Benjamin Holbech Jensen:
Insulin Resistance. A Fine-Tuned Interplay Between Diet, Intestinal Microbes and Immunity

Date: 29-09-2016    Supervisor: Karsten Kristiansen

Insulin resistance (IR) is escalating with alarming pace and is no longer restricted to westernized countries. As a forerunner for some of the most serious threats to human health including metabolic syndrome, cardiovascular diseases, and type 2-diabetes, the need for new treatment modalities alleviating IR is indisputable.

On this note, animal models are useful tools. Despite obvious differences between mice and man, murine models benefit from reliability, genetic manipulability, and a uniform phenotype. Therefore, the objective of this thesis was to disentangle the multifaceted etiology of IR using a variety of animal models to experimentally address clinical observations. We performed series of experiments combining immunometabolism, dietary interventions, as well as manipulation of host genetics and the gut microbiota. The latter complements the coding potential of the mammalian genome with approximately 100 fold and has thus tremendous impact on host phenotype. This is supported by findings in human fecal samples where the abundance of Prevotela copri was strongly associated with IR. Intriguingly, the same bacterium was, by another group, shown to be predictive for the responsiveness of high fiber dietary interventions. Using well-controlled proof of concept mouse studies, we found that gavaging high fat diet (HFD)-fed mice with P. copri aggravated IR and glucose intolerance. Remarkably, the Prevotella family was profusely present in healthy chow-fed (high in fiber) mice, whereas it was close to absent in mice fed either a HFD or a low fat diet (unpublished data) drained for fibers. Reintroducing P. copri into this fiber-reduced environment exacerbated IR. This suggests that timing is essential and that potential probiotic treatment modalities should be convoyed by adequate dietary interventions.

We further show that improving the inflammatory toning, using fish oil as fat source, protects mice against diet induced obesity and -inflammation while preserving insulin sensitivity, even in the absence of free fatty acid receptor 4. Conversely, HFD-induced intestinal dysbiosis is associated with IR independent of weight gain.

In conclusion, the data presented in the current thesis, supported by a thorough review of available literature, advocate that 1) Inflammation is a triggering event fueling IR; 2) Commensal microbes can, when mistreated, aggravate IR and glucose intolerance; and 3) Diet orchestrate host-microbe interactions, albeit only for species already present in the community, why personalized treatment may be key for successful response rates. Thus, novel treatment modalities to increase gut health and decrease inflammation – without jeopardizing protective immunity – may prove pivotal to curb the mounting prevalence of IR.