The Many Faces Of Intestinal Microflora – Part IV

EDITORIAL COMMENT

In the last installment of this series on intestinal microflora, I would like to focus on three aspects of the subject that carry great importance concerning the clinical management of the dysbiotic patient:

  1. Emotional Stress
  2. Introduction of probiotic organisms
  3. Use of  “prebiotics,” substances that promote the growth of probiotic organisms.

I.    EMOTIONAL STRESS

While this subject has received a great deal of attention recently as a causative factor in chronic illness, little mention has been made of the idea that emotional stress may cause its damage by altering gut microflora. Unfortunately, I have been able to find little published research on this subject.  However, what is available is worth noting.  As most of you are now well aware, the adrenal cortical hormone, cortisol, is primarily responsible for most of the negative effects of stress of all types, including emotional.  Also, recall from the previous newsletters in this series that the quality of mucus and hydrochloric acid production in the gut has a profound effect on microbial populations.  Tannock (1) notes:

“Corticosteroids influence the production of mucus in the stomach of rats; cortisone acetate and prednisolone reduce the amount of mucin in the gastric mucosa.  If stress influences the secretion of mucus in other parts of the gastrointestinal tract…mucosa-associated populations of microbes could be affected.”

Tannock also notes:

“Emotional stress in humans…can result in decreased secretion of hydrochloric acid in the stomach.  Hydrochloric acid secretion in the stomach of monogastric animals has an important influence on the numbers and types of microbes present in that site.  The human stomach normally contains only small numbers of gram-positive bacteria (lactobacilli and streptococci).  These bacteria are believed to be transient organisms entering the gastrointestinal tract in food and saliva.  Humans suffering from gastric achlorhydria have other types of bacteria present in the stomach (coliforms and Bacteroides), and a relatively large number of these bacteria may be present.”

In addition, please note the comments by Finegold et al (2) concerning a study on the fecal microflora of five human subjects over a five month period:

“One unique finding was the marked variation in one organism (Bacteroides thetaiotaomicron), which was felt to be related to an ‘anger-stress’ situation experienced by one of the subjects.”

Much has been stated recently concerning how the clinical course of many maladies can be improved by optimization of cortisol levels through the use of stress management techniques and nutritional intervention.  It should also be noted that dysbiosis is another condition that may likely benefit from the above therapeutic procedures.         

II.   PROBIOTICS

Most individuals in this country who are even remotely familiar with the subject of  clinical nutrition are aware of the improvements that can be gained not only in intestinal function, but overall health, by the ingestion of  probiotic organisms, i.e., lactic acid bacteria and bifidobacteria.  Of course, this type of therapy did not start recently with the development of lactobacillus and bifidus containing supplements.  For, fermented milk products containing these organisms have been showing empirical benefits for generations.  However, many may be unaware of the rationale for giving these organisms or the mechanism for their effect.  Furthermore, the idea that ingestion of probiotics improves health is not without controversy.  What follows are highlights from the peer reviewed literature that explain these points.

A.  Types of organisms – Rafter (3) points out the following concerning the types of probiotic preparations available in the marketplace:

“The probiotics preparations currently on the market are in the main based on lactic acid bacteria (lactobacilli, bifidobacteria, and streptococci).  There are also other microorganisms used as probiotics.

B.  What are the general effects of these organisms and mode of action? – Again Rafter states:

“Effects and modes of action can differ.  The most evident effects involve changes in viable counts of microorganisms in the intestinal flora after ingestion.  These effects can…be caused by competition for adhesion sites and nutrients between the ingested microorganisms and potential pathogens.  Another mode of action for the probiotic can be production of antibacterial substances.  However, the influence of a probiotic supplement is not always that pronounced.  There can also be an alteration of microbial metabolism in the gut, which can be detected as, for instance, altered bacterial enzyme activities, changed pH, or influence on levels of cholesterol.”

C.  Of the probiotic organisms, is any more important than the others? – Of the papers reviewed, the consensus seems to be that bifidobacteria is the most important.  Consider the statement made by Mitsuoka (4) that originally appeared in the first installment of this series:

“The available evidence suggests that the presence of bifidobacteria in the large intestine helps to maintain health and that these species are far more important throughout life as beneficial intestinal bacteria than is Lactobacillus acidophilus.  In other words, the reduction or disappearance of bifidobacteria in the human intestine indicates an unhealthy state.”

