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RESEARCH




The Science of Probiotics


The digestive tract forms the largest of our human “barrier” surfaces and is in direct communication with our external environment, controlling intake of vital nutrients as well as neutralising toxins and pathogens. Its structural integrity is crucial to our healthy functioning, as is the ecosystem of trillions of microorganisms spread across its surface and others, such as the genito-urinary tract, the respiratory tract and the skin. The myriad and variety of bacteria, fungi and protozoa is central to normal health and, only when an appropriate balance is maintained, does the GI tract function most effectively.

Lactobacilli, Bifidobacteira and Bacteroides are three major bacterial types found in normal adult gut. Other organisms are frequently isolated and these include Streptococci, E.Coli, and yeasts but these generally comprise a minor component of the microflora.

Functions
The gut microbiota play a vital role in health, particularly in the areas of nutrition and metabolism, immune function and protection, including:

  • Maintenance of appropriate gut pH.
  • Digestive function through enzyme activity i.e breakdown of lactose.
  • Modulation of immune function.
  • Production of antimicrobial substances, thus defending against invaders and maintaining a healthy balance of microflora.
  • Synthesis of vitamins (such as folic acid, biotin, riboflavin and vitamin k), amino acids and recycling of nitrogen.
  • Synthesis of short chain fatty acids to provide energy to the epithelial cells and throughout the body.
  • Other metabolic functions – the microbial flora can detoxify and transform many substances (e.g. deconjugation bile acids.)

Microbial Balance
The gut microflora are generally stable due to regulation of the ecosystem by competition for nutrients, space, inhibition etc. When the equilibrium of the microflora is disputed, it is possible for inflammation and disease to occur due to increased colonisation of pathelogenic organisms and extra stimulation of the immune system. There are numerous factors that may influence this stability of the microbial flora and these include:

Antibiotic Therapy
Antibiotics have a detrimental effect on not only the pathogenic organism, but also the beneficial bacteria which may leave the gut open to eventual invasion by further opportunistic pathogens.

Stress and Trauma
Both everyday stressful living and specific incidences of trauma affect the balance of the microbial flora in a detrimental manner. The effect of stress results in decreased gastric and intestinal secretions leading to an increase in the intestinal pH and a concomitant reduction in gut mobility. The consequence of these changes is that the conditions become more favourable for the growth of the more opportunistic pathogens such as E.coli and the Streptococci and much less favourable for the inherently slower growing Lactobacilli and Bifidobacteria (1).

Diet
The introduction of the modern Western diet, high in processed and refined foods, has led to a decrease in consumption of beneficial microrganisms. Although the detailed effects of diet on the balance of the microbial flora have yet to be elucidated, it appears that diet can affect the equilibrium of the gastrointestinal microflora.

The normal gastrointestinal flora may be re-established when the adverse influences causing the abnormal distribution of the microflora are eliminated. The most effective way to achieve re-establishment is by the administration of preparations containing high numbers of Lactobacilli (particularly L.acidophilus, which is a normal inhabitant of the gut) and Bifidobacteria.

IT’S ALL IN THE STRAIN
There have been over 400 different types of organisms isolated from the gut (2,3). However many of these are found only occasionally or are found in very small numbers. The bulk of the microbial population is comprised of several important types of bacteria. Such organisms must be able to contend with a variety of conditions specific to the gastrointestinal tract, they must survive the acidic conditions created by the gastric juices, and must also be resistant to bile salts and intestinal secretions.

Increasing evidence has shown the critical role played by the microflora in everyday
well-being. Hence there is growing interest in the use of microbial preparations to supplement the diet.

As scientific research has advanced, not only the definition of the characteristics which are desirable in probiotic products are beginning to become apparent, but also the shortfalls which have been associated with this type of product. These include the inability of the chosen organisms to survive stomach acidity or colonise the human gut, inadequate selection of bacteria used in these preparations (sometimes resulting in potentially pathogenic organisms being included), insufficient product quality control resulting in poor specification, and inadequate storage life. All of which may be further compounded by a lack of sufficient information on what the product is, how it works, and how it is best administered. An analysis of ten products by Coeuret et al (4) found that eight of these products were incorrectly labelled, either by quantity or strain.

