How does the gut microbiota shape systemic immunity?

Our lab is striving to define how the commensal gut microbiota, environmental/metabolic factors and the genetic/epigenetic equipment of the host impacts on systemic immunity during health and complex diseases, such as multiple sclerosis (MS), inflammatory bowel disease (IBD), Alzheimer’s disease liver fibrosis/hepatocellular carcinoma and cancer.

MICROBIAL INDUCED FIBROSIS - DEFINE THE IMPACT OF THE GUT MICROBIOTA ON THE DEVELOPMENT OF LIVER FIBROSIS/ HEPATOCELLULAR CANCER

One of the main goals in our lab is to define the mechanism how commensal gut microbial signals initiate pre-cancerogenic liver fibrosis.

Hepatic fibrosis is the result of chronic liver damage from various etiologies including alcohol abuse, obesity, viral hepatitis or is of idiopathic origin and affects several million people in the United States. In general, LF is reversible, however chronic fibrotic liver disease may progress to cirrhosis and/or hepatocellular cancer (eventually requiring a liver transplant) that are irreversible end stage diseases. Despite the fact that hepatic fibrosis is a major health concern, and microbial signals correlate with disease severity, so far there are no direct cause-effect studies that mechanistically demonstrate the impact of systemic microbial signals on the development of LF. 

Sophisticated in vivo transgenic mice, gnotobiotic mice, fecal microbial transplants (mouse/humans)) and in vitro approaches are combined with single cell RNAseq as well as Next Gen metagenomic sequencing.  In this project our lab collaborates with the Liver Research Center in Pittsburgh to establish a strong translational axis. 

The ultimate goal is to identify novel biomarkers of early onset fibrosis, which help to identify individuals at risk to develop primary liver fibrosis and to develop novel treatment options to prevent/revert fibrosis and thus avoid liver cancer.

TUMOR MICROBIOME

It is known that bacteria inhabit the tumor microenvironment. However there are several fundamental questions that have not been addressed in sufficient detail.
Do some bacteria inhabit only specific tumors (tissue specificity)?
Can bacteria impact cancer immune therapy via modulating the host immune system?
How do tumor intrinsic bacteria modulate the tumor microenvironment?
Besides tumor mouse models, this project will have a strong translational link by collaborating with the transplant center and the liver research center in Pittsburgh.

TRAINED IMMUNITY - DETERMINE THE IMPACT OF THE GUT MICROBIOTA ON INNATE IMMUNITY

Our lab aims to interrogate how microbial signals affect the immune system of the host. In particular, we want to study how hematopoietic stem cells (HSCs) are affected by microbial signals in health and during disease in the context of trained immunity. The field of trained immunity is understudied. It is very intriguing that both murine and human HSC’s express TLRs, such as TLR2, TLR4 and TLR9 and thus are evolutionary prone to directly respond to microbial signals. Even more, microbial signals have the capacity to alter the transcriptional program and are able to dictate the differentiation of HSCs into either the myeloid or lymphoid linage. Furthermore, bacterial stimuli can train HSCs and their progenitors, which result in mature progeny that is equipped with a different transcriptional profile that enables them to better respond to a re-occurring bacterial stimulus. We will address the scientific questions by usage of several transgenic mouse lines, single cell RNAseq of sorted cell populations combined with in vitro and imaging tools. We will collaborate with several clinical institutions @ Pittsburgh to address human relevance of the study.

DETERMINE THE ROLE OF SPONTANEOUS BACTERIAL TRANSLOCATION ON SYSTEMIC IMMUNITY

The host is constantly communicating with microbes. The human body is not sterile and live bacteria can be detected in healthy individuals. What leads to gut bacterial translocation? And is there a specific “window of opportunity” where gut microbiota predominately translocates into extra-intestinal organs?
Germ free mice are much more susceptible to infections and have a substantially impaired myeloid immune system. Is there a requirement for bacterial translocation? Is this a symbiotic process, which is beneficial to the host? Is this a required mechanism that trains the innate immune system to combat infections? 
Our lab will define which microbial (type/strain of commensal), environmental/metabolic (age, nutritional status, temperature) and genetic/epigenetic factors impact on spontaneous gut bacterial translocation and will evaluate its effects on development of the immune system during health and distress. 
We will use a strong imaging approach, bacterial flow cytometry/sorting, genetic bacterial engineering and gnotobiotic mouse models combined with targeted fecal microbial transplants and metagenomic/metatranscriptomic sequencing.

The Meisel lab is currently accepting graduate students for rotations in the laboratory, as well as applications for postdoctoral fellows.