Physiology

Basic studies of the physiological and pathophysiological functions in the gastrointestinal tract

Regulation of the gastrointestinal and systemic physiological functions by the enteric nervous, endocrine, immune and luminal chemosensory systems

Gastrointestinal (GI) physiological functions, including transepithelial nutrient/ion/ fluid transport, gastrointestinal motility, and intestinal host-defense, are regulated by a specific regulatory system in the GI tract, which consists of the enteric nervous system (ENS), enteric endocrine system (EES), enteric immune system (EIS), and enteric luminal chemosensory system (ELCS). In addition, it has been recently suggested that the GI regulatory system controls not only local GI functions, but also systemic homeostasis. Moreover, we have hypothesized that an additional role of the GI regulatory system is to control the condition of enterobacterial flora consisting of at least 1,000 species and >100 trillion bacteria. Recently, role of the enterobacterial flora for the condition of host health is attracting attention. However, there is little knowledge about direct interaction between the enterobacterial flora and the host intestinal mucosa. Therefore, we are investigating the mechanism of luminal chemosensing and the physiological responses (e.g. peristaltic motility and transepithelial fluid secretion) in the GI tract and in whole body as one of the direct interactions. While the luminal chemosensory system in the upper digestive tract is generally considered to sense some nutrients from food, the ELCS in the lower digestive tract is hypothesized to sense some metabolites produced by the enterobacterial flora, in order to control their conditions. Therefore, we are investigating the regulatory system in the GI tract in order to provide evidence for clinical applications using physiological experiments and morphological observations, which are supported by molecular biology and biochemical techniques. Importantly, human intestinal specimens removed for in vitro physiological measurements from colorectal cancer patients are available for use in our laboratory.


1. Regulatory mechanism of transepithelial ion/fluid secretion and GI motility
Interactions between the ENS, EES, EIS, and luminal chemosensory system have been investigated by in vivo and in vitro measurements of GI motility and transepithelial transport to clarify the regulatory mechanism of GI functions. Immunohistochemistry, RT-PCR, and Western blot analyses support the results of the physiological experiments.
2. Effects of enterobacterial metabolites on GI functions
The predominant enterobacterical metabolites in the large intestine are short-chain fatty acids (SCFAs), which are acetate, propionate, and butyrate. Their total concentration in the large intestinal lumen is approximately 100 mM. Mechanisms underlying the SCFA-induced contractile and secretory effects have been investigated in the small and large intestines of humans and experimental animals. We have found that the SCFA receptors, FFA2 (GPR43) and FFA3 (GPR41), are expressed in enteroendocrine L cells, which contain the incretin hormone, glucagon-like peptide 1 (GLP-1). In addition, we are investigating the role of the expression of taste- and olfactory-related proteins in the GI tract.
3. Pathophysiological studies in the GI tract
Some potential causes of colorectal cancer are environmental and dietary habits. Although there is some controversy, dietary fiber is thought to reduce the risk of colorectal cancer. A tumor suppressor gene, SLC5A8, is the gene for an SCFA transporter, sodium-dependent monocarboxylate transporter 1 (SMCT-1). SCFAs are produced from fermentable dietary fibers by enterobacteria. Therefore, we are investigating the expression of SLC5A8 (SMCT-1) and some SCFA-related proteins in normal, precancerous, and cancerous colonic biopsies taken during a colonoscopy.

Professor

Atsukazu KuwaharaDVM, PhD
kuwahara@u-shizuoka-ken.ac.jp
TEL +81-54-264-5707

Professor

Shinichiro KarakiPhD

Details are here

http://physiology.u-shizuoka-ken.ac.jp/

 

Figure.1

In vitro measurements of the transepithelial ion transport by Ussing flux chamber technique (A), and GI motility by force or a displacement transducer (B)

Figure.2

Hematoxylin and eosin staining of human rectal mucosa (A) and immunohistochemical imaging of the rat enteric nerve plexuses (B)

References

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  2. Pflügers Arch., 461, 141-152 (2011)
  3. Am. J. Physiol. Gastrointest. Liver Physiol., 296, G971-G981 (2009)
  4. Cell Tissue Res., 324, 353-360 (2006)
  5. Neurogastroenterol. Motil., 17, 585-594 (2005)