The KU School of Medicine encourages research by residents and faculty. Learn about the work being done with microbiome research.
The human gastrointestinal tract has a protective covering of mucus that harbors trillions of microorganisms, which influences the host during health and disease. These microbes are confined to the gut lumen and in the healthy state, do not cross the epithelial barrier.
However, underlying genetic susceptibility and environmental factors (e.g., diet) can induce significant dysbiosis thus distorting microbe-host homeostasis to influence inflammatory disease evolution (Figure 1). The intestinal stem cells (ISCs), located at the base of the intestinal crypts, maintain the mucosal barrier by playing a key role in governing the proliferation and differentiation of the intestinal epithelium. Lgr5 is an ISC marker necessary for epithelial turnover and crypt regeneration in the gut.
A unique epithelial subset, called tuft cells, marked by Dclk1 (Doublecortin-like Kinase-1) resides in the gastrointestinal tract of many vertebrates and may be involved in sensing gut microbes via taste receptors to contribute towards gut homeostasis. However, it remains to be elucidated if ISCs marked by either Lgr5 or Dclk1, are directly involved in sensing and responding to gut bacteria.
Similarly, how colonic stem cell population responds to environmental factors such as diet is not well understood. An elegant study recently showed that Lgr5+ stem cells are highly susceptible to DSS-induced damage and that dietary cues can impact stem cells' regulatory networks (1). Likewise, Yilmaz OH et al. (2) described increases in Lgr5+ stem cell number in mice exposed to calorie restriction. These studies clearly highlight the gaps in our understanding of how nutrients and diet overall affect the ISCs in the gut.
Microbiota-derived metabolites play a central role in the communication between microbes and their host with short-chain fatty acids (SCFAs) being the most studied. SCFAs are primarily derived from fermentation of dietary fibers and play a pivotal role in host gut, metabolic and immune function. In response to infection by enteric pathogens or during inflammatory bowel disease (IBD) however, there is significant dysbiosis with reduced numbers of SCFAs-producing bacteria and reduced butyrate concentration that is linked to a marked increase in the number of proinflammatory immune cells in the gut mucosa of these patients (Figure 1).
The overarching goal of my laboratory is to delineate whether environmental factors such as diet influence ISCs through modulation of gut bacteria. We employ a three-pronged approach including cell culture, mouse models and human samples to examine the cause-&-effect relationship between nutrients (e.g., SCFAs) and ISCs. We believe that the role of stem cells in establishing relative risk needs to be investigated in much more depth in order to provide firm rationale for conducting and interpreting marker studies in humans. Understanding the relationship between microbial dysbiosis and reduced SCFA concentration during diseases like IBD or even Colorectal Cancer (CRC) may lead to novel therapeutic interventions.
1. Davidson LA, Goldsby JS, Callaway ES, Shah MS, Barker N, Chapkin RS. Alteration of colonic stem cell gene signatures during the regenerative response to injury. Biochem Biophys Acta. 2012 Oct;1822(10):1600-7.
2. Yilmaz ÖH, Katajisto P, Lamming DW, Gültekin Y, Bauer-Rowe KE, Sengupta S, Birsoy K, Dursun A, Yilmaz VO, Selig M, Nielsen GP, Mino-Kenudson M, Zukerberg LR, Bhan AK, Deshpande V, Sabatini DM. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature. 2012 Jun 28;486(7404):490-5.