טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentKorach-Rechtman Hila
SubjectThe Genetics and Nutrition Effects on the Gut
Microbiome and the Microbiota Relation with
Pathogens Carriage
DepartmentDepartment of Biotechnology and Food Engineering
Supervisor Professor Yechezkel Kashi


Abstract

The gut is heavily colonized by a complex microbial community, affected by host genetics and environmental factors. Accumulative data correlate the microbiome with disease-associated alternations, but the factors responsible for microbial alterations and its effect on the host is yet to be deciphered. In this research we further investigated few of these factors.

First, we implied a unique genetic model that allowed us to uncover specific taxa, that their gut-persistence is driven by host-genetics. Microbiota of BALB/c and C57BL/6J inbred-lines was compared to their F1-reciprocal-crosses-hybrids. The microbiota of the two inbred-lines was found to be more distinct than the genetically-identical F1-hybrids, supporting the role of host genetics in determining its gut microbiota. To further understand taxa heritability, we challenged taxa gut-persistence by continues-exposure to altered microbiota, through co-habitation of the two inbred-lines. Results demonstrate temporary microbial-alterations in co-cultured mice, which disappeared upon separation, suggesting that the microbiome tend-to-maintain a host comprehensive bacterial-signature.  

We also evaluated the effect of high-fat nutrition on the microbiome, in correlation with atherosclerosis. We supplemented C57BL/6J mice with soybean-oil (SO) enriched diet and equivalent levels of linoleic-acid (LA). Our results indicate that SO, but not LA cause dysbiosis to several taxa which were previously linked to atherosclerosis. Next, we tested how the microbiota is affected by acrolein, a toxic α,β-unsaturated-aldehyde, a byproduct of thermal-treatment of fats, carbohydrates, and amino-acids. We supplemented apoE-/- mice with acrolein and the antioxidant-rich-pomegranate-juice (PJ) and analyzed changes in the microbiota. We found that acrolein caused dysbiosis, in correlation with atherosclerosis clinical-markers. Nevertheless, combining PJ with acrolein abolished most of the microbiota shift induced by acrolein.

The effect of Carbapenem-Resistant-Enterobacteriaceae (CRE) carriage in humans was also studied. CRE are highly drug-resistant pathogens whose incidence is rapidly increasing in a variety of clinical settings. To test if the microbiota composition is correlated with CRE-carriage, we analyzed the gut microbiota of hospitalized CRE-carriers and non-carriers, and healthy adults. We found that CRE-carriers had a lower phylogenetic-diversity and dysbiotic microbiota. Concurrently with Enterobacteriaceae bloom, we observed a depletion of anaerobic-commensals. The corresponding metabolic pathways alterations were analyzed and differences were observed in pathways involved in Enterobacteriaceae growth and virulence, repression of the immune-system, and corruption of the intestinal-epithelial-barrier and function. The dysbiosis combined with the metabolic changes, may explain the higher prevalence of blood-stream-infections we observed in CRE-carriers.

Finally, as all projects described above targeted bacteria, we characterized the relatively-unexplored eukaryotic domain. We found different eukaryotic profiles of BALB/c and C57BL/6J inbred-lines, which remained relatively stable while aging.

Collectively all of our finding may serve as a base for: (1) probiotics and prebiotics administration in a personalized costume due to the host's genetics; (2) demonstrating the presence of atherosclerosis associated taxa in the gut microbiome that may be further developed into non-invasive and inexpensive biomarkers; (3) prebiotics, probiotics and beneficial foods (such as PJ) supplementation for atherosclerosis prevention; (4) prevention and alternative treatments for antibiotic resistance bacteria and specifically CRE; and (5) lead to a better understanding of our gut microbial eco-system including the eukaryotic-domain.