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    The effect of weaning food substrate on segmented filamentous bacteria in infant small intestinal immune barrier maturation : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Nutrition at Massey University, Palmerston North, New Zealand (School of Food and Advanced Technology)
    (Massey University, 2021) Oemcke, Linda
    Appropriate and complete maturation of the gastrointestinal tract (GIT) barriers is crucial as it contributes to overall health and wellness. Maturation of the small intestinal immunological barrier has gained interest due to GIT-associated disorders such as inflammatory bowel disease thought to be caused by improper maturation. The transition from milk-based feeding to complementary feeding in healthy infants at weaning introduces new antigens and microbes into the GIT. These changes induce immune cell production and is thought to be the final stages in the maturation process of the immunological barrier. It is during this maturation process at weaning that segmented filamentous bacteria (SFB) are thought to play a role. These Gram-positive, obligate anaerobic, spore-forming commensals have been observed in the faeces of 6–25-month-old infants and the terminal ileum of weanling rodents. The abundance of ileal and faecal SFB increases at weaning, peaks then decreases post-weaning and remains at that lower plateau throughout life. The transient abundance change of SFB has also been correlated with immune markers, immunoglobulin A (IgA) concentration in faeces and interleukin 17 (IL-17) concentration in blood plasma. The reported correlation between SFB, IgA and IL-17, and the timing at which the abundance of SFB changes at weaning, suggests that weaning foods might have an influence on changes in SFB abundance and hence on the immunological barrier. The published SFB genome identified carbohydrate metabolic and transport genes and a published study also reported an influence of complex substrates from the diet on SFB abundance. These findings suggested that a diet supplemented with complex carbohydrates may enhance the ileal SFB abundance, which had not been investigated at weaning previously. The aim therefore of this thesis was to investigate whether the complex carbohydrate inulin would influence the ileal and faecal abundances of SFB at weaning and would modulate the concentration of the GIT immune markers, IgA in faeces, and IL-17 in plasma. The hypothesis was that a weaning diet enriched with inulin would increase the peak abundance of SFB in the terminal ileum which would then enhance GIT immune barrier maturation. Initial method development showed that the temporal profile of SFB colonisation in the ileal tissue and contents of weanling rats was similar to those published for mice and infants of corresponding weaning age. Additionally, and for the first time, whole tissue homogenisation was favoured over ileal mucosal scraping as the ideal collection technique due to lower variability in whole ileal tissue data. These methods were implemented in a final study where inulin was selected because it is commonly found in weaning foods such as fruit and vegetables and is also routinely added to bovine-based milk formulas to supplement the deficit of oligosaccharides (compared to human milk). Results revealed that inulin did not influence the peak abundance of SFB, regardless of inulin dosing (0%, 2.5%, 5%, 10%) or sample type (ileal tissue, ileal contents, faeces), three days post-weaning in 24-day-old Sprague-Dawley rats. There were no differences of inulin dosing on ileal and faecal SFB abundances, blood plasma IL-17 and faecal IgA concentrations, nor between male and female rats. This outcome from the inulin intervention suggests that SFB may not utilise inulin directly or a longer period of adaptation to the inulin-supplemented diet might be required to assess if there is a long-term effect on ileal SFB abundance. The findings do not rule out other complex carbohydrates with potential influence on ileal SFB abundance. Further investigation would entail determining any interactive effects among inulin-supplemented diet, SFB abundance, and immune markers at broader time-points beyond the expected peak of SFB abundance post-weaning. In addition, analysis could be carried out to determine the abundance of other microbes relative to the predicted pre- and post-weaning SFB abundance changes. Further investigations will advance our understanding on the ability of specific food substrates to manipulate SFB and important members of the GIT microbiota and in turn support the development of high-value foods for overall health benefits in infants.
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    Effect of Faecalibacterium prausnitzii on intestinal barrier function and immune homeostasis : a dissertation presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Nutritional Science, Massey University, Manawatū, New Zealand
    (Massey University, 2017) Maier, Eva
    Various gastrointestinal (GI) diseases, for example inflammatory bowel disease, are linked to impaired barrier function, chronic inflammation and dysbiosis of the resident microbiota. Faecalibacterium prausnitzii, an abundant obligate anaerobe of the healthy human microbiota, has reduced abundance in the GI tract of people with these diseases, and has been suggested to exert beneficial effects. Only a few studies have investigated its mechanisms of action, partly due to the difficulty of co-culturing live obligate anaerobes with oxygen-requiring human cells. The novel apical anaerobic co-culture model used in this study allows this co-culture through the separation of anaerobic and aerobic compartments. This model was used to investigate the effects of live F. prausnitzii (strains A2-165, ATCC 27768 and HTF-F) on intestinal barrier integrity, measured by transepithelial electrical resistance (TEER) of the intestinal epithelial cell line Caco-2, and on immune homeostasis, specifically on Toll-like receptor (TLR) activation. Method development was required to adapt these assays to the novel model and to optimise the growth of F. prausnitzii co-cultured with Caco-2 cells and TLR-expressing cell lines while maintaining their viabilities. Firstly, the optimised co-culture conditions were used to determine the effect of the three F. prausnitzii strains on barrier integrity of healthy and tumour necrosis factor alpha (TNF-α) treated Caco-2 cells. Live and growing F. prausnitzii did not alter the TEER across healthy Caco-2 cells. However, under TNF-α mediated inflammatory conditions, dead F. prausnitzii decreased TEER, whereas live bacteria maintained TEER. Secondly, the TLR activation assay was adapted to be carried out in the novel model. Using the adapted assay conditions it was determined that live F. prausnitzii induced greater TLR2 and TLR2/6 activation than dead F. prausnitzii. Collectively, these results indicate greater immuno-stimulatory effects of live F. prausnitzii, via TLR2 activation, and this effect is potentially linked to its barrier maintaining properties, because previous research showed enhancement of barrier integrity induced by TLR2 signalling. This new knowledge contributes to the understanding of how F. prausnitzii may maintain immune homeostasis in the GI tract. Unravelling the biological mechanisms used by prevalent species of the human microbiota, such as F. prausnitzii, will ultimately allow better comprehension of microbial regulation of GI function.
