Abstract
The human gastrointestinal tract contains an overwhelming number of living microorganisms with an increasingly recognized impact on human health. The ability to effectively protect against invading species while maintaining tolerance to commensals and avoiding destructive inflammatory responses to harmless luminal substances is a key feature of the intestinal immune system. In this context, dendritic cells (DCs) present in the tissues lining the human gut are central players involved in microbial sensing and shaping of appropriate adaptive immune responses.
Probiotics are live microorganisms which when administered in adequate amounts confer a health benefit on the host. While the majority of probiotic microorganisms studied to date are lactic acid bacteria, research in yeasts with potentially beneficial influences on human health has mainly revolved around Saccharomyces boulardii. This yeast has shown a positive impact on disease outcome in clinical studies of inflammatory bowel disease, indicating an ability of S. boulardii to influence human immune responses underlying intestinal inflammation. Consequent to this focus on S. boulardii as the fundamental probiotic yeast, very little is known about hundreds of non-Saccharomyces yeasts in terms of their interactions with the human gastrointestinal immune system and potential contribution to gastrointestinal homeostasis.
The aim of the present PhD thesis was to explore the probiotic potential of non-Saccharomyces yeasts in terms of interactions with cells of the human gastrointestinal tract. Specifically, the included publications represent scientific investigation of non-Saccharomyces yeast modulation of human DC function, induction of human T cell responses indicating inflammation versus tolerance, capacity for enhancing human epithelial cell barrier function, and properties of pathogen inhibition.
In a large-scale in vitro study, 170 strains representing 75 diverse yeast species were evaluated for modulation of inflammatory cytokine secretion by human DCs, as compared to cytokine responses induced by S. boulardii. Our findings demonstrate high diversity in yeast-induced cytokine profiles and reveal distinct clustering of yeasts inducing similar cytokine profiles in human DCs, highlighting clear species distinction within the Kluyveromyces and Metschnikowia genera. In addition, we find the cytokine-inducing interactions between yeasts and human DCs to occur independently of yeast viability.
In a second study, we further characterized the immune modulating properties of the food-related yeast Kluyveromyces marxianus in terms of adaptive immune responses indicating inflammation versus tolerance. Our findings demonstrate similar DC cytokine secretion profiles induced by K. marxianus and S. boulardii, primarily driven by Dectin-1 recognition of conserved β-glucan components in yeast cell walls. Upon co-incubation of yeast exposed DCs and naive T cells, we find that S. boulardii induces a strong IFNγ response indicating TH1 mobilization. In contrast, our findings reveal K. marxianus as a potent inducer of Foxp3+ regulatory T cells, a characteristic that may benefit human health in conditions characterized by excessive inflammation.
In a third study, we evaluated non-Saccharomyces yeast modulation of human intestinal epithelial cell barrier function in vitro, and explored yeast properties of pathogen inhibition in a challenge assay with enteropathogenic Salmonella Typhimurium. Our findings demonstrate distinct patterns of non-Saccharomyces yeast modulation of epithelial cell barrier function, and identify K. marxianus and Metschnikowia gruessii as capable of significantly delaying Salmonella-induced disruption of epithelial cell barrier function.
In conclusion, data presented in the current thesis demonstrate significant interactions between non-Saccharomyces yeasts and cells of the human gastrointestinal tract and identify K. marxianus as a strong candidate for further development as a novel yeast probiotic.
Probiotics are live microorganisms which when administered in adequate amounts confer a health benefit on the host. While the majority of probiotic microorganisms studied to date are lactic acid bacteria, research in yeasts with potentially beneficial influences on human health has mainly revolved around Saccharomyces boulardii. This yeast has shown a positive impact on disease outcome in clinical studies of inflammatory bowel disease, indicating an ability of S. boulardii to influence human immune responses underlying intestinal inflammation. Consequent to this focus on S. boulardii as the fundamental probiotic yeast, very little is known about hundreds of non-Saccharomyces yeasts in terms of their interactions with the human gastrointestinal immune system and potential contribution to gastrointestinal homeostasis.
The aim of the present PhD thesis was to explore the probiotic potential of non-Saccharomyces yeasts in terms of interactions with cells of the human gastrointestinal tract. Specifically, the included publications represent scientific investigation of non-Saccharomyces yeast modulation of human DC function, induction of human T cell responses indicating inflammation versus tolerance, capacity for enhancing human epithelial cell barrier function, and properties of pathogen inhibition.
In a large-scale in vitro study, 170 strains representing 75 diverse yeast species were evaluated for modulation of inflammatory cytokine secretion by human DCs, as compared to cytokine responses induced by S. boulardii. Our findings demonstrate high diversity in yeast-induced cytokine profiles and reveal distinct clustering of yeasts inducing similar cytokine profiles in human DCs, highlighting clear species distinction within the Kluyveromyces and Metschnikowia genera. In addition, we find the cytokine-inducing interactions between yeasts and human DCs to occur independently of yeast viability.
In a second study, we further characterized the immune modulating properties of the food-related yeast Kluyveromyces marxianus in terms of adaptive immune responses indicating inflammation versus tolerance. Our findings demonstrate similar DC cytokine secretion profiles induced by K. marxianus and S. boulardii, primarily driven by Dectin-1 recognition of conserved β-glucan components in yeast cell walls. Upon co-incubation of yeast exposed DCs and naive T cells, we find that S. boulardii induces a strong IFNγ response indicating TH1 mobilization. In contrast, our findings reveal K. marxianus as a potent inducer of Foxp3+ regulatory T cells, a characteristic that may benefit human health in conditions characterized by excessive inflammation.
In a third study, we evaluated non-Saccharomyces yeast modulation of human intestinal epithelial cell barrier function in vitro, and explored yeast properties of pathogen inhibition in a challenge assay with enteropathogenic Salmonella Typhimurium. Our findings demonstrate distinct patterns of non-Saccharomyces yeast modulation of epithelial cell barrier function, and identify K. marxianus and Metschnikowia gruessii as capable of significantly delaying Salmonella-induced disruption of epithelial cell barrier function.
In conclusion, data presented in the current thesis demonstrate significant interactions between non-Saccharomyces yeasts and cells of the human gastrointestinal tract and identify K. marxianus as a strong candidate for further development as a novel yeast probiotic.
| Original language | English |
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| Publisher | Department of Food Science, Faculty of Science, University of Copenhagen |
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| Number of pages | 163 |
| Publication status | Published - 2015 |