Why is Bifidobacteria so essential?  Consider the points made by Gibson and Roberfroid (5) concerning the ways bifidobacteria benefit the host:

  1. “Bifidobacteria produce strong acids as metabolic end products (acetate, lactate).  These lower the pH of the medium and may thus exert an antibacterial effect.  Further work has indicated that bifido-bacteria are able to excrete a metabolic end product that is directly inhibitory to a range of Gram-positive and Gram-negative pathogenic bacteria.”
  2. Bifidobacteria helps reduce blood ammonia levels.
  3. “Bifidobacteria produce vitamins, largely of the B group, as well as digestive enzymes such as casein phosphatase and lysozyme.”
  4. “Certain cellular components of bifidobacteria act as ‘immunomodulators’, i.e., they promote immuno-logical attack against malignant cells.  This activation of the immune system will also contribute towards improved host resistance to pathogens.”
  5. “These flora have also been shown to restore the normal intestinal flora during antibiotic therapy.”
  6. Bifidobacterium longum used as a probiotic has been reported to prevent bacterial translocation.”

Mitsuoka (4) is even more expansive on the benefits of  bifidobacteria, suggesting they may have a relationship to aging:

“In aging persons, bifidobacteria are diminished, whereas clostridia, including C. perfringens, lactobacilli, streptococci, and Enterobacteriaceae increase.  These changes are considered a result of aging, but they actually may help to accelerate senescence.”

D.  Since much of what was stated above concerns endogenous lactobacilli and bifidus, is there value in ingesting these microorganisms supplementally?  –  This is a very controversial question among researchers with no clear

consensus.  On the positive side, Gibson and Roberfroid (5) state:

“It has been hypothesized that probiotics administered to humans can have positive effects in a number of biomedical conditions.  These include diarrhea, constipation, colitis, recolonization by pathogens, flatulence, gastroenteritis, gastric acidity, immunostimulation, hypercholesterolemia, hepatic encephalopathy, and carcinogenesis.”

Of the claims stated above, the one concerning carcinogenesis has generated much interest.  Rafter (3) states:

“It should be pointed out…that there is no direct experimental evidence of cancer suppression in humans as a result of consumption of lactic cultures in fermented or unfermented dairy products.  However…there is a wealth of indirect evidence in the literature…”

Rafter reported research findings that suggest three ways in which ingested probiotic organisms may prevent colon cancer:

1.    Some factors in fried meat are known to increase the presence of mutagens in both the feces and urine. Studies have shown that ingestion of  L. acidophilus in human subjects lowers mutagenic activity in each of the above excretions.  Rafter suggests the following mechanism to explain the above effect:

“…it is possible that the L. acidophilus supplements are influencing excretion of mutagens by simply binding them in the intestine.”

2.    Recall from parts II and III in this series that the microfloral enzymes beta-glucuronidase, nitroreductase, azoreductuse can convert ingested substances to carcinogenic factors.  Rafter points out several studies that show a decrease in the activity of these enzymes when L. acidophilus is fed to healthy volunteers over varied periods of time ranging, depending on the study, from ten days to three weeks.  Unfortunately, one of these studies noted the following:

“A reversal of the effect was observed within 10-30 days of stopping Lactobacillus feeding, indicating that continuous consumption of these bacteria was necessary to maintain the effect.”

Furthermore, the following caveat by Rafter should be kept in mind:

“…we still do not know how or whether a reduction in these enzyme activities affects cancer rates in humans.  Indeed, the origin of the carcinogens causing this disease in humans is still unknown.  It can also be mentioned that the reports published to date do not always find reductions in the same enzymes, although findings with beta-glucuronidase and nitroreductase are most consistently positive.”

3.    Recall from previous newsletters in this series that one of the positive effects of gut organisms is to metabolize potentially carcinogenic bile acids that are produced in higher amounts when a high fat diet is ingested.  Rafter reports two studies, one utilizing L. acidophilus and the other using Strep. faecium, that demonstrate a decrease in fecal bile acids when these bacteria were supplemented.  However, as with the              enzymes discussed above, the author notes that neither of these studies provide positive proof that ingestion of probiotic organisms can prevent colon cancer.

Finally, Rafter summarizes the ways in which lactic acid bacteria might inhibit colon cancer:

“…such mechanisms might include: enhancing the host’s immune response; suppressing the growth of intestinal microflora incriminated in producing putative carcinogen(s) and promotors; binding potential carcinogens; producing antitumorigenic or antimutagenic compounds in the colon; alteration of physiologic conditions (such as pH) in the colon, affecting the metabolic activity of intestinal microflora and the action of bile acids, and causing quantitative and/or qualitative alterations in the bile acid-degrading bacteria.”

