Lactobacillus, omega-3 fatty acids and FODMAPs influence on the gut microbiome

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O'Donnell, Shane
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University College Cork
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Introduction: Many aspects of the human gut microbiome, the diverse combination of microorganisms that are present in the large intestine, impact human host functioning and homeostasis. As we uncover greater understanding of the links between human health and the microbial communities present within the host, we unveil new potential therapies for moderating human disorders. These potential therapies appear most pertinent for gut derived disorders such as Irritable Bowel Syndrome (IBS) and Inflammatory Bowel Disease (IBD). Dietary therapy has emerged as a popular method for managing IBS, and has become increasingly popular for managing IBS like symptoms present in IBD. The most effective dietary therapy, the low FODMAP diet, starves the microbiome of substrates that may result in the production of hydrogen in vivo. We hypothesise that the microbiome could be modulated with Lactobacillus strains to achieve this positive outcome, without the need for maintaining a diet low in Fermentable Oligo-, Di-, Monosaccharides and Polyols (FODMAP). Our research also examines new low FOMDAP foods, capable of potentially removing unwanted microbial fermentation while providing more food options for individuals on a low FOMDAP diet. Appropriate manipulation of, or starvation of, groups of bacteria present in the gut microbiome may reduce the volume of hydrogen produced, providing relief from the bloating and pain often experienced as part of these conditions. Methods: To develop these two potential therapies, we selected Lactobacillus strains that were capable of degrading FODMAP carbohydrates to potentially effect change on the microbiome. Three Lactobacillus strains: L. rhamnosus DPC 6071, L. casei DPC 6072 and L. casei DPC 6083, were selected based on their ability to ferment FODMAP carbohydrates. IBS and IBD were induced in C57/Bl6 mice via the maternal separation model and DSS induced colitis, respectively. During both murine trials the three Lactobacillus strains were administered. We examined the compositional change within the murine microbiome and the resulting production of specific SCFAs to understand whether the the added strains were increasing or decreasing potential hydrogen production. Physiological and immunological changes were recorded and compared between groups. Ex vivo fermentation in the presence of a human microbiome facilitated the examination of microbial changes caused by the new low FODMAP foods in comparison to their high FODMAP counterparts. The most suitable low FODMAP foods were selected based on their impact on the human microbiome ex vivo. Results: This work seeks to understand the potential for targeting the microbiome to reduce FODMAP induced IBS like symptoms. We discovered three strains that are capable of robust FODMAP degradation, survival of GI transit and effective adherence to human Caco-2 cells. The genomic potential of these strains was examined to understand carbohydrate fermentation capacity and the nature of their antibiotic resistance. This research presented a platform to explore the strains impact on in vivo systems using a murine model. Assessing the impact of a highly fermentable diet and Lactobacillus administration in a murine model facilitated a more in depth understanding of this interaction. A diet high in FODMAP carbohydrates caused an increase in microbial diversity, an increase in carbohydrate fermenting microbial groups such as Bifidobacterium, Lachnospiraceae and Roseburia, and subsequent increase in almost all SCFAs analysed. Lactobacillus consumption led to a robust increase in Lactobacillus within the murine caecum. The proliferation of L. rhamnosus DPC 6071, L. casei DPC 6072 and L. casei DPC 6083 resulted in an increase in CD19+ immune cells, increased abundance of microbial groups linked to anti-inflammatory effects and increased propionate levels, indicative of a reduction in net hydrogen production. Despite the maternal separation model proving to be an ineffective IBS model, increased propionate production indicates the Lactobacillus strains may alter the metabolism of the microbiome to reduce hydrogen production. Previous research has revealed that probiotic strains may have a protective effect against chemically induced colitis in murine models. Due to the presence of FODMAP induced pain and bloating symptoms in IBD, we were also interested in exploring the potential protective effect these Lactobacillus strains may have on the physiological impact of Dextran Sulfate Sodium (DSS) induced colitis in mice. Mice that received Lactobacillus strains prior to DSS challenge demonstrated reduced weight loss, increased colon length and a reduced blood serum immune response. Lactobacillus strains persisted in the microbiome throughout DSS challenge and for the seven day recovery period after. Lactobacillus fed mice had significantly reduced alpha diversity after DSS treatment, indicating that the Lactobacillus strains became a dominant member of the microbiome. The survival of at least one Lactobacillus strain within the gut ecosystem, even during severe environmental perturbations, suggests that the strains occupied a niche and as such were capable of stabilising the host microbiome. The overall scope of our research included the production of low FODMAP food alternatives such as pasta and bread. In vitro digestion and ex vivo faecal fermentation assessed the most suitable low FODMAP prototypes for use in a low FODMAP diet, based on their impact on the human microbiome present during fermentation. Our results suggest that the low FODMAP bread, low FODMAP pasta and inulinase treated bread are suitable candidates for incorporating in a low FODMAP diet. Furthermore, malted lentils and malted buckwheat provide a low FODMAP version of their raw counterparts that do not negatively impact the microbiome. Conclusions: The findings from this research present two potential novel therapies for FODMAP-induced IBS. L. rhamnosus DPC 6071, L. casei DPC 6072 and L. casei DPC 6083 persist in the murine microbiome, altering the SCFA profile of the microbiome. Increased propionate, a marker for reduced hydrogen, was observed in Lactobacillus supplemented animals. The three Lactobacillus strains, selected for their ability to degrade FODMAPs, modulated the murine immune response to DSS induced colitis, moderating its severity. Low FODMAP bread, inulinase treated bread, low FODMAP pasta, malted lentils and malted buckwheat were determined to be suitable replacements for their high FODMAP counterparts as part of a low FODMAP diet, based on their impact on the human microbiome after ex vivo fermentation. These data require human trials to corroborate the findings, however, the results of this thesis present potential novel approaches to managing FODMAP-induced symptoms.
Microbiome , FODMAP , IBS , IBD , Lactobacillus , Omega 3
O'Donnell, S. 2021. Lactobacillus, omega-3 fatty acids and FODMAPs influence on the gut microbiome. PhD Thesis, University College Cork.