Gastrointestinal (GI) nematode infections comprising Necator, Ancylostoma, Ascaris as well as Trichuris affect around a quarter of the worlds population and the associated morbidity brings huge socio-economic loss. Increased rural-urban migration in developing countries has led to the adoption of new diets with increased consumption of sugary and fatty foods. Therefore, people face the dual burden of GI nematode infection and that of diet-related illnesses. In this thesis, the well-described murine model of GI nematode infection, Trichuris muris, was used to investigate the effect of high fat diet (HFD) on immune-regulated protection. C57BL/6 mice were fed either normal chow (12% energy from fat) or HFD (60% energy from fat) for 12 weeks. The mice were then infected with a low dose of T. muris eggs, known to produce a chronic, Th1 cytokine mediated response during standard chow nutrition. To mimic natural infection, mice were also given 7 to 9 weekly repeated trickle low doses of T. muris eggs. The mice were sacrificed either 21 or 42 days (single dose group) post infection or 2 weeks after the final infection (trickle dose group). The T. muris infected normal chow mice remained asymptomatic, while hyperglycaemia, elevated serum leptin and non-alcoholic fatty liver disease induced by a HFD were not reversed by a single or trickle low dose T. muris infection. Strikingly, single or trickle low dose T. muris infected HFD induced obese (HFDIO) mice had significantly lower worm burdens, higher serum levels of parasite specific IgG1 and reduced levels of parasite specific IgG2a/c in comparison to the normal chow fed controls. However, mice already infected with a single low dose T. muris infection retained a chronic infection when started on a HFD at either day 13 or day 32 post infection. Therefore, HFD induces changes in the naive host that drive resistance against T. muris in the pre-fed HFD mice. Furthermore, immune cells from the mesenteric lymph node of HFDIO mice showed a trend towards increased production of helminth expelling Th2 cytokines and there was a significant reduction in CD4+Interferon gamma+ T-cells in comparison to cells collected from normal chow mice. Finally, work showed that RAG-/- HFDIO mice had significantly reduced worm burden in comparison to RAG-/- normal chow mice at day 42 post infection suggesting that innate immunity plays a role in enhancing resistance in HFDIO mice. Overall these findings suggest that dietary fat enhances resistance to chronic T. muris infection. However, more work is needed to define the mechanisms involved and how they can be translationally targeted to boost immune responses in infected communities.
|Date of Award||31 Dec 2019|
- The University of Manchester
|Supervisor||Richard Grencis (Supervisor), David Thornton (Supervisor) & John Worthington (Supervisor)|
- T. muris
- High fat diet