In addition some probiotic supplements now contain multi-strain cultures, some of which have no safe use history in human health and nutrition. These bacteria may be antagonistic to each other and may alter the gut flora in an undesirable way. So it should not be believed that if one bacterium is good, numerous cultures combined together are even better. On the contrary, most of the positive research available for probiotics is based around one or a combination of a small select number of strains. Only a few select cultures have been proven to be beneficial and almost all the others are yet to be proven. So including a range of potentially unnecessary strains may compromise the potency, safety or efficacy of the product.

There have been several proposed criteria which may be considered important in the selection of probiotic strains which include:

  1. Use of organisms which are non-pathogenic and of human origin
  2. Organisms must remain viable during transit through the acidic conditions of the stomach
  3. Organisms must be bile tolerant
  4. The organisms must have the ability to adhere to the gut epithelial tissue
  5. The organisms must be genetically stable
  6. The organisms should have the ability to produce antimicrobial substances and inhibit known pathogens
  7. The organisms should have a positive effect on the immune system and certain metabolic pathways
  8. The organism should also be able to retain viability during manufacturing processes and delivery mechanisms into the body (4,16,17)
  9. The organisms should have a proven clinical research track record.

Of the potentially beneficial bacteria, the lactic acid bacteria (including Lactobacilli and Bifidobacteria) are frequently used as probiotics as certain species confer health benefits on the host, and they have the most potential to fulfil all the criteria required of probiotic organisms. Organisms which have been extensively researched and which are generally recognised as safe (GRAS) include Lactobacillus and Bifidobacterium species, such as L. acidophilus, L. rhamnosus, L. plantarum, L. casei, B. bifidum, B. infantis, B. longum among others (5). In terms of naturopathic use, the acidophilus and bifidobacterium species are also naturally resident and predominant in the gut and so utilising these gives the best possibility of returning the bowel flora to a ‘normal stage of balance’.

Other probiotic organisms, both resident and transient, may be used to meet specific clinical objectives.

PROBIOTICS IN PRACTICE

Infant flora
Pregnancy, birth and early infancy are vital times for development of microbiota and an appropriate balance can be critical to health. Up to the point just before birth the gastronintestinal tract is totally devoid of microorganisms, but colonisation quickly takes place during birth, with the newborn being exposed to the mother’s vaginal and faecal microflora as well as organisms from the environment (6,7,8). It has been shown that there are differences between the microflora of naturally born infants and those delivered by caesarean. Caesarean section infants have profoundly different microflora in the first months of life and abnormalities remain at 7 years and probably lifelong and may be at increased risk of allergy compared to vaginal birth infants. In healthy, breast fed infants it is Bifidobacteria that tend to dominate, most notably Bifidobacterium infantis with enterobacteria and enterococci present in small quantities. According to Rasic (1992) (9): “Bifidobacteria provide unfavourable conditions for the growth of pathogens. For instance, studies on Shigella sp infections and enteropathogenic Escherichia coli in breast fed infants in Guatemala have shown low incidence of both infections due to the predominance of bifidobacteria in the intestinal tract…the species Bifidobacterium infantis showed the greatest protective effect”.

During weaning other organisms colonise including Lactobacilli, Bacteroides, and Streptococci (10). In a recent trial, the gut flora of breast vs formula fed infants was still significantly different at 6 months (11). Results show formula feeding leads to a persistent reduction in Bifidobacteria compared to breastfeeding even after the period of breastfeeding is completed. This reduction in Bifidobacteria numbers can be corrected by either probiotic or prebiotic supplementation.

Dysbiosis as a result of antibiotic use
Antibiotic use has been widespread until recent attempts to curb prescriptions due to the high profile publicity surrounding Clostridium difficile infection in hospitals. Administration of a range of antibiotics such as penicillin, clindamycin, vancomycin and tetracycline result in proliferation of Candida albicans in the intestine (12,13). In a significant number of people the overgrowth progresses to a stage of mucosal colonisation and triggers an inflammatory response. There is an increased risk of this occurring in pregnancy or when taking the contraceptive pill. Trials have shown that supplementation with probiotics following antibiotic use prevent multiplication of Candida (14). A randomised placebo controlled double blind trial conducted in the UK in partnership with Addenbrookes Hospital, Cambridge Gastroenterology Department demonstrated significant reduction of opportunistic pathogen re-growth following use of antibiotics.

