Is It Time to Consider Generic Probiotic Effects?

Over the past 20+ years, the probiotic field has seen steady progress toward understanding that not all probiotics are the same. Early on, “probiotic” was used as a general term, a usage that masked that it comprises numerous genera, species and strains. Even the early scientific community did not fully embrace this concept – one need only to look at papers published pre-2000 to see that often strain designations were not even indicated for studied strains. In time, however, “strain-specificity of health effects” became an oft-repeated message (Sanders, 2007, 2009). Today, even popular press writers seem to understand the importance of strain-specificity (Schaffer 2011).

Strain-specificity is clearly demonstrated in numerous in vitro and animal models, where different strains are compared head-to-head (Jensen, et al. 2012; Macho Fernandez et al. 2011). But the evidence for strain-specificity in human studies is not entirely sufficient, as no studies actually report a clinical endpoint with different strains of the same species.  A few human studies compare efficacy of different probiotic preparations (Weizman, et al. 2005; Canani et al. 2007; O’Mahoney, et al. 2005), and found different results with different probiotic products.

However, is this thinking too simplistic? In the case where similar mechanisms operate in different strains, isn’t it likely they can also mediate the same health effect?  Even the European Food Safety Authority, the purveyor of probiotic criticism that has led to the word “probiotic” being pulled off much of the European market (see previous post), approved a claim that yogurt cultures can improve lactose digestion in lactose intolerant people. This benefit was ascribed not to specific strains but to “yogurt cultures”, namely two species of distinct genera with a common mechanism: production of lactase.

Numerous factors have been shown to impact probiotic functionality, of which strain is only one (see Table below). So the key question is, what amount of the variability observed in probiotic functionality can be accounted for by strain differences, and what amount is due to other factors (such as those delineated in Table 1)? Variations due to strain differences may in some cases be dwarfed by other factors such as host diet or host microbiota. It is likely that such findings will depend on the nature of the health effect. Bacteriocin inhibition of a gut pathogen may be highly strain-specific, but stimulating secretory IgA levels may be a more common probiotic attribute.

This distinction becomes important when we consider the meta-analysis process applied so frequently to the probiotic field today (Summary of systematic reviews and meta analyses in probiotics through February 2013). The validity of such analyses is often criticized based on the premise that it is not reasonable to group all the different probiotics into one “class.” The aim of a systematic review and meta-analysis is to bring a rigorous, unbiased process to bear on determining the strength of evidence for a health effect.  Assembling all relevant information is fundamental to this process. To the extent that results on one strain can inform conclusions about other similar strains, then like strains should be analyzed as a single group.

Numerous meta-analyses conclude, with some cautions, that “probiotics” (as a class) are beneficial. This suggests that many probiotic strains do share the same effects. If what is important is to deliver a bolus of live bacteria to the small intestine to interact with immune cells, then perhaps any number of bacteria may serve this purpose equally well.

Instead of viewing probiotic effects as necessarily strain-specific, perhaps it is time to be open to the idea that there may be a spectrum of probiotic functions, some of which involve capabilities unique to only one or a few strains but others which are more general to larger groups of microbes.

Table. Factors affecting probiotic function in vivo

Host

  • Genetics
  • Diet
  • Microbiota
Microbe

  • Taxonomy
  • Genetic composition (what traits is the microbe capable of)
  • Gene expression/translation (what traits does the microbe express in response to the particular environment)
  • Growth phase

 

References:

  1. Canani RB, Cirillo P, Terrin G, Cesarano L, Spagnuolo MI, De Vincenzo A, Albano F, Passariello A, De Marco G, Manguso F, Guarino A. 2007. Probiotics for treatment of acute diarrhoea in children: randomised clinical trial of five different preparations. BMJ. 335(7615):340.
  2. Jensen H, Grimmer S, Naterstad K, Axelsson L. 2012. In vitro testing of commercial and potential probiotic lactic acid bacteria.  Int J Food Microbiol. 153(1-2):216-22.
  3. Macho Fernandez E, Valenti V, Rockel C, Hermann C, Pot B, Boneca IG, Grangette C. 2011. Anti-inflammatory capacity of selected lactobacilli in experimental colitis is driven by NOD2-mediated recognition of a specific peptidoglycan-derived muropeptide. Gut. 2011 Aug;60(8):1050-9. Erratum in: Gut. 2011 Oct;60(10):1444. Fernandez, Elise Macho [corrected to Macho Fernandez, Elise].
  4. O’Mahony L, McCarthy J, Kelly P, Hurley G, Luo F, Chen K, O’Sullivan GC, Kiely B, Collins JK, Shanahan F, Quigley EM. 2005. Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology. 128(3):541-51.
  5. Sanders, M.E. 2009. How do we know when something called “probiotic” is really a probiotic? A guideline for consumers and healthcare professionals. Functional Food Rev 1:3-12. Open access.
  6. Sanders, ME. 2007. Probiotics: strains matter. Functional Food and Nutraceuticals. June, pages 34-41.
  7. Schaffer A.  2011. Is Yogurt Good for You? The pros and cons of probiotics. Slate Magazine, July 20.
  8. Weizman Z, Asli G, Alsheikh A. 2005. Comparison of Two Probiotic Agents: Effect of a Probiotic Infant Formula on Infections in Child Care Centers. Pediatrics 115:5-9.