By Evan Hayes

While today it may seem axiomatic that the microbiome plays a major role in homeostasis it was revolutionary at the time when Hippocrates stated,“natural forces within us are the true healers of disease.” In that time, we have continued to determine, through trial and clinical observation, that illness can be genetic, epigenetic, metabolic, physiological, infectious or caused by a deficiency. No matter what the cause, all can be very heavily influenced by the patient’s age, gender, lifestyle, and most importantly, the microbiome.1

Gut microbiota and their hosts have a well-established and evolved symbiosis. It has long been understood that the bacteria benefit the host’s metabolism by production of metabolites and chemical messengers and their combination is commonly referred to as a ‘super organism’. But what has been less researched and understood, is the relationship that these bacterial communities have on each other and other microbiota such as yeasts and fungi and how these syntrophic interactions are thought to be essential in achieving optimal health.

The ancient world utilised the processes and benefits of yeast fermentation in particular in brewing and baking applications and were aware of the negative aspects of some yeasts. Hippocrates mentions thrush in the mouth. In “Of the Epidemics”, Hippocrates described oral candidiasis (around 400 B.C.) but modern science did not even identify yeasts until the seventeenth century when Anton van Leeuwenhoek the “Father of Microbiology” viewed them under his newly invented microscope.

Microbiome research has predominantly been on the bacterial flora. Less however, is understood of fungal species, also known as the mycobiome, living in symbiosis with bacteria as commensals in our body. It is also probable that the mycobiome exerts a distinct influence on the microbiome. Commensal fungi that normally inhabit our bodies have been much less studied, as fungi form the minority of the total commensal organisms in humans, a large portion of these fungi are also unculturable.

Yeasts are predominantly fungi (red rice yeast is a mould) and they are eukaryotic single celled microorganisms. About 1500 yeasts have been classified which represent about 1% of all described fungi. A large variety of fungi are found in the human gastrointestinal (GI) tract and there is no consensus yet on the ideal fungal mycobiome. There are diverse fungal communities in all sections of the human gut consisting mainly of the phyla Ascomycota, Basidiomycota, and Zygomycota. Yeast classification was traditionally based on their physiological and biochemical profiles. However, this fails to distinguish between several yeast species or cultivars for example differences in Saccharomyces cerevisiae sub species. Even though genetically very close, there are differences, which may be related to the number of genes involved in protein synthesis and stress response. Molecular methods have been developed and applied to yeast strain typing and identification which have enabled us to properly differentiate different types of yeast that have different effects in concert with each other, bacteria and the body. The fungal mycobiota is sensitive and responds (directly or indirectly) to disease states and intervention, often times iatrogenically through treatment.2

Similar to bacteria in the microbiome, yeasts can be generally classified into three categories: parasitic, opportunistic parasites and beneficial probiotics. It has been well-documented that yeast and yeast products are applicable as probiotics. The most studied, and in many cases predominantly identified yeast, conferring a beneficial advantage, is Saccharomyces.

Saccharomyces has the advantage of being naturally resistant against all antibiotics by being a yeast.3 It also helps maintain the microbiome by decreasing the antibiotic-induced reduction in the intestinal microbiota and by supporting a faster regeneration of the intestinal microbiota following antibiotic therapy.4

By the nature of their differences Saccharomyces yeast variations have different benefits within the body either as a probiotic, prebiotic or synbiotic. For example

Saccharomyces boulardii (SB) has a high optimal growth (37 °C) and has a high acid resistance, whereas Saccharomyces cerevisiae (SC) does not. As a consequence, S. boulardii exhibits a faster growth rate within the intestinal tract than S. cerevisiae.5 This predominantly allows SB to thrive in the human body while limiting SC. However, there is a benefit in the body hydrolysing SC to avail of its key nutrients and compounds in the small intestine. These support bacterial probiotics and S.boulardii.4  Another key advantage of Saccharomyces cerevisiae is that it demonstrates hybrid behaviours of cerevisiae and boulardii.6 For instance, Lynside Pro GI+ can withstand the gastrointestinal tract and provide anti-inflammatory support in the face of intestinal pain, including that caused by irritable bowel syndrome (IBS).6

Saccharomyces yeast variations perform different functions within the host which can be categorised into:

  1. Antimicrobial effects
  2. Nutritional effects
  3. Inactivation of bacterial toxins
  4. Quorum sensing
  5. Trophic effects
  6. Immuno-modulatory effects
  7. Anti-inflammatory effects
  8. Cell restitution and maintenance of epithelial barrier integrity.
Antimicrobial

An antimicrobial effect may be exerted by yeast through several mechanisms. One of them is irreversible binding of bacteria to the yeast surface, preventing their adhesion to the mucous membranes and resulting in subsequent elimination. It has been shown that SB has the ability to bind enteric pathogens to mannose as a receptor.5 Research has demonstrated that the yeast S. boulardii can inhibit adherence of Clostridium difficile to cells, due to its proteolytic and steric hindrance activity via the modification of the eukaryotic cell surface receptors involved in adhesion of C. difficile. 6

Yeasts may also inhibit pathogens through action on microbial virulence factors. A study performed on human colonic cells infected by Salmonella enterica showed that in in presence of SB the pathogen motility was reduced.4

