The Probiotic Panacea

My insides are aching, doc. I just finished a round of antibiotics. I had the worst diarrhea with it and it’s getting worse. My guts and my brain are all out of sorts and I’ve been hearing that something called probiotics might help. They seem like the magic pill for painful bowels, or infections or immune issues or skin problems. Like the antidote to the antibiotic.

So tell me doc, how do I go about my copious consumption? Hook me up.

“I think you should indiscriminately throw billions, in fact hundreds of billions of bacteria at it.” – said no-one ever, except maybe a Naturopath. “I’ll call them pro-biotics.”

We’ve grouped certain species (about 3) human-inhabiting bacteria into a category, called “pro-biotics”, which means “in favour of life”. I mean, something with that kind of reputation has to be good, right? I wish it were that easy.

For those of you who know me, you know I don’t like medical claims to be vague. “Probiotics” are vague. It can be any quantity and selection of many species of bacteria, and each one can claim to treat certain conditions with different concentrations or strains. This, I find suspiciously industry-crafted and in my searching, the scientific backing for these claims is lacking.

I use probiotics regularly in practice, because I’ve been told to by my education. I use probiotics myself because I’ve seen my own health improve with them. I tell patients to take high doses of the strains I know, because I’ve seen so many people improve with their administration. This is enough for me as a clinician, but it is not enough for me, as a researcher. I yearn to know more. So learn, we will.

Probiotics is an imprecise and all encompassing term, that means a supplement or food that contains microorganisms that are beneficial to health.

The species of bacteria that seem to be most spoken of /marketed/studied:

1. Lactobacillus acidophilus & L. rhamnosis

2. Bifidobacterium bifidus, B. infantis (animalis), B. longum, B. plantarum.

In all my researching, I still haven’t quite uncovered why or how we honed in on these specific bacteria as the “beneficial strains” out of the 400-500 species that live in our gut (1),  but I guess most medical discoveries are like mold on cheese; a chance finding.

I like this quote from Peekhaus, which reflects that choosing 2-8 species, out of 500, to be the primary healers may be a little narrow minded and inflexible.

We know little of substrates for growth. We do not know for certain which nutrients allow for intestinal colonization by any individual bacterium … The diversity of microorganisms in the gut ecosystem is believed to reflect their abilities to occupy different ecological niches. The nutrient/ niche theory… postulates that the numerous ecological niches within the intestine are defined by nutrient availability. According to this hypothesis, individual species have a preference for one or a very few of the plethora of substrates that arise in the intestine from ingested food, epithelial and bacterial cell debris, and the mucus lining of the epithelium. The result is a balanced ecosystem in which each of the numerous intestinal niches is occupied by an individual bacterium, with individual population sizes being determined by the available concentration of the preferred nutrient. (1)

In plain language: The wider the variety of nutrients, substances, pieces of food that we ingest, the more balanced the flora within us. Bacteria have preferences that we cannot predict, it’s our job to give them a buffet.

If we are a rich and diverse universe of eukaryotic cells, both human and bacterial, I might consider the term “commercial or proprietary probiotic strains” a little xenophobic, and slightly (if not outright) reminiscent of the colonial era. In fact, we even use the words colonization in reference to the desired effect of using said probiotics. It seems a little reductionist to me. But, I am a scientist and a clinician, so I think; if we are going to be shoving isolated organisms down people’s throats, all in the name of health, I’d like to do the due diligence to find out if this Foreign Aid:

  1. Does what we say it does.
  2. Is accepted by the recipient.
  3. Fosters independence from aid.

Aren’t these all things we would normally ask about “saviours”?

I will answer these 3 questions AFTER we do some learning about the human microbiome.

In addition to being “outnumbered” overall (hey! coexist, don’t get so territorial) , there are 100 x the number of bacterial cells in our gut, than human cells in our entire body. (2, 3).  It’s a trip. Don’t think too hard about it. Just think – the gut is where the party is, and that’s where we will be focusing our energy. 

So who is at the party? The top 10 bacterial species, we know of, most to least likely to encounter in a random person’s colon (ie; not concentration, but incidence) (3):

  • Bacteroides fragilis
  • Enterococcus faecalis
  • Escherichia Coli
  • Klebsiella spp
  • Enterobacter spp.
  • Bifidobacterium bifidus
  • Lactobacillus spp
  • Clostridium perfringens
  • Staphylococcus aureus
  • Proteus mirabilis

Can you see why I’m surprised that we narrowed in on the two species above? I mean the research shows that these are clearly the bacteria that do something protective/different, but I’m just surprised, considering their relative incidence.

How will we break this all down? Let’s go area by area – given the sheer number, it’s easier than bacteria by bacteria. 