In discussing the controversial issue of whether ingestion of probiotics can improve health, I have, so far, quoted authors that have sided towards the positive.  Thus, in fairness, the comments of  Tannock (6) should also be kept in mind:

“It can be argued that the bacteria contained in probiotics have special properties that will affect the well being of the host.  This type of argument cannot withstand scientific testing, however, because the bacterial strains used in current probiotics have been chosen largely on the basis of their amenability to industrial scale cultivation and survival ability during storage.  Most, if not all, of the characteristics of these strains have been determined under in vitro conditions, and scientifically valid field trials of efficacy are rarely made.”

 E.   What are the properties of a quality probiotic?  Gibson and Roberfroid (4) state:

  1. The probiotic must be capable of being prepared in a viable manner and on a large scale (e.g., for industrial purposes.
  2. During use, and under storage, the probiotic should remain viable and stable.
  3. It should be able to survive in the intestinal ecosystem.
  4. The host animal should gain beneficially from harboring the probiotic.”

 Certainly the most argued of the points listed above is whether ingested organisms can withstand the effects of such factors as gastric and bile acids.  The authors point out:

“There is some evidence that at least a proportion of the bifidobacteria is able to reach the colon.”

As you can see, the idea that the ingestion of probiotics is efficacious is far from being universally accepted.  Gibson and Roberfroid (5) further elaborate on all the factors that weigh against the idea that probiotic ingestion might be beneficial:

“The probiotic microorganism needs to establish in the colon and, preferably, become active.  For increased persistence the probiotic may need to adhere to the intestinal epithelium.  Here difficulties arise.  The probiotic is likely to be in some sort of stressed state due to its encounters with the adverse conditions referred to above.  This would probably compromise its chances of survival.  Next, the bacteria would need to compete for nutrients and ecological sites of colonization with a previously established microbial flora compromising several hundred other bacterial species.  Indeed, the data…indicate that when the product containing the probiotic is no longer consumed, the added bacteria are rapidly washed out of the colon.”

Is there a way to overcome the limitations stated above?  Gibson and Roberfroid suggest the use of  “prebiotics”:

“…which are not viable entities but rather are growth substrates specifically directed toward potentially beneficial bacteria already growing in the colon.”

III.  Prebiotics

What are the properties of a prebiotic?  Gibson and Roberfroid (5) state:

“In order for a food ingredient to be classified as a prebiotic, it must 1) be neither hydrolyzed nor absorbed in the upper part of the gastrointestinal tract; 2) be a selective substrate for one or a limited number of beneficial bacteria commensal to the colon, which are stimulated to grow and/or are metabolically activated; 3) consequently, be able to alter the colonic flora in favor of a healthier composition; and 4) induce luminal or systemic effects that are beneficial to the host health.”

According to the above authors, many nondigestible carbohydrates, peptides, and proteins serve as nourishment for colonic organisms, However, most do not qualify as prebiotics because they feed both beneficial and harmful microbial species.  One family of carbohydrates, though, the fructooligosaccharides (FOS) do qualify because, as stated by Hudson and Marsh (7),  they feed primarily bifidobacteria and, secondarily, lactobacilli.  FOS are composed of two major substances, oligofructose and inulin.  These compounds can be found in foods such as onion, garlic, chicory, Jerusalem artichoke, asparagus, and wheat.

Given the limitations of supplementation of only probiotic organisms, Gibson and Roberfroid (5) point out that preparations containing both organisms and FOS have many potential advantages.  They state:

“Such an approach could ultimately produce the following nutritional benefits; improved survival of live bacteria in food products with, as a consequence, prolonged shelf life; an increased number of ingested bacteria reaching the colon in a viable form; stimulation in the colon of the growth and implantation of both exogenous and endogenous bacteria; and activation of the metabolism of these bacteria (it is important to emphasize that only the metabolically active bacteria can promote health).  This approach will be particularly important if the bacteria that are targeted utilize specific substrates, as is the case for bifidobacteria.”

A concern that has arisen regarding FOS ingestion has been the fact that, since it is a sugar, it may affect carbohydrate and lipid regulation, particularly in diabetic patients.  Hidaka et al (8) point out the following results concerning their experiments in this area:

“…the daily intake of fructooligosaccharides ameliorates the derangements of carbohydrate and lipid metabolism in diabetic patients.”       

Thus, not only did FOS show no detrimental affects on sugar metabolism in diabetes, it actually provided improvement.