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    Studies on the protective role of probiotics and milk calcium on Salmonella Typhimurium infection in mice : a thesis presented in partial fulfillment of the requirements for the degree of Master of Science in Nutritional Science at Massey University, Palmerston North, New Zealand
    (Massey University, 2000) Lin, Hai
    The current studies were carried out to evaluate the efficacy of a newly identified LAB strain - DR10TM (Bifidobacterium lactis) on host immunity and susceptibility to Salmonella typhimurium (S. typhimurium) infection in mice. In addition, the effect of elevated milk calcium levels combined with DR10TM was studied in mice infected with S. typhimurium. After initially establishing a murine infection model, the effect and efficacy of DR10TM in preventing S. typhimurium infection and stimulating immunity was examined. The results showed that DR10TM could significantly enhance resistance against S. typhimurium infection and stimulate a wide range of immune parameters including non-specific and specific immune responses. In another study the S. typhimurium infection model was used to examine the effect of milk calcium and the combination of different amounts of milk calcium with DR10TM on host immunity and prevention of S. typhimurium infection in mice. These results demonstrated that milk calcium was very effective in reducing the severity of infection and a high amount of milk calcium combined with DR10TM increased the ability of DR10TM to prevent S. typhimurium infection. The findings of the current study were significant in that they demonstrated the effect and efficacy of DR10TM on promoting enhanced resistance to enteric infection and stimulating immunity, provided additional evidence of the role played by the enhanced immune system in protecting against enteric infection, and ascertained the synergism between milk calcium and LAB in the prevention of S. typhimurium infection.
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    The effect of probiotics on host mucosal immune responses : a thesis presented in partial fulfilment of the requirements for the degree of Master of Science in Nutritional Science at Massey University, Palmerston North, New Zealand
    (Massey University, 1998) Wong, Mei Ching
    Lactic acid bacteria (LAB) are a group of Gram-positive anaerobic bacteria that convert carbohydrates and complex sugars into lactic acid as the end product through fermentation. Several species of LAB have been used as probiotics. Probiotics are mono- or mixed cultures of live microorganisms which, when orally administered to animals or man, benefit them by improving the balance of the indigenous microflora. Lactic acid bacteria are claimed to have several beneficial effects; one of them being stimulation of the immune system. Many studies have demonstrated the immunostimulatory effects of LAB and various mechanisms have been suggested as to how LAB stimulate the immune system. These include the ability of LAB to translocate to Peyer's Patches (PP) and other gut-associated lymphoid tissues (GALT) for immunological processing by immunocompetent cells and production of cytokines. There were three aims in our present studies. The first was to determine the effect of dose of an immunoenhancing probiotic strain L. rhamnosus on the mucosal and serum immune responses of mice to oral antigens cholera toxin (CT) and ovalbumin (OV). The second aim was to examine the effect of viability of L. rhamnosus on these responses. Various mucosal immune parameters were measured in these studies. Results indicate that the immunostimulatory effects of L. rhamnosus were dose-dependent and that the 1 x 109 cfu dose was the most appropriate dose for L. rhamnosus for its immunostimulatory effects. Viability also affects the immunostimulatory effects of L. rhamnosus as shown by the higher efficacy of viable L rhamnosus than non-viable L. rhamnosus in stimulation of several aspects of the mucosal immune system. In some other immune parameters, non-viable L. rhamnosus was found to be the same as, or more effective than the viable bacteria. These findings were significant in that they provide additional evidence of the dose- and viability-dependency of different LAB. This information will help those involved in the development of probiotic products to consider these factors when formulating their products so that the concentration of live LAB can be adjusted to ensure the product can convey the maximum beneficial effect to the consumer. The third aim of our studies was to examine the role played by the immune system in protecting against enteric infection. It was found that L rhamnosus increased the resistance of mice to S. typhimurium infection as demonstrated by the lower numbers of bacteria found in the liver and spleen, and a maintenance of liveweight. This was also accompanied by increased mucosal and systemic immune responses to S. typhimurium. This result suggests that the immune system may play an important role in mediating the protection against enteric infection. Various other mechanisms have also been postulated by which LAB protect against enteric infection, for example, production of antibacterial substances, competition for adherence to the gut wall and for nutrients. However, the precise role and relative importance of these mechanisms in mediating protection against enteric infection is unknown.