Obesity is a major predictor for type 2 diabetes. The etiology and comorbidities of these two diseases are associated. Diabetics are twice as likely to contract any type of infection and at greater risk of worse clinical outcomes to infection. However, the individual effects of diet, glycemia and obesity on risk and severity of enteric infection has not been elucidated. Here we show that high blood glucose (i.e. hyperglycemia), independent of obesity, is sufficient to promote mortality during infection with Citrobacter rodentium, a diarrhea-causing pathogen in mice. Mortality was caused by dehydration as a result of excessive Wnt/β-catenin signalling. Our findings highlight the importance of glucose lowering and fluid therapy as opposed to immunological dysfunction, gut barrier defects or bacteraemia as modifiers of outcomes from enteric infection during diabetes. Future work should develop a more comprehensive understanding of the molecular changes that connect hyperglycemia, Wnt/β-catenin pathway and fluid balance during infection. We used the most common model to cause diet-induced obesity in mice to study another enteric pathogen. We showed that long- and short-term high-fat diet (HFD) feeding promoted the colonization and expansion of adherent-invasive Escherichia coli. Higher pathogen burdens in the intestinal tissues and feces were detected in diet-induced obese mice, which coincided with increased distal gut pathology. Initiating the diet one day prior or after infection was sufficient to promote the expansion of adherent-invasive E. coli in the absence of robust weight gain implicating components of diet as a major determinant of pathogen burden. We isolated the dietary factor and found that low fibre content of the high-fat diet was partially responsible for the increased intestinal pathogen burden. Future work should determine how lower fibre alters host and bacterial metabolism in order to promote overgrowth of adherent-invasive E. coli in the gut. / Thesis / Doctor of Philosophy (PhD) / Obesity and diabetes are major public health issues that are connected in many ways, including how diet changes glucose metabolism. Diabetics have a higher risk of contracting infections and also have worse outcomes from infections. It was unknown what factors of obesity or diabetes influence how the immune system combats bacterial infections. The gut is an important site as it is where diet, the immune system, and metabolism all directly interact. We discovered that high blood sugar was associated with death related to dehydration in diabetic, but not necessarily obese mice infected with a diarrhea causing bacteria. Diet-induced obesity in mice infected with bacteria associated with Crohn's disease, showed an overgrowth of bacteria and worse intestinal damage. We isolated the key dietary factor responsible, which was low fibre rather than high fat or sugar. Even one day of lower dietary fibre promoted overgrowth of infectious bacteria in the gut.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/25223 |
| Date | January 2020 |
| Creators | Lau, Trevor |
| Contributors | Schertzer, Jonathan, Biochemistry and Biomedical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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