Probiotics: Background. Actions

Background and Relevant Pharmacokinetics

The generally accepted definition of a probiotic is ‘a live microbial food supplement which beneficially affects the host animal by improving its intestinal microbial balance’. This definition is, however, rather limited as some probiotics are transient and do not take up residence in the intestinal tract. A better definition may be ‘[a] microbial dietary supplement that beneficially affect the host physiology by modulating mucosal and systemic immunity, as well as improving nutritional and microbial balance of the intestinal tract’.

The gastrointestinal tract is sterile at birth. Normal gut flora develops gradually over time and is influenced by factors such as composition of the maternal gut microflora, diet, degree of hygiene, use of antibiotics or other medication, the environment and possibly genetic aspects. Once established, a person’s individual gut flora remains surprisingly constant throughout life. This is likely to be due to the fact that the gut immune system learns to recognise and tolerate those bacterial species acquired during early infancy. It is therefore very difficult to alter the composition of the gut flora after this time. Successful colonisation with probiotics is therefore most often transient, as the gastrointestinal tract has many defences that inhibit this process. The intestines are host to 1014 microbes representing 400-500 different species.

Clinical note — Prebiotics

There is another concept associated with the microflora and intestinal health: prebiotics, which are compounds that modify the environment of the gastrointestinal tract to favour proliferation of the beneficial intestinal microflora. Herbal and nutritional prebiotics include the fibre-supplement known as slippery elm (Ulmus fulva), oligofructose and inulin. The prebiotic approach, while promising, has not been thoroughly tested by controlled clinical trials.

Chemical Components

Probiotics include Bifidobacteria (e.g. B. bifidum), Lactobacillus acidophilus, L. bulgaricus, L. casei, L. gassen, L. plantarum, L. reuteri, L. GG (variant of L. casei subsp. rhamnosus, named after Drs Gorbach and Goldin who first isolated the strain in 1980), Lactobacillus strain LB, Saccharomyces boulardii (a yeast), Streptococcus thermophilus and Streptococcus salivarius.

Historical Note

Eating foods containing microorganisms to improve health has a long tradition. As far back as 1908, Metchnikoff, the Nobel laureate, stated that ‘ingested lactobacilli can displace toxin-producing bacteria, promoting health and prolonging life’. The term ‘probiotics‘ was first coined in 1965 in reference to substances produced by protozoa that stimulated the growth of other organisms. It has since been applied to those microorganisms found naturally in foods that are able to improve health by stimulating the growth of beneficial organisms. Although it has taken the most part of a century for scientists to investigate their health benefits, there are now several thousand studies on probiotics available on Medline, the majority published since 2000.

Food Sources

Fermented foods of dairy or vegetable origin, such as yoghurt and sauerkraut respectively, are a source of probiotics. Of these, dairy sources such as yoghurt are most popular and may contain probiotics, especially Lactobacillus acidophilus and bifidobacteria strains.

Deficiency Signs and Symptoms

Clear deficiency signs are difficult to establish because the symptoms may vary enormously. Local signs and symptoms of an imbalance of the intestinal flora (intestinal dysbiosis) include bloating, flatulence, abdominal pain, diarrhea and/or constipation and fungal overgrowth (such as Candida).

Imbalance of the intestinal flora may result from the use of antibiotics, chronic diarrhea or constipation. Additionally, babies exclusively fed on infant formulas will have slower colonisation of the gut than those who are breastfed, as breast milk allows for the transfer of oligosaccharides to the baby. This appears to be of particular concern in premature babies requiring intensive care as they acquire intestinal organisms slowly, which allows for the colonisation of bacterial species that tend to be virulent. It has been suggested that the aberrant colonisation of the premature infant’s gut may contribute to the development of necrotising enterocolitis and, therefore, probiotics supplementation may be a useful approach for prevention.

Probiotics: Main Actions

The positive effects of probiotics are a result of several different mechanisms.

ENHANCED IMMUNE RESPONSE

Immune system modulation and the prevention of gastrointestinal tract colonisation by a variety of pathogens are perhaps the most important actions of probiotics.

Probiotics bind to intestinal epithelial cells and inhibit the binding of pathogenic bacteria to the gut wall by production of inhibitory substances such as bacteriocins, lactic acid and toxic oxygen metabolites. Of the toxic oxygen metabolites, hydrogen peroxide is of major importance as it exerts a bactericidal effect on many pathogens. The ability to produce bacteriocins, hydrogen peroxide and other antimicrobial compounds is strain-dependent and requires the presence of folic acid and riboflavin in the case of lactobacilli. Binding to the gut wall also initiates signalling events that result in the synthesis of cytokines. Studies in germ-free mice have proven that intestinal bacteria are essential for a healthy systemic immune system.

Lactobacillus GG has been well studied in this regard and shown to modulate intestinal immunity by increasing the number of IgA and other immunoglobulin-secreting cells in the intestinal mucosal and stimulates the local release of IFNs.

Helicobacter pylori infection

Several in vitro studies have shown that certain probiotics inhibit or kill H. pylori, prevent its adhesion to mammalian epithelial cells and prevent IL-8 release. In vivo models demonstrate that pretreatment with a probiotic can prevent H. pylori infections and/or that administration of probiotics markedly reduces an existing infection. Clinical efficacy has also been established for the use of probiotics as prevention or treatment, according to a review of six clinical studies.

DIGESTIVE PROCESSES

The gut bacteria carry out a number of biochemical functions, including deconjugation and dehydroylation of bile acids, the conversion of bilirubin to urobilinogen, the metabolism of cholesterol to coprostanol, production of vitamins K, B1, B2, B6, B12 and generation of short-chain fatty acids. Probiotics are involved in balancing colonic microbiota and aid in the treatment of diarrhea associated with travel and antibiotic therapy, and control of rotavirus and Clostridium difficile-induced colitis.

CHEMOPREVENTATIVE EFFECTS

Antimutagenic activity against chemical mutagens and promutagens has been demonstrated for different strains of Lactobacillus acidophilus, Bifidobacteria and the organic acids usually produced by these probiotics, with live cells producing the most positive results. Some probiotics also reduce faecal enzymes implicated in cancer initiation, by producing butyric acid, which affects the turnover of enterocytes and neutralises the activity of dietary carcinogens, such as nitrosamines. Additionally, enhancing host immunity and qualitative and quantitative changes to the intestinal microflora and physicochemical conditions are important contributing factors.

Probiotics: Other Actions

CHOLESTEROL-LOWERING ACTIVITY

This has been established in several clinical trials (see ‘Clinical Use’ below)

ALLERGY

High-level antigen exposure during the first few months of life is suspected of predisposing individuals to allergic sensitisation and, therefore, various atopic conditions. The intestinal microflora plays a major protective role against the development of allergy because it reduces antigen transport through the intestinal mucosa.