chaudharilab

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Research

Research Interests

Considered a new organ system in the body, the gut microbiome has specific biochemical interactions with other organs, directly affecting host physiology. Metabolites produced by gut bacteria represent one of the most dominant ways the microbiome interacts with the host. The Chaudhari Lab is interested in deciphering the unique gut metabolome and studying the biological functions of these metabolites. We integrate metabolite chemistry with cell biology, and use a variety of in vitro and in vivo biological systems to study how microbial metabolites influence health and disease

Approach

The Chaudhari Lab performs all levels of microbiome research.

  1. We have a high-resolution LC/MS instrument to perform targeted and untargeted metabolomics to identify novel microbial metabolites differentially prevalent in disease vs healthy states.
  2. By using state-of-the art NMR facilities at University of Wisconsin-Madison, we perform structure elucidation for previously uncharacterized small molecules associated with disease.
  3. Using physiologically active cell culture assays, we elucidate the cell signaling pathways induced by metabolites.
  4. We identify bacterial strains that produce small molecules shifted in disease using anaerobic culturing of gut commensal communities.
  5. Genetic engineering of gut commensals or manipulation of the gut microbiome using precision antibiotics allows us to design a “healthy” microbiome.
  6. We test our discovered microbial and small molecule mechanisms in vivo.

Current Projects

1. Disruption of intestinal integrity:

Recent studies have identified microbial natural products as key factors that induce gut inflammation. However, several studies have implicated a role of the microbiome in influencing diseases that affect multiple organs and disrupt whole-body homeostasis. The gut epithelial monolayer forms a biochemical and physical barrier that prevents parenteral organs from being exposed to intestinal luminal contents. Thus, the intestinal epithelium forms the first line of defense against dietary factors that can affect metabolic disease. Despite its importance, the mechanism of how the microbiome induces gut permeability in metabolic diseases remains largely unstudied. The Chaudhari Lab will study the link between microbial metabolites present in high concentrations in the gut and disruption of intestinal epithelial lining. Refs:  Science Advances 2022, Cell Host & Microbe 2021

Caco-2 cells when differentiated in transwells form a monolayer, complete with tight junctions and microvilli. The monolayer forms a physical and biochemical barrier mimicking the gut epithelium and can be used to study metabolites that affect gut permeability.

1. Disruption of intestinal integrity:

Recent studies have identified microbial natural products as key factors that induce gut inflammation. However, several studies have implicated a role of the microbiome in influencing diseases that affect multiple organs and disrupt whole-body homeostasis. The gut epithelial monolayer forms a biochemical and physical barrier that prevents parenteral organs from being exposed to intestinal luminal contents. Thus, the intestinal epithelium forms the first line of defense against dietary factors that can affect metabolic disease. Despite its importance, the mechanism of how the microbiome induces gut permeability in metabolic diseases remains largely unstudied. The Chaudhari Lab will study the link between microbial metabolites present in high concentrations in the gut and disruption of intestinal epithelial lining. Refs: Science Advances 2022, Cell Host Microbe 2021

Caco-2 cells when differentiated in transwells form a monolayer, complete with tight junctions and microvilli. The monolayer forms a physical and biochemical barrier mimicking the gut epithelium and can be used to study metabolites that affect gut permeability.

2. Redefining folate status:

Humans are auxotrophic for folates. There is emerging evidence that suggests a correlation between circulating folate status and metabolic disease onset. Particularly, excessive folate has been shown to influence risk of cardiovascular disease, colorectal cancer, and IBD, with pediatric folate levels directly correlating with severity of inflammation. 

Folate status is characterized by the amount of folate in systemic circulation. However, the gut harbors the highest concentration of folate in the body, at levels several fold higher than in blood. An analysis of folate levels in the gut and other organs of patients and disease models is severely lacking. Dietary folates can also modulate the microbiome, which can directly impact intestinal homeostasis. With different countries implementing divergent policies on folate fortification, the impact of high folate consumption on the microbiome and manifestations of metabolic syndrome warrants further study. We have several projects in lab that involve studying the role of folates from the diet, microbiome, and the host on disease development and progression.

2. Redefining folate status:

Humans are auxotrophic for folates. There is emerging evidence that suggests a correlation between circulating folate status and metabolic disease onset. Particularly, excessive folate has been shown to influence risk of cardiovascular disease, colorectal cancer, and IBD, with pediatric folate levels directly correlating with severity of inflammation. Folate status is characterized by the amount of folate in systemic circulation. However, the gut harbors the highest concentration of

folate in the body, at levels several fold higher than in blood. An analysis of folate levels in the gut and other organs of patients and disease models is severely lacking. Dietary folates can also modulate the microbiome, which can directly impact intestinal homeostasis. With different countries implementing divergent policies on folate fortification, the impact of high folate consumption on the microbiome and manifestations of metabolic syndrome warrants further study. We have several projects in lab

that involve studying the role of folates from the diet, microbiome, and the host on disease development and progression.

3. Studying microbial folate signaling:

Over the past two decades, microbially derived products have gained a greater visibility for their role in regulating metabolism via nuclear and membrane receptors. Therefore, it is not sufficient to limit analyses of the microbiome as a whole in inducing disease. Folate is a general term used to describe several individual folate molecules that have differential effects on host signaling. Importantly, gut bacteria synthesize their own unique folates, and have the ability to modify dietary folate, together accounting for about half of the body’s folate reservoir. Further, inhibition of bacterial folate synthesis leads to reduced gut inflammation. Therefore, bacterial folates can induce inflammation and host signaling pathways, directly contributing to disease. Ref: Developmental Cell 2016

4. Screening novel compounds for therapeutics:

We develop novel physiologically-active cell culture models that can be made high-throughput.

We generate and test compound libraries in their ability to induce signaling pathways in our cell culture models that can improve disease phenotypes. Further, identification of bacterial machinery responsible for making metabolites that disrupt intestinal homeostasis will allow generation of precise chemical tools that can manipulate the gut microbiome to elicit responses at organismal levels. Refs: Science Advances 2022, Nature Chemical Biology 2021, Nature Chemical Biology 2020

4. Screening novel compounds for therapeutics:

We develop novel physiologically-active cell culture models that can be made high-throughput.

We generate and test compound libraries in their ability to induce signaling pathways in our cell culture models that can improve disease phenotypes. Further, identification of bacterial machinery responsible for making metabolites that disrupt intestinal homeostasis will allow generation of precise chemical tools that can manipulate the gut microbiome to elicit responses at organismal levels. Refs: Science Advances 2022, Nature Chemical Biology 2021, Nature Chemical Biology 2020

5. C. elegans as a microbiome research model:

As a pioneering research model, C. elegans studies have led to several breakthroughs in modern science – from the discovery of apoptosis to the Nobel prize winning discovery of RNA-interference. The Chaudhari Lab leverages C. elegans as an in vivo model to study gut microbial interactions with the host. The diet of C. elegans consists of bacteria, resulting in accumulation of bacterial products in the intestine, similar to that in higher eukaryotes. A study of bacterially-derived metabolites, such as amino acids, bile acids, and folates in C. elegans has the potential to allow discovery of novel functions of these metabolites, and in expanding C. elegans research to new paradigms.

Refs: Developmental Cell 2016, Nature Communications 2017, Developmental Biology 2017