Specifically there was statistically significant reduction of Staphylococci, Enterococci and Enterobacteria (coliforms) in patients given proprietary high strength blend of Lactobacillus acidophilus and Bifidobacterium bifidum after antibiotic dosage. The effect was more profound if the probiotics were given both with and following antibiotics (15).

Another trial using the same probiotic blend demonstrated greater than 70% reduction in antibiotic resistance in coliforms and enterococci (16).

Clostridium difficile infection
A further Addenbrookes double blind placebo controlled trial showed significant competitive inhibition of Clostridium difficile in hospitalised patients taking probiotics. 67% of control patients developed diarrhoea as opposed to 18% of the probiotic treated patients (17).

Autism and other developmental conditions
Many children suffering from autism may have concomitant dysbiosis due to antibiotics being given at a young age and may present with a history of bowel symptoms and respiratory/skin allergies with mood disorders, possibly occurring later or concurrently. A possible relationship between gluten, casein, and autism was first articulated by Kalle Riechelt, M.D. in 1991. Based on studies showing a correlation between autism and increased urinary peptide levels, Reichelt hypothesized that some of these peptides may have an opiate effect. Further work determined opioid peptides such as casomorphines (from casein) and gluten exorphines and gliadorphin (from gluten) as possible suspects, due to their chemical similarity to opiates. Reichelt hypothesizes that long term exposure to these opiate peptides may have effects on brain maturation and contribute to social awkwardness and isolation and this appears to be partially substantiated by a recent Cochrane report confirming that, although evidence is mixed, exclusion of wheat and dairy may result in improvements in autusm. Lactobacillus rhamnosus has also been identified as an inducer of higher levels of the immunoprotective antibody slgA, important in children prone to gastrointestinal inflammation and infection. It also demonstrates properties of opiate-peptide degradation alongside Lactobacillus crispatus. Initial findings suggest that a combination of these alongside a proprietary blend of Lactobacillus acidophilus and Bifidobacterium bifidum strains may reduce urine levels of opioid peptides.

Immune support and allergy
Developing appropriate colonies of probiotic organisms in the infant is critical to long-term immune function. In particular the infant immune system is predisposed to TH2, or antibody forming, response. Contact with normal flora has the effect of balancing the TH1 and TH2 immune responses, potentially stabilising the immune-inflammatory response and increasing oral tolerance of foods.

Lactobacillus bulgaricus has been shown to down-regulate pro-inflammatory cytokines in gut tissue samples taken from Crohn’s suffers whilst Lactobacillus rhamnosus is a potent stimulator of interleukin 12, which positively enhances cell-mediated immunity. In a comprehensive research review, one author Gill (2003) gives several examples of enhanced immunity including (for example) that rhamnosus fed subjects had more phagocytically active blood leukocytes than controls. Overall the author concludes that non-specific and specific immune responses may be enhanced by probiotic administration including lactobacillus rhamnosus.

Progression of research in the field of probiotics continues to advance our knowledge and provides the potential for many more new developments and discoveries. As the public and conventionally trained doctors and researchers become more and more aware of the health benefits probiotics can offer, so the amount of research and new discoveries progresses. Probiotics, if selected and used appropriately, may have a wide range of applications both in restorative and preventative health and, crucially, offer this without side effects. The current increasing trend in probiotic interest looks only to increase and the future in the field of probiotics looks very positive indeed.

