measuring-intestinal-barrier-permeability-detecting-flux-fluorescent

Measuring Intestinal Barrier Permeability by Detecting Flux of Fluorescent Tracers Across Human Colonoid Monolayers

The intestinal barrier is a critical site of regulation between luminal antigens and the host immune system, and its dysregulation is implicated in ...

Children's Hospital Colorado

University of Colorado

Active episodes of inflammatory bowel disease (IBD), which include ulcerative colitis and Crohn's disease, coincide with profound shifts in the composition of the microbiota and host metabolic energy demand. Intestinal epithelial cells (IEC) that line the small intestine and colon serve as an initial point for contact for the microbiota and play a central role in innate immunity. In the 1980s, Roediger et al proposed the hypothesis that IBD represented a disease of diminished mucosal nutrition and energy deficiency ("starved gut") that strongly coincided with the degree of inflammation. These studies informed the scientific community about the important contribution of microbial-derived metabolites, particularly short-chain fatty acids (SCFA) such as butyrate, to overall energy homeostasis. Decades later, it is appreciated that disease-associated shifts in the microbiota, termed dysbiosis, places inordinate demands on energy acquisition within the mucosa, particularly during active inflammation. Here, we review the topic of tissue energetics in mucosal health and disease from the original perspective of that proposed by the starved gut hypothesis.

Revisiting the "starved gut" hypothesis in inflammatory bowel disease.

Inflammatory diseases of the digestive tract, including inflammatory bowel disease, cause metabolic stress within mucosal tissue. Creatine is a key energetic regulator. We previously reported a loss of creatine kinases (CKs) and the creatine transporter expression in inflammatory bowel disease patient intestinal biopsy samples and that creatine supplementation was protective in a dextran sulfate sodium (DSS) colitis mouse model. In the present studies, we evaluated the role of CK loss in active inflammation using the DSS colitis model. Mice lacking expression of CK brain type/CK mitochondrial form (CKdKO) showed increased susceptibility to DSS colitis (weight loss, disease activity, permeability, colon length, and histology). In a broad cytokine profiling, CKdKO mice expressed near absent interferon gamma (IFN-γ) levels. We identified losses in IFN-γ production from CD4 and CD8 T cells isolated from CKdKO mice. Addback of IFN-γ during DSS treatment resulted in partial protection for CKdKO mice. Extensions of these studies identified basal stabilization of the transcription factor hypoxia-inducible factor in CKdKO splenocytes and pharmacological stabilization of hypoxia-inducible factor resulted in reduced IFN-γ production by control splenocytes. Thus, the loss of IFN-γ production by CD4 and CD8 T cells in CKdKO mice resulted in increased colitis susceptibility and indicates that CK is protective in active mucosal inflammation.

Fundamental role for the creatine kinase pathway in protection from murine colitis.

Hope for the gut: new evidence suggests Western diet damage can be undone.

Inflammatory bowel disease is associated with intestinal energetic derangements, including reduced creatine kinase (CK) expression. CK is critical to cellular energetics, catalyzing bidirectional transfer of high-energy phosphate between creatine and ATP, and phosphocreatine (PCr) and ADP. However, the impact of CK loss on intestinal epithelial cells (IECs) remains unclear. We aimed to characterize energetic and functional consequences of CK deficiency in IECs and identify a treatment to circumvent CK loss.

Article	Year
Revisiting the "starved gut" hypothesis in inflammatory bowel disease. Immunometabolism (Cobham, Surrey)\| PubMed ID: 36644501	2023
Fundamental role for the creatine kinase pathway in protection from murine colitis. Mucosal immunology\| PubMed ID: 37716510	2023
Hope for the gut: new evidence suggests Western diet damage can be undone. American journal of physiology. Gastrointestinal and liver physiology\| PubMed ID: 40139253	2025
Phosphocreatine Rescues Intestinal Epithelial Metabolic Dysfunction Related to Creatine Kinase Loss and Is Protective in Murine Colitis. Cellular and molecular gastroenterology and hepatology\| PubMed ID: 40562094	2025

Geetha Bhagavatula

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