FOS) occurs naturally in many foods including onions, wheat, honey, leeks and garlic. Fermentation of FOS in the colon has been shown to have the following effects:
- Increased numbers of bifidobacteria in the colon
- Increased calcium absorption
- Increased faecal weight
- Reduced gastrointestinal transit time
- Possible lowering of blood lipid levels
Increased levels of colonic bifidobacteria benefits human health by:
- producing compounds that inhibit potential pathogenic agents,
- reducing the blood ammonia levels
- producing vitamins and digestive enzymes.
Inulin is classed as a soluble, fermentable but non-digestible dietary fibre, belonging to the class of dietary fibres known as fructans. Dietary sources of Inulin include chicory root. Once consumed inulin is hydrolysed to FOS. Consumption of relatively low levels of Inulin has been shown to significantly increase the levels of faecal bifidobacteria2.
Galactooligosaccharides (GOS) are derived from enzymatic conversion of lactose. They have been shown to be an excellent substrate for beneficial bacteria, specifically lactobacilli and bifidobacteria.
Lactulose was used 40 years ago as a prebiotic infant formula supplement to increase the numbers of lactobacilli in the infant intestine. Lactulose is a non-digestible synthetic disaccharide that is now licensed for the treatment of hepatic encephalopathy and constipation.
Breastmilk contains large amounts of prebiotic oligosaccharides, including GOS. These help to promote increased gastro-intestinal levels of Lactobacilli and Bifidobacterium, potentially restricting the number of pathogenic bacteria.
Product safety
The probiotics in common use today have largely been derived from fermented foods or contain microbes that live naturally within a healthy human. They have also been used as supplements for a significant period of time.
Lactobacilli are considered relatively safe based on their widespread use in fermented food, their colonisation of the human body and the low level of infection attributed to them. As Bifidobacteria are considered to be equally safe, the use of probiotic supplements in a healthy population is relatively low risk. Use of these supplements in patients with reduced immune function or significant disease should be restricted to the microbial strains and recognised indications with proven efficacy.
Product Quality
It is important to remember that probiotics, prebiotics and synbiotics are generally classed as foods rather than medicines. This means that they don’t undergo the same testing procedures as medicines and we cannot be certain that:
- The product contains the bacteria stated on the label
- The product contains sufficient bacteria to have a beneficial effect
- The bacteria are able to survive long enough to reach the colon
As probiotics contain live micro-organisms they are susceptible to die off during storage. This die off can result in sub-therapeutic doses of the probiotic strain being administered especially towards the end of a treatment course when the extent of die off will be greatest. Responsible manufacturers will include an overage within the product to compensate for any possible die off although some probiotic products on the market have been shown to fail the label claims regarding numbers and types of viable microbes.
Product claims
Probiotics and prebiotics are typically classified as food products or supplements, consequently no specific medical claims can be made regarding the clinical use of these products.
Prescriptions
Probiotics are increasingly being prescribed for some of the clinical conditions listed above. These products can be prescribed as a food. Under the Human Medicines Act, any food, drug, toiletry or cosmetic may be prescribed on an NHS prescription unless the product is listed in Part XVIIIA of the Drug Tariff. For example, whisky is not on the blacklist, so a prescription for this item would be passed for payment by the NHSBSA Prescription Services. The prescriber may however be questioned by their Local Area Team about the appropriateness of prescribing this item at NHS expense.
Conclusion
It is well recognised that the colonic microflora is important for health and that modification of the microbiota using probiotics, prebiotics or synbiotics can produce health benefits.
Whilst there is currently data available regarding specific clinical applications of these supplements further research is required before they can undertake a key role in disease prevention and treatment.
A table comparing selected probiotic products is available to download.