Other Scobiotic mechanisms exerting antimicrobial effect are utilisation of substrates, modification of the environment and release of various compounds. S. boulardii can also assist the host immune system by inducing the release of immunoglobulins and cytokines in response to the yeast itself.4

SB also acts by inactivation of bacterial toxins. For example, SB releases, in vivo, a 54-kDa serine protease that digests toxins A and B of Clostridium difficile and the BBM receptor of toxin A.9 It has been also been shown that protein phosphatase from SB is able to dephosphorylate and partially inactivate the endotoxin (LPS) of Escherichia coli.5

Nutritional & Prebiotic effects

The degradation of cerevisiae in the stomach releases hundreds of endogenous compounds, similarly SB releases at least 1500 compounds during its passage through gastrointestinal tract.4

Saccharomyces influences the growth of gut microflora and the host by its metabolism (uptake of substrates and release of products or multitude of cell components by dying cells).

Nutritional yeasts are nutrient-packed. These yeast cells are well-known source of proteins, B-complex vitamins, dietary fibres, nucleic acids, vitamins, minerals, (K, P, Se Cr, Zn). The nutrients supplied by Saccharomyces are in most cases biologically active, including a biologically active form of chromium known as glucose tolerance factor.

Yeasts are a potential source for prebiotic β-glucans. This polysaccharide is characterised by d-glucose monomers linked by β-glycosidic bonds. There are significant structural differences in β-glucans depending on the source and method in which they are obtained. This polymer is a healthier food additive.

Quorum sensing

Yeasts such as S.cerevisiae are digested in the stomach acid and release hundreds of substrates into the GIT. Some of the released compounds are quorum sensing molecules.

In the presence of the correct probiotic bacteria or pathogenic bacteria, these compounds influence metabolism and properties of microorganisms, for example, increasing (probiotic) and reducing (pathogen) the ability of adhesion or filamentation in the intestine.

In cases where pathogenic bacteria grow beyond normal levels, yeasts can communicate via mating factors which can modulate or attenuate the biomass growth. This has most likely played a significant role in bacterial adaptation and evolution within the microbiome and the presence of yeast within that microbiome can play an important role in developing and maintaining gut health.9

Trophic effects

S.boulardii CNCM I-745 has pronounced effects on digestive enzymes of the brush border membrane, known as trophic effects. While vitamins are necessary exogenous organic compound which must be ingested, enzymes may help to transform bigger to smaller compounds absorption by the brush border in the gastrointestinal tract. The brush border is the structure formed by microvilli, increasing the cellular surface area responsible for secretion, absorption, adhesion and transduction of signals.5

The microvilli-covered brush border membrane (BBM) is the site of terminal carbohydrate digestion as well as nutrient and water absorption. It contains digestive enzymes, as well as transporters that allow absorption of the digested nutrients. However, during diarrhoeal episodes, intestinal epithelial cells can be damaged and replaced with immature cells which do not contain digestive enzymes. Therefore, osmotic effects due to nutrient malabsorption can make the diarrhoeal episodes more severe. S. boulardii were found to secrete a number of different digestive enzymes that can function in the same way as BBM enzymes when they are absent.6

Additionally, SB cells contain substantial amounts of polyamines which are known to affect cell maturation, enzyme expression and membrane transport. In fact, polyamines and S. boulardii can enhance the expression of intestinal enzymes, resulting in enhanced synthesis of brush border membrane proteins (enzymes and carriers) helping to restore damaged brush borders.6

Anti-inflammatory effects,

SB is effective in treatment of inflammatory bowel diseases. There are several possible mechanisms of this anti-inflammatory effect, such as anti-inflammatory actions through released compounds that modify epithelial cells and the mucosal immune system signalling pathways.4

Another mechanism could be exerted by Saccharomyces through blocking activation of nuclear factor-kappa B (NF-kB) and mitogen activated protein kinase (MAPK), resulting in down regulation of pro-inflammatory compounds such as interleukin 8 (IL-8), tumor necrosis factor alpha (TNF- a) and interferon gamma (IFN- g).10

SB and secreted-proteins of SB can interfere with (NF-kB) and modulate the activity of ERK1/2 and p38, which inhibits the production of pro-inflammatory cytokines.6

Immuno-modulatory effects

The commensal microbiota has an essential role in autoimmunity. SB enhances the effects of enzymes in the intestinal mucosa and through this improves the production of secretory IgA.

Immunomodulation could be exerted by the interactions of SB with mucosal dendritic cells and may protect against invading pathogens such as C. difficile through a stimulation of the host’s intestinal, mucosal immune response.5

Cell restitution and maintenance of epithelial barrier integrity.

Bacterial infections leading to inflammatory bowel diseases (IBD) can result in intestinal epithelial cell damage. Remission of IBD requires both the cessation of inflammation and cell restitution within the damaged epithelium, which is affected by enterocyte migration. SB accelerate enterocyte migration by secretion of motogenic factors that enhance cell restitution through the dynamic regulation of α2β1 integrin activity.11

 Summary

The combination of these mechanisms results in a reduction of pathogenic adhesion or colonisation and an attenuation of the overreacting inflammatory immune response.

Yeasts work together, independently, work with the bacteria, work against the pathogens, provide a nutrient source, and provide exogenous compounds that also have separate effects with bacteria. Hence, they work as an effective and cooperative part of a synbiotic/ ScobioticTM.

*References available upon request