Intestinal cancer development in response to oral infection with high-fat diet induced type 2 diabetes in collaborative cross mice under different host genetic background effects
Authors: Lone Iqbal M. , Milhem Asal , Nun Nadav Ben , Iraqi Fuad A. 
Published: June 2022

Abstract
Background: Type 2 diabetes (T2D) is a metabolic disease with an imbalance in blood glucose concentration. There are significant studies currently showing association between T2D and intestinal cancer developments. High fat diet (HFD) plays part in the disease development of T2D, intestinal cancer, and infectious diseases through many biological mechanisms, including, but not limited to inflammation. Understanding the systems genetics of the multimorbidity of these diseases will provide an important knowledge and platform for dissecting the complexity of these diseases. Furthermore, in this study we used some machine learning (ML) models to explore more aspects of diabetes mellitus.Aims: The ultimate aim of this project is to study the genetic factors, which underline T2D development, associated with intestinal cancer in response to a HFD consumptions and oral co-infection, jointly or separately, on the same host genetic background. Materials & Methods: A cohort of 307 mice of eight different CC mouse lines in the four experimental groups was assessed. The mice were maintained on either HFD or Chow diet (CHD) for 12 weeks period, while half of each dietary group was either co-infected with oral bacteria or un-infected. Host response to a glucose load and clearance was assessed using intraperitoneal glucose tolerance test (IPGTT) at two time points (weeks 6 and 12) during the experiment period and, subsequently was translated to area under curve (AUC) values. At week 5 of the experiment, mice of group two and four were co-infected with Porphyromonas gingivalis (Pg) and Fusobacterium nucleatum (Fn) strains, three times a week, while keeping the other uninfected mice as a control group. At week 12, mice were sacrificed, small intestines and colon were extracted and subsequently the Polyp counts assessed, as well the intestine lengths and size measured. Results & conclusions: Our results have shown that there is a significant variation in polyp's number in different CC lines, with a spectrum between 2.5 and 12.8 total polyps on average. There was a significant correlation between area under curve (AUC) and intestine measurements, including polyp counts, length and size. In addition, our results have shown a significant sex-effect on polyp development and glucose tolerance ability with males more susceptible to HFD than females by showing higher AUC in the glucose tolerance test. The ML results showed that classification with random forest could reach the highest accuracy when all the attributes were used.These results provide an excellent platform for proceeding towards understanding the nature of the genes involved in resistance and rate of development of intestinal cancer and T2D induced by HFD and oral co-infection. Once obtained, such data can be used to predict individual risk for developing these diseases and to establish the genetically based strategy for their prevention and treatment.