Research group Group Faye

Both Isopentenyl pyrophosphate (IPP) and E-4-hydroxy-3methyl-but-2-enyl pyrophosphate (HMBPP) act as nonpeptidic pattern molecules (PAMPs) designated as phosphoantigens (pAg). These are intensively studied in pathogens like Mycobacterium tuberculosis and Plasmodium falciparum as well as cancer. IPP only differs from HMBPP by a hydroxyl group. However, more than 10,000 times higher concentration is required of IPP to reach an effect equivalent of HMBPP on i activation and proliferation of Vγ2Vδ9 T cell. 

In Nature IPP is used as building block in the synthesis of numbers of various isoprenoid compounds that are essential for cell survival, such as cholesterol, vitamins, hormones, odors etc. Two pathways exist for synthesizing IPP; 1) the mevalonate (MVA) pathway is utilized by fungi, archaea and eukaryotes and some bacteria.  2) The methylene erythrophosphate (MEP) pathway is used by many bacteria and apicomplexan parasites, like malaria and toxoplasma and includes the IPP-precursor HMBPP. Plants and a few bacteria use both pathways.

A distorted gut flora is known to contribute to several disease conditions like, inflammatory bowel disease, obesity, diabetes, anorexia and different mental illnesses. The balance between bacteria utilizing MEP and MVA pathway for isoprenoid synthesis in human gut has not been studied before. Our primary aim is to investigate the effect of changing the balance between these groups on appetite, immunity and behavior.

In a pilot study we fed mice by oral gavage with a low dose of HMBPP, IPP or water and the weight gain was recorded continuously during 7 weeks.  We then studied differential gene transcription in tissues like, brain, gut, and small intestine. Putative changes in mice gut microbial content are gained from fecal sample after the 7 weeks of the treatments. Moreover, we analyze the transcriptional responses of spleen, kidney and salivary glands for effects on immune gene regulation in particular. 

We will use known MEP or MVA pathway inhibitors to treat fecal samples from healthy humans.  From samples achieved, the remaining bacteria are determined by 16S RNA sequencing to confirm the reduction of MEP and MVA bacteria, respectively. Germ free (GF) mice are treated then by oral gavage with mainly MEP or MVA pathway microbiota from humans and their effects on behavior, appetite and transcription in relevant mice tissues are followed. Mice social behavior is recorded by video camera using an Etno/Vision XT 7 Noldus apparatus.