Current Research

Probiotics and the Microbiome: The Next Level of Understanding

 

It is harder to think of a hotter topic in both science and Natural Medicine right now, than the microbiome. With research accumulating from ventures such as the Human Microbiome Project and Metagenomics of the Human Intestinal Tract, a disrupted microbiome (i.e. dysbiosis) is increasingly being linked to many chronic diseases, particularly inflammatory bowel disease, autoimmune conditions, metabolic syndrome, arthritis and autism.[1] The use of probiotics as a potential strategy to correct dysbiosis has therefore become an important consideration for a variety of patient presentations, but first we must understand what constitutes a healthy microbiome, and then consider where exactly probiotics fit in.

 

The Ideal Microbiome – Diversity is Key

In the search for the ‘ideal microbiome’ several studies have investigated healthy cohorts including some of the Palaeolithic cultures in the world, and people living a simple agrarian (i.e. rural, agricultural) lifestyle. The results of Palaeolithic subjects were found to be heterogeneous; that is, despite seemingly similar lifestyles and states of health, no consistent microbial composition is shared amongst these groups.[2],[3],[4] Similarly, agrarian studies found mixed results when searching for the ideal microbiome, highlighting that a ‘one-size fits all’  optimal microbiome has not been identified.[5],[6]

Despite science having been unable to identify the ideal ratio or composition of microbiota, research does suggest having a large diversity of bacterial species could confer benefit. Furthermore, animal models and human epidemiological studies have linked a reduction in bacterial diversity to chronic diseases such as obesity, insulin resistance, and inflammatory bowel disease.[7]

 

Key Genera Have Been Identified

In addition to diversity, another key finding in microbiome research is healthy individuals typically host appreciable levels of certain bacterial genera. Over 80% of these individuals have higher levels of what are known as ‘core’ commensal groups, belonging to six genera: Faecalibacterium, Eubacterium, Clostridium, Blautia, Ruminococcus and Roseburia. Research is emerging that these genera are predominantly the functional contributors of the microbiome, and that adequate levels may be the common denominator in the hunt for a healthy microbiome.[8]

 

Supporting the Function of the Microbiome

The core bacteria within the six identified key genera, are all capable of metabolising fibre into butyrate with the exception of Blautia. In contrast, many other gut bacterial species only partially metabolise fibre; instead creating intermediate products such as lactate and acetate. However, a process known as ‘cross-feeding’ allows these intermediate products to be used as fuel for the key genera (Figure 2).[9] There is a strong consensus in the literature that butyrate plays a critical role in promoting host health; with adequate butyrate production considered a hallmark of a healthy microbiome.[10] Enhancing core butyrate-producing bacteria levels, via cross-feeding, therefore plays an important metabolic role in host health by supporting healthy microbiome function.

 

figure_2.png 

Figure 2: Bacterial cross-feeding contributes to the important role butyrate-producing bacteria play.[11]

 

Function Trumps Composition 

The recognition of the importance of butyrate production supports the view of many researchers, that we should be more interested in the output of a healthy microbiome, rather than who is present. A landmark paper from the Human Microbiome Project showed that despite wide variation in microbiome phylum in various sites of the body in healthy subjects, the metabolic output of the microbiome at each site was very consistent (Figure 3).[12]  This is known as ‘functional redundancy’, where more than one species can perform a given role in an ecosystem; therefore the loss of a particular species does not spell the collapse of the whole community.[13] This supports the importance of the metabolic function of the microbiome as a marker of health, rather than its composition.  

 

figure_3.png 

 

Figure 3:  Functional redundancy - despite a large variation in phyla between healthy subjects, the metabolic output is consistent in each body site.[14]

 

Probiotics are not Commensals 

With this updated recognition of the hallmarks of a functional microbiome, comes a new understanding of what roles our primary gut microbiome therapy (i.e. probiotics) perform. One of the most important paradigm shifts is that probiotics cannot be considered to be interchangeable with commensal microbiota. The human microbiome has now been found to contain over 1000 species, with Lactobacilli spp and Bifidobacteria spp (the two most common genera of probiotics) comprising only 5%.[15] Though we now know probiotics do not constitute a significant portion of the gut microbiome, and are considered transient species,[16] they exert appreciable benefits to native commensal populations, and the functional layers of the gastrointestinal tract as they pass through.

 

Probiotics Promote the Growth of Native Commensal Bacteria

Supplementation with certain Lactobacilli and Bifidobacteria strains offer a highly effective therapy in dysbiotic situations. However, rather than replacing commensal bacteria, specific probiotic strains act as catalysts for the regrowth of diminishing species: producing metabolites that modify the growth or behaviour of other commensal groups (via cross-feeding), altering environmental conditions (such as intestinal pH and nutrient availability), and by interacting with the human immune system (via dendritic cells), which has a regulating effect on both pathogen and commensal growth.[17],[18]

 

Beyond Commensal Benefits

In addition to modulating the microbiome, certain probiotics provide beneficial programming effects on the host’s receptors, which commensal bacteria can’t provide.[19] Through strain-specific interactions with immune receptors (such as the toll-like receptor family), probiotics can assist in ‘reprogramming’ the immune system to assist in conditions of immune dysregulation such as allergy, autoimmunity, or recurrent infection.[20] Specific probiotic strains also maintain mucosal health, up-regulating gene activity and the expression of tight junction proteins, as found in studies utilising Lactobacillus rhamnosus (LGG®).[21],[22]

Furthermore, a 2015 study revealed LGG® supplementation altered the motility of butyrate-producing Roseburia and Eubacterium, enabling these beneficial bacteria to penetrate deeper into the mucus layer, increasing butyrate availability for the intestinal epithelium.[23]Through these beneficial regulating actions on commensal bacteria, the immune system, and gut function, probiotics not only help to restore and maintain a healthy microbiome, but have significant systemic impacts with implications for the management of chronic disease.