One final, very important concern should be pointed concerning FOS ingestion.  Hudson and Marsh (7) state:

“…intestinal gas production with bloating and abdominal discomfort are common complaints following ingestion of inulin and fructo-oligosaccharides and at least one study suggests that prolonged ingestion of this carbohydrate does not invoke an adaptive response.”

Are there other foods or substances that enhance growth of probiotic organisms?  Mitsuoka (4) point out the following:

A. Tea polyphenols – These compounds were found to enhance the growth of several lactobacillus and bifidus species and, in turn, retard the growth of some clostridia.

B. Panax ginseng – Panax ginseng enhances the growth of Bifidobacterium breve and B. longum without promoting  clostridia or E. coli.  From these findings the author concludes:

“These results suggest that the pharmacologic actions of panax may be explained at least in part by its effect on intestinal flora.”

Author’s Comment:  Given the fact that the peer-reviewed literature is somewhat equivocal on the efficacy of pro- and prebiotics in addressing various ailments, I would like to offer some thoughts of my own.  In my opinion, the anecdotal evidence suggests that use of these substances will be beneficial in a large number of cases.  However, clinical feedback also suggests that significant amounts of patients will not see a positive response.  In situations where this approach is unsuccessful, consider the idea that implantation was denied either due to overgrowth of dysbiotic organisms or poor health of the gut lining.  Several herbal antimicrobials are now available that will address the former situation with minimal or no side effects.  Supplements containing nutrients such as L-Glutamine, partially hydrolyzed protein, and/or butyrate have been found to be helpful with the latter issue.

CONCLUSION

I would assume, after reading these four installments on intestinal microflora, that you now realize the tremendous complexity of this “organ-within-an-organ” (9).  However, I hope you now also realize that the symbiotic relationship that we have with this world within us should not be an afterthought, as it often is, but should be of primary consideration when any attempts are made at improving the health of patients.  In closing, I would ask that you think of the gut microflora as an ever faithful, vigilant watch-dog standing guard at the primary barrier that separates us from a universe of hostile factors.  Like any good watch-dog, if it is treated well and given optimal nourishment, it will give years of unrelenting good service.  However, if it is mistreated, it just might bite, possibly leading to a very unpleasant demise.  Remember the sage wisdom of V.E. Irons:

   “Death begins in the colon!”

Moss Nutrition Report #115 – 12/01/1995

REFERENCES

1.   Tannock, G.W., “Effect of Dietary and Environmental Stress on the Gastrointestinal Microbiota,” in Human Intestinal Microflora in Health and Disease, Hentjes, D.J. ed., Academic Press, New York, 1983, pp. 517-535.

2.   Finegold, S.M. et al, “Normal Indigenous Intestinal Flora,” in Human Intestinal Microflora in Health and Disease, Hentjes, D.J. ed., Academic Press, New York, 1983, pp. 3-31.

3.   Rafter, J.J., “The Role of Lactic Acid Bacteria in Colon Cancer Prevention,” Scand. J. Gastroenterol., Vol. 30, No. 6, pp. 497-502, June, 1995.

4.   Mitsuoka, T., “Intestinal Flora and Aging,” Nutr. Rev., Vol. 50, No. 12, pp. 438-446, December, 1992.

5.   Gibson, G.R. and Roberfroid, M.B., “Dietary Modulation of the Human Colonic Microbiota: Introducing the Concept of Prebiotics,” J. Nutr., Vol. 125, No. 6, pp. 1401-1412, June, 1995.

6.   Tannock, G.W., “Role of Probiotics,” in Human Colonic Bacteria: Role in Nutrition, Physiology, and Pathology Gibson, G.R. and Macfarlane, G.T. eds., CRC Press, Boca Raton, 1995, pp. 257-271.

7.   Hudson, M.J. and Marsh, P.D., “Carbohydrate Metabolism in the Colon,” in Human Colonic Bacteria: Role in Nutrition, Physiology, and Pathology, CRC Press, Boca Raton, 1995, pp. 61-73.

8.   Hidaka, H. et al, “The Effects of Undigestible Fructooligosaccharides on Intestinal Microflora and Various Physiological Functions on Human Health,” in Advances in Exp. Med, Vol. 270: New Developments in Dietary     Fiber, Furda., I. and Brine, C.J. eds., Plenum Press, New York, 1990, pp. 105-117.

9.   Grimble, G.K., “Essential and Conditionally Essential Nutrients in Clinical Nutrition,” in Organ Metabolism and Nutrition: Ideas for Future Critical Care, Kinney, J.M. and Tucker, H.N. eds., Raven Press, New York, 1994, pp. 267-300.