Project 07

 Host-microbial crosstalk along the gut-liver axis in metabolic disease

• Principial Investigators:
  • TUD: Hani Harb
  • ETH: Emma Wetter Slack 
• Students:
  • TUD: Nirnisha Pramanik (1st year-PhD student), Shadi Hambo (affiliated 2nd year-PhD student), Muhammed Afthab Tharakathel Abdul Majeed (affiliated 2nd year-PhD student)

Background: Extensive alterations in microbiome composition and function have been described in response to Western dietary patterns and in particular in obese individuals. Increased abundance of opportunistic pathogens is hypothesized to be a key driver of inflammation associated with these conditions and active contributions of the microbiota to the progression of metabolic diseases such as non-alcoholic fatty liver disease (NAFLD) have been reported. However, the specific pathways of crosstalk between mucosal immunity, intestinal physiology and the microbiota in metabolic disease remain poorly understood. The Zeissig group has long-standing expertise in the study of interactions between metabolism and immunity in the intestine and the liver and has established a range of metabolic disease models (obesity, non-alcoholic fatty liver disease [NAFLD], non-alcoholic steatohepatitis [NASH]). The Slack group has extensive expertise in the mechanistic study of host-microbial interactions and has established worldwide unique facilities to carry out real-time volatile metabolomics under full-barrier axenic  conditions.

Aims: We aim in this project to investigate how metabolically induced alterations in intestinal physiology affect microbiota composition and function and how they contribute to hepatic and systemic metabolic inflammation. Additionally, we aim to assess the mechanisms driving host-microbial interactions that lead to metabolic disease progression and thus identify potential therapeutic targets.

Added value through the collaboration between Dresden & Zurich: The Zeissig lab provides expertise in mouse models of metabolic diseases and the study of host-microbial interactions in the regulation of intestinal and hepatic immunity. The Slack laboratory has extensive expertise in gnotobiotic studies including a unique setup for comprehensive metabolomic assessment under axenic conditions, within-host population dynamics of microbes, microbiome engineering technologies and computational modelling. Expertise of the two PIs will be combined to identify novel therapeutic and diagnostic targets in metabolic inflammation.

Synergies: We will collaborate with projects 5 and 8 in a clinical study that will involve lean and obese individuals at different glycemic states (diabetes, prediabetes, normoglycemic) with or without NAFLD, to address several aims of the three projects. Additionally, interactions with these two projects will extend regarding the role of infection and/or of dietary interventions in microbiota composition and function.