 

Harnessing the Power of Probiotics for Microbiome Change

Bacterial diversity is a key to an optimal microbiome, however the function of the microbiome trumps the composition when it comes to health. As composition is so variable, there is not a single hero bacterial species we need to replace, but rather it is what the microbiota ultimately yield that is important. Selecting appropriate strains of probiotics can therefore provide a powerful catalyst for the correction of gastrointestinal function, significantly impacting systemic diseases including inflammatory bowel disease and autoimmune conditions.


 

References



[1] Wilson M. An introduction to the human tissue microbiome. In: Nibali L, Henderson B, editors. The human microbiota and chronic disease: dysbiosis as a cause of human pathology. Hoboken (NJ): John Wiley and Sons. 2016:p5.

[2] Dehingia M, Talukdar NC, Talukdar R, Reddy N, Mande SS, Deka M, et al. Gut bacterial diversity of the tribes of India and comparison with the worldwide data. Sci Rep. 2015 Dec 22;5:18563.

[3]  Rampelli S, Schnorr SL, Candela M, Rampelli S, Centanni M, Consolandi C, et al. Gut microbiome of the Hadza hunter-gatherers. Nat Commun. 2014 Apr 15;5:3654. 
[4] Tito RY, Macmil S, Wiley G, Najar F, Cleeland L, Qu C, et al. Phylotyping and functional analysis of two ancient human microbiomes. PLoS One. 2008;3(11):e3703.
[5] Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, et al. Human gut microbiome viewed across age and geography. Nature. 2012  May 9;486(7402):222-7.  
[6] Simrén M, Barbara G, Flint HJ, Spiegel BM, Spiller RC, Vanner S, et al. Intestinal microbiota in functional bowel disorders: a Rome foundation report. Gut. 2013 Jan;62(1):159-76.
[7] Cotillard A, Kennedy SP, Kong LC, Prifti E, Pons N, Le Chatelier E, et al. Dietary intervention impact on gut microbial gene richness. Nature. 2013 Aug 29;500(7464):585-8.

[8] Dehingia M, Talukdar NC, Talukdar R, Reddy N, Mande SS, Deka M, et al. Gut bacterial diversity of the tribes of India and comparison with the worldwide data. Sci Rep. 2015 Dec 22;5:18563.

[9] Scott KP, Antoine JM, Midtvedt T, van Hemert S. Manipulating the gut microbiota to maintain health and treat disease. Microb Ecol Health Dis. 2015 Feb 2;26:25877.

[10] Scott KP, Antoine JM, Midtvedt T, van Hemert S. Manipulating the gut microbiota to maintain health and treat disease. Microb Ecol Health Dis. 2015 Feb 2;26:25877.

[11] Scott KP, Antoine JM, Midtvedt T, van Hemert S. Manipulating the gut microbiota to maintain health and treat disease. Microb Ecol Health Dis. 2015 Feb 2;26:25877.

[12] Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature. 2012 Jun 13;486(7402):207-14.

[13] Moya A, Ferrer M. Functional Redundancy-Induced Stability of Gut Microbiota Subjected to Disturbance. Trends Microbiol. 2016 May;24(5):402-13.

[14] Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature. 2012 Jun 13;486(7402):207-14.
[15] Moré MI, Swidsinski A. Saccharomyces boulardii CNCM I-745 supports regeneration of the intestinal microbiota after diarrheic dysbiosis - a review. Clin Exp Gastroenterol. 2015 Aug 14;11:237-55.
[16] Guilliams TG. Dysbiosis or Adaptation: How Stable Is the Gut Microbiome? Altern Ther Health Med. 2016 Oct;22(S3):10-12.
[17] Sanders ME. Impact of probiotics on colonizing microbiota of the gut. J Clin Gastroenterol. 2011 Nov;45 Suppl:S115-9.

[18] Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, stability and resilience of the human gut microbiota. Nature. 2012 Sep 13;489(7415):220-30.

[19] Lebeer S, Vanderleyden J, De Keersmaecker SC. Host interactions of probiotic bacterial surface molecules: comparison with commensals and pathogens. Nat Rev Microbiol. 2010 Mar;8(3):171-84.

[20] Gómez-Llorente,Munoz S, Gil A. Role of Toll-like receptors in the development of immunotolerance mediated by probiotics. 21–24 October 2009, The 3rd International Immunonutrition Workshop, Platja D'Aro, Girona, Spain.

[21] Di Caro S, Tao H, Grillo AN, Elia C, Gasbarrini G, Sepulveda AR, et al. Effects of Lactobacillus GG on genes expression pattern in small bowel mucosa. Dig Liver Dis. 2005 May;37(5):320-9.

[22] Lebeer S, Vanderleyden J, De Keersmaecker SC. Host interactions of probiotic bacterial surface molecules: comparison with commensals and pathogens. Nat Rev Microbiol. 2010 Mar;8(3):171-84.
[23] Eloe-Fadrosh EA, Brady A, Crabtree J, Drabek EF, Ma B, Mahurkar A, et al. Functional dynamics of the gut microbiome in elderly people during probiotic consumption. MBio. 2015 Apr 14;6(2): e00231-15.