We were sterile in utero. Immediately upon birth, with oxygen and exposure to vaginal bacteria (L.acidophilus from the vaginal canal & B. bifidum that originated in the mother’s feces) (3), or non-vaginal bacteria from the environment, we were colonized.

By one week, all infants are colonized by a wide variety of organisms. In one study, during that first week, 61%  of vaginally delivered babies were colonized with Bacteroides fragilis, whereas only 9% of Cesaerean sectioned babies had this species present (4).

In addition, breast-fed infants (whether vaginally birthed or not), had higher B. bifidum counts and lower Enterobacteria and Streptococci. This breast-fed bacterial balance, seemed to keep the  Bacteroides & Clostridium from rising excessively as well (4)  

“By the end of the second year, the composition and metabolism of the child’s microflora resembles closely those of the adult and is more stable. Such a flora forms a dense layer, which acts as a remarkably effective barrier against the colonisation of exogenous bacteria.” (4) 

Breastmilk has what we call “prebiotics”.  The Bifido spp. are not being exogenously replaced by mother’s milk, instead the oligosaccharides in breastmilk are preferential to colonic bifidobacterium and lactobacillus, which encourages their growth (3, 5) . Also, it was found that human milk has a lower buffering capacity than cow’s milk. As such lactic and acetic acids produced by endogenous bifidobacteria can lower the pH of the colon contents to pH 5, thus preventing the growth of pathogens and many organisms normally found in adults and in bottle-fed infants(6).

We are constantly fluxing from the day we are born, to the day we pass on – because of what we eat, feel, do, touch  – and thus the human microbiome cannot be reduced to a snapshot. Every individual has unique, but stable strains of bacteria that go along our life journey with us (1, 7).  Weaning, teeth eruption and hormone function are the developmental stages that affect composition of normal intestinal flora. Within these fluctuations, there is a general pattern of which bacterial species are found where (3).

Stomach – Gastric acidity is intended to kill bacterial species. Only acid resistant bacteria have been shown to survive this stomach acid. Bacteria are transient, not colonized in the stomach (3, 5, 7).

Small Intestine –  The small intestine should be relatively low in bacteria (5, 7, 8). In the duodenum & jejunum most bacteria, except L. Acidophilus are transient in nature. The bacteria in this region are often gram positive, and reflective of the oropharynx, and rarely exceed 10’3 (3, 5). The ileum  begins a transition and increase concentrations of gram negative, anaerobic colonic bacteria . Concentrations can be 10’9 immediately proximal to ileocecal valve (5, 9). If gastric acidity is not adequate, or SI motility is poor, overgrowth of bacteria can occur in the upper small intestine (8). 

Large Intestine – Bacteroides spp. is in highest concentration followed by B. Bifidus . In the colon, these anaerobes outnumber aerobes, like E.Coli & Lactobacillus 100-1000:1 (3, 7)

Vagina – From puberty to menopause the vaginal epithelium contains glycogen due to the actions of circulating estrogens (3). L. acidophilus predominates, being able to metabolize glycogen to lactic acid. This dominance, and low pH inhibits colonization by other opportunistic species like Candida albicans (3).

Now to the questions:

1. What does our gut flora actually do for us?

First they METABOLIZE:

  • Fermentation of non-digestible dietary residue and endogenous mucus (6)
  • Unabsorbed carbohydrates are salvaged by bacterial disaccharides, and metabolized to Short Chain Fatty Acids (SCFAs) (5).
  • Butyrate is almost completely consumed by the colonic epithelium, and it is a major source of energy for colonocytes. (7)
  • Acetate & Propionate go into the portal system, and are then metabolized in muscle and liver tissue, respectively (7)

Then they GROW:

Control of epithelial cell proliferation and differentiation; (7)

Which leads to PROTECTION:

3 ways bacteria act as a barrier:

  1. Adherent non-pathogenic bacteria can prevent attachment and subsequent entry of pathogen entero-invasive bacteria into the epithelial cells.
  2. Bacteria compete for nutrient availability in ecological niches and maintain their collective habitat by administering and consuming all resources.
  3. Bacteria can inhibit the growth of their competitors by producing antimicrobial substances called bacteriocins (7).

    PROTECTION: 

    Gut Associated Lymphoid Tissue (GALT) is the largest pool of immunocompetent cells in the body. In a germ free environment, lymphoid tissue are low in density, specialized follicle structures are small and circulating concentrations of immunoglobulins in blood are low. Th2 immune response remains high in germ free mice.  (7)

    METABOLISM/GROWTH: 

    Development and homoeostasis of the immune system (7)

     

    Short-chain fatty acids, gut microbiota–derived bacterial fermentation products, regulate the size and function of the colonic Treg pool and protect against colitis. (10)

    SCFA stimulate epithelial cell growth in LI & SI (7)

    Bacteroides and clostridium genera increase the incidence and growth rate of colonic tumours induced in animals, whereas other genera such as lactobacillus and bifidobacteria prevent tumorigenesis (7)

    Butyrate inhibits and reverses neoplastic growth. (7)

    Lactobacillus rhamnosus strain GG has also been useful as a prophylaxis and treatment of diarrhea in children, especially in those who are not breastfed (2,7).Potential treatment and recovery from antibiotic associated diarrhea, requires strain evaluation (13,14,15).

