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During postnatal intestinal development, the intestinal epithelium is highly proliferative, and this proliferation is regulated by signaling in the intervillous and crypt regions. This signaling is primarily mediated by Wnt, and requires membrane trafficking. However, the mechanisms by which membrane trafficking regulates signaling during this developmental phase are largely unknown. Endotubin (EDTB, MAMDC4) is an endosomal protein that is highly expressed in the apical endocytic complex (AEC) of villus enterocytes during fetal and postnatal development, and knockout of EDTB results in defective formation of the AEC and giant lysosome. Further, knockout of EDTB in cell lines results in decreased proliferation. However, the role of EDTB in proliferation during the development of the intestine is unknown. Using Villin-CreERT2 in EDTBfl/fl mice, we deleted EDTB in the intestine in the early postnatal period, or in enteroids in vitro after isolation of intervillous cells. Loss of EDTB results in decreased proliferation in the developing intestinal epithelium and decreased ability to form enteroids. EDTB is present in cells that contain the stem cell markers LGR5 and OLFM4, indicating that it is expressed in the proliferative compartment. Further, using immunoblot analysis and TCF/LEF-GFP mice as a reporter of Wnt activity, we find that knockout of EDTB results in decreased Wnt signaling. Our results show that EDTB is essential for normal proliferation during the early stages of intestinal development and suggest that this effect is through modulation of Wnt signaling. [Display omitted] • Endosomal regulation of proliferation. • Endotubin expression in stem cell compartment. • Endotubin regulation of Wnt signaling. • Membrane trafficking regulates Wnt signaling. [ABSTRACT FROM AUTHOR]

The gastrointestinal tract is particularly vulnerable to off-target effects of antineoplastic drugs because intestinal epithelial cells proliferate rapidly and have a complex immunological interaction with gut microbiota. As a result, up to 40–100% of all cancer patients dosed with chemotherapeutics experience gut toxicity, called chemotherapeutics-induced intestinal mucositis (CIM). The condition is associated with histological changes and inflammation in the mucosa arising from stem-cell apoptosis and disturbed cellular renewal and maturation processes. In turn, this results in various pathologies, including ulceration, pain, nausea, diarrhea, and bacterial translocation sepsis. In addition to reducing patient quality-of-life, CIM often leads to dose-reduction and subsequent decrease of anticancer effect. Despite decades of experimental and clinical investigations CIM remains an unsolved clinical issue, and there is a strong consensus that effective strategies are needed for preventing and treating CIM. Recent progress in the understanding of the molecular and functional pathology of CIM had provided many new potential targets and opportunities for treatment. This review presents an overview of the functions and physiology of the healthy intestinal barrier followed by a summary of the pathophysiological mechanisms involved in the development of CIM. Finally, we highlight some pharmacological and microbial interventions that have shown potential. Conclusively, one must accept that to date no single treatment has substantially transformed the clinical management of CIM. We therefore believe that the best chance for success is to use combination treatments. An optimal combination treatment will likely include prophylactics (e.g., antibiotics/probiotics) and drugs that impact the acute phase (e.g., anti-oxidants, apoptosis inhibitors, and anti-inflammatory agents) as well as the recovery phase (e.g., stimulation of proliferation and adaptation).

Background: Tissue repair and regeneration in the gastrointestinal system are crucial for maintaining homeostasis, with the process relying on intricate cellular interactions and affected by micro- and macro-nutrients. Iron, essential for various biological functions, plays a dual role in tissue healing by potentially causing oxidative damage and participating in anti-inflammatory mechanisms, underscoring its complex relationship with inflammation and tissue repair., Objective: The study aimed to elucidate the role of low dietary iron in gastrointestinal tissue repair., Methods: We utilized quantitative iron measurements to assess iron levels in inflamed regions of patients with ulcerative colitis and Crohn's disease. In addition, 3 mouse models of gastrointestinal injury/repair (dextran sulfate sodium-induced colitis, radiation injury, and wound biopsy) were used to assess the effects of low dietary iron on tissue repair., Results: We found that levels of iron in inflamed regions of both patients with ulcerative colitis and Crohn's disease are elevated. Similarly, during gastrointestinal repair, iron levels were found to be heightened, specifically in intestinal epithelial cells across the 3 injury/repair models. Mice on a low-iron diet showed compromised tissue repair with reduced proliferation. In standard diet, epithelial cells and the stem cell compartment maintain adequate iron stores. However, during a period of iron deficiency, epithelial cells exhaust their iron reserves, whereas the stem cell compartments maintain their iron pools. During injury, when the stem compartment is disrupted, low iron levels impair proliferation and compromise repair mechanisms., Conclusions: Low dietary iron impairs intestinