Meta-Analysis of the Turnover of Intestinal Epithelia in Preclinical Animal Species and Humans

Abstract

Due to the rapid turnover of the small intestinal epithelia, the rate at which enterocyte renewal occurs plays an important role in determining the level of drug-metabolizing enzymes in the gut wall. Current physiologically based pharmacokinetic (PBPK) models consider enzyme and enterocyte recovery as a lumped first-order rate. An assessment of enterocyte turnover would enable enzyme and enterocyte renewal to be modeled more mechanistically. A literature review together with statistical analysis was employed to establish enterocyte turnover in human and preclinical species. A total of 85 studies was identified reporting enterocyte turnover in 1602 subjects in six species. In mice, the geometric weighted combined mean (WX) enterocyte turnover was 2.81 6 1.14 days (n = 169). In rats, the weighted arithmetic mean enterocyte turnover was determined to be 2.37 days (n = 501). Humans exhibited a geometric WX enterocyte turnover of 3.48 6 1.55 days for the gastrointestinal epithelia (n = 265), displaying comparable turnover to that of cytochrome P450 enzymes in vitro (0.96-4.33 days). Statistical analysis indicated humans to display longer enterocyte turnover as compared with preclinical species. Extracted data were too sparse to support regional differences in small intestinal enterocyte turnover in humans despite being indicated in mice. The utilization of enterocyte turnover data, together with in vitro enzyme turnover in PBPK modeling, may improve the predictions of metabolic drug-drug interactions dependent on enzyme turnover (e.g., mechanism-based inhibition and enzyme induction) as well as absorption of nanoparticle delivery systems and intestinal metabolism in special populations exhibiting altered enterocyte turnover.

Collective ERK/Akt activity waves orchestrate epithelial homeostasis by driving apoptosis-induced survival

“…An epithelium is a self-organizing tissue that coordinates cell division and death to maintain its barrier function. This ability, called epithelial homeostasis (EH), is especially important due to frequent apoptosis observed in multiple epithelia, which can lead to complete tissue turnover in a few days in the intestinal epithelium (Darwich et al 2014). EH takes advantage of behaviors, such as sensing of cell density, epithelial extrusion, spindle orientation, apoptotic-neighbor communication, and cell-cell adhesion dynamics to maintain barrier function and epithelial integrity (Macara et al 2014).…”

Iron transport proteins: Gateways of cellular and systemic iron homeostasis

“…Iron directed for storage in ferritin would serve to retain iron in the enterocyte and prevent its absorption into the body. This iron would be eventually lost through the routine sloughing of enterocytes, which turn over approximately every 3 days in humans and mice (34). Ferritin is a large multimeric protein composed of 24 heavy (H) or light subunits in various proportions depending on the tissue.…”

Long-range function of secreted small nucleolar RNAs that direct 2′-O-methylation

“…We applied this method for analysis of Rpl13a snoRNAdirected rRNA modifications to tissues harvested 3 weeks following surgery from KO and WT parabionts. Because new rRNA transcription correlates with cell replication (33) and 2Ј-O-methylation occurs on nascent rRNAs (34), we chose for study the intestinal epithelium, where cells turn over every 2-3 days (35). Liver tissue served as a negative control, because…”