    Absorption of calcium, magnesium, iron (6). 

    Bifidobacterium in breastfed infants compared to bottle-fed had increased resistance to various diseases(6). Lactobacillus & Bifidobacterium reduce inflammation in colon and cecum, and pro-inflammatory cytokines (5).

    Production and absorption of vitamin K2(Menaquinone) & Production of Vitamin B12 (post absorption site) (6) 

    2. Do we absorb the probiotics we take?

    There are three main obstacles that a probiotic supplement must overcome, sequentially – Gastric acidity,  Bile salt exposure and lysis, and the migrating motor complex (or lack of function in), leading to stasis and small intestinal bacterial overgrowth (5, 6, 7).

    Nevertheless, many probiotic strains can withstand the rigors of passage through the upper gastrointestinal tract and enter the colon in a viable state in sufficient amounts to affect its microecology and its metabolism (6).

    Lactobacillus spp. (the predominant small intestine bacteria)  is intrinsically resistant to acidic environments. L. rhamnosis GG is commercial product that has shown  superior survival in acidic environments (11).

    On testing, the hardiest strains in each obstacle:

    Gastric acidity : L. Acidophilus 2401, 2409 & B. longum 1941 & B. pseudolongum 20099 (6)

    Bile salt survival : B. longum 1941, B. infantis 1912 & B. pseudolongum 20099, L. acidophilus 2404 & 2415 (6).

    Motility : A functioning migrating motor complex (regular peristalsis of the small intestine)  is critical to prevent bacterial overgrowth in the small intestine (5, 9, 12). This motility is also responsbile to transporting administered probiotics past the bile salts, and into the colon. A dysfunctional MMC been seen in radiation enteropathy, pancreatitis, small bowel resection (5, 12). The reduced motility compounded by lowered gastric acidity & lowered antimicrobial function, can lead to overgrowth and pathogenic bacterial translocation (5). 

    Survival rates are estimated at 20-40% due to gastric acid & bile salts (6). On testing, with the use of known probiotic species and strains, it was determined that the delivery of B. bifidum and L. acidophilus to the cecum was ~ 30% and 10% of the administered dose, respectively (6).

    3. Do these probiotics colonize, or are they transient?

    There is no evidence that probiotics colonize the human intestine (6, 7). They seem to pass into feces without having multiplied or adhered. For continuous benefit, they must be ingested continuously (6). It is possible that colonization is not a necessary aspect of positive results in probiotic therapy (6). Pre-biotics, however, pass into cecum and stimulate bifidobacterium multiplication (6).

    The recovery rate of an antibiotic-resistant strain ofBifidobacterium in the feces was determined after it was administered to human volunteers. The recovery rate was 29.7% ± 6.0% of the ingested dose, which is consistent with the percentage survival during pro- biotic passage through the gastrointestinal tract. When administration of this strain was stopped, it was no longer recovered in the feces (6).

    And so.

    “Although probiotics have been proposed for use in inflammatory, infectious, neoplastic, and allergic disorders, the ideal probiotic strain for any one of these indications has yet to be defined.” (5)

    Possibly, if we can’t sort through the soup to find the flavour, maybe it’s the hidden ingredient, love, that brings out the best in each ingredient. Maaaaybe, it’s wholesome, homemade, real ingredient food.

    Or, we could focus on Inulin & Fructo-oligosaccharides (FOS) –  now labeled as “Pre-biotics”. They are not digested in the upper intestine, but fermented in the colon by our endogenous microbiome (5, 6).  Both are present in significant amounts in many edible fruits and vegetables including wheat, onion, chicory, garlic, leeks, artichokes, and bananas (5).

    Remember the Peekhaus quote from the beginning? Give them a buffet, and many will grow.

    On eating 15 g of  FOS, compared to eating sucrose, fecal bifidobacterial counts increased almost 10- fold, whereas those of bacteroides, coliforms, and cocci decreased.(6)

    Specifically, we know that the fibre fermentation products SCFAs and lactic acid are beneficial (See table above). In addition lactulose (a synthetic prebiotic) has been used clinically to provide symptomatic relief in severe liver disease. Bifidobacteria and other colonic organisms metabolize lactulose, the colonic contents become acidic, converting NH to NH +, which serves to draw the NH from the blood to the colon. NH + is then excreted in the feces. (6)

    What else do colonic bacteria eat?