References
1. Kelly GS. Nutritional and botanical interventions to assist with the adaptation to stress. Altern Med Rev. 1999 Aug;4(4):249-65
2. Collind DM, Gibson GR: Probiotics, prebiotics, and synbiotics:approaches for modulating the microbial ecology of the gut. Am J Clin Nutr. 1999;69(Suppl):1052S-7S
3. Bourlioux P, Kloetzko B, Guarner F, Braesco V. The intestine and its microflora are partners for the protection of the host: report on the Danone Symposium “The intelligent Intestine”, held in Paris, June 14, 2002. Am J Clin Nutr. 2003 Oct;78(4):675-83
4. Coeuret V, Gueguen M, Vernoux JP. Numbers and strains of lactobacilli in some probiotic products. Int J Food Microbiol. 2004 Dec 15;97(2):147-56
5. Stanton C, Gardiner G, Meehan H, Collins K, Fitzgerald G, Lynch PB, Ross RP. Market potential for probiotics. Am J Clin Nutr. 2001 Feb;73(2 Suppl):476S-483S
6. Drisko JA, Giles CK, Bischoff BJ. Probiotics in health maintenance and disease prevention. Altern med Rev. 2003 May;8(2):143-55
7. Mackie RI, Sghir A, Gaskins HR: Developmental microbial ecology of the neonatal gastrointestinal tract. Am J Clin Nutr 1999;69(Suppl):1035S-45S.
8. Karimi O, ena AS. Probiotics: Isolated bacteria strain or mixtures of different strains? Two different approaches in the use of probiotics as therapeutics. Drugs Today (Barc). 2003 Aug;39(8):565-97
9. Rasic, J Bifidobacteria and diarrhoea control in infants and young children. Intern Clin Nutr Review Jan 1992
10. Fanaro S, Chierici R, Guerrini P, Vigi V: intestinal microflora in early infancy: composition and development. Acta Paediatr Suppl. 2003 Sep;91(441):48-55
11. Rinne M, Kalliomäki M, Salminen S and Isolauri E (2006) Probiotic intervention in the first months of live: short-term effects on gastrointestinal symptoms and long-erm effects on gut microbiota. Journal of Pediatric Gastroenterololgy and Nutrition 43, 200-205
12. Gotz V et al (1997) Prophylaxis against ampicillin associated diarrhoea with a lactobacillus preparation. American journal Hospital Pharmacist 1979 36:754-57
13. Vanderhoof J, Whitney DB, Antonson DL et al. lactobacillus GG in the prevention of antibiotic-associated diarrhoea in children. J Pediatr 1999;135:564-8
14. Kennedy, M. J., and P.A. Volz. 1985. Ecology of Candida albicans gut colonization: inhibition of Candida adhesion, colonization, and dissemination from the gastrointestinal tract by bacterial antagonism. Infect. Immune. 49:654-663
15. Jennifer A.J Madden, Susan F. Plummer, James Tang, Iveta Garaiova, Nigel T. Plummer, Mary Herbison, John O. Hunter, Takashi Shimada, Lei Cheng, Tao Shirakawa Effect of probiotics on preventing disruption of the intestinal microflora following antibiotic therapy: A double-blind, placebo-controlled pilot study. International Immunopharmacology 5 (2005) 1091-1097
16. Susan F. Plummer, Iveta Garaiova, Tinnu Sarvotham, Simon L. Cottrell, Stephanie Le Scouiller, Mark A. Weaver, James Tang, Philippa Dee, John Hunter Effects of probiotics on the composition of the intestinal microbiota following antibiotic therapy International Journal of Antimicrobial Agents 26 (2005) 69-74
17. Susan F Plummer, Mark Weaver, Janine C Harris, Philippa Dee, John Hunter. Clostridium Difficile pilot study: effects of probiotic supplementation on the incidence of c difficile diarrhoea. International Microbiology 2004, 7:59-62
18. Millward C, Ferriter M, Calver S, Connell-Jones G. Gluten- and casein-free diets for autistic spectrum disorder. Cochrane Database of Systematic Reviews 2008, Issue 2
19. Borruel, N., Carols, M., Casellas, F., Antolin, M., de Lara, F., Espin, E;, Naval, J;, Guarner, F;, malagelada, J.R.(2002) Increased mucosal tumour necrosis factor alpha production in Crohn’s disease can be downregulated ex vivo by probiotic bacteria. Gut 2002;51:659-664
20. Hessle, C;, hanson, A., Wold, AE., 1999. Lactobacilli from human gastrointestinal mucosa are strong stimulators of Il-12 production. Clinical and Experimental Immunology. 116: 276-282
21. Gill, H.S. 2003. Probiotics to enhance anti-infective defences in the gastrointestinal tract. Best Practice & Research Clinical Gastroenterology. 17(5): 755-773




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