    • Naturally occurring sugar acids
    • Galacturonate from pectin
    • Gluconate and ketogluconate from muscle tissue
    • Mucus layer of epithelial tissue
    • Mucus is a complex gel of glycoproteins, glycolipids, NAG, NAGalac, Galac, fucose, sialic, glucuronate, galacturonate (1). Bacteria like it.

    “Unicellular organisms need biodiversity for growth. ” (7). One of the most important features of the intestinal ecosystem of healthy adults is its stability, within the changing climate (4).

    Now: Questions I have about Probiotics. Because, you can't be a scientist without questions.

    1. Is recolonization possible in adulthood, or is a microbiome like a fingerprint?

    2. Can fecal transplantation reset a colonic microbiome, or is it transient, as with oral probiotics?

    3. How are dosages of supplements/transplants being chosen, and how is individual biodiversity affected by “mono-cropping” or sharing beneficial bacteria?

    4. Is commensal bacteria transient and responsive to our diet and intestinal nutrients, and if so, can we cultivate a new biome, as opposed to sow it?

    5. Can microbiomes combine/share/influence one another, if living in close proximity?

    6. How much bacterial DNA do we inherit as we grow with our biome, and what kind of cellular memory comes in the merging?

    References:

    1. Peekhaus, N., Conway, T. (1998). What’s for dinner?: Entner Doudoroff Metabolism in escherichia Coli. J Bacterio 3495 -3502
    2. Moayyedi P, Ford AC, Talley NJ, et al. The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review. Gut 2010;59:325-332
    3. Todar, K.J. (2012). Chapter 5: Normal Flora of Humans. Online Textbook of Bacteriology.  http://textbookofbacteriology.net/normalflora_3.html. Last Accessed Dec 15, 2013.
    4. Kleessen, B. Bezirtzoglou and Matto J. (2000). Culture-Based knowledge on biodiversity, development and stability of human gastrointestinal microflora. Microbial ecology in health and disease. Suppl 2; 53-63
    5. Quigley, E.M.M., Quera, R. (2006) . Small Intestinal Bacterial Overgrowth: Roles of Antibiotics, Prebiotics and Probiotics. Gastroenterology: February Supplement. S78-S89
    6. Bezkorovainy, A. (2001). Probiotics: determinants of survival and growth in the gut. Am J Clin Nutr. 73; (suppl) 399S-406S
    7. Guarner, F., Malagelada, J-R., (2003). Gut flora in health and disease. Review article Lancet. 361: 512-519
    8. DiBiase, J.K. (2008) Nutritional consequences of small intestinal bacterial overgrowth. Practical Gastroenterology. Nutrition issues in gastroenterology, series #69 Carol Rees Paris, R.D. M.S. Series Editor.  p. 15 – 28
    9. Takahashi, T. (2012). Mechanism of interdigestive migrating motor complex. J neurogastroenterol Motil.  18 (3) 246-257
    10. Smith, P.M., Howitt, M.R., Panikov, N., Michaud, M., Gallini, C.A., Bohlooly-Y, M., Glickman, J.N., Garrett, W.S. (2013) The Microbial Metabolites, Short-Chain Fatty Acids, Regulate Colonic Treg Cell Homeostasis. Science 2 August 2013:  Vol. 341 no. 6145 pp. 569-573
    11. Corcoran, B.M., Stanton, C., Fitzgerald, G.F.,  & Ross, R.P. (2005). Survival of probiotic lactobacilli in acidic environments is enhanced in the presence of metabolizable sugars. Applied and environmental microbiology. Jun; 71 (6). p 3060-3067.
    12. Deloose, E, Janssen, P, Depoortere, I, Tack, J. (2012) The migrating motor complex: control mechanisms and its role in health and disease. Nat Rev Gastroenterol Hepatol. 2012 Mar 27;9(5):271-85.
    13. Dethlefsen, L., Huse, S., Sogin, M.L., Relman, D.A. (2008). The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16SrRNA sequencing. PLoS Biol. Nov 18;6 (11):e280.pL
    14. Hempel, S., Maher, A.R., Wang, Z., Miles, J.N.V., Shanman, R., Johnsen, B., Shekelle, P.G.(2012). Probiotics for the Prevention and Treatment of Antibiotic-Associated Diarrhea: A Systematic Review and Meta-analysis JAMA. 2012;307(18):1959-1969
    15. Sainsbury, A., Ford, A.C. (2011). Treatment of irritable bowel syndrome: beyond fiber and antispasmodic agents. Ther Adv Gastroenterol. 4(2) 115-127.
    health researchThara VayaliProbiotics, Lactobacillus, Bidifdobacterium, Microbiome, Gut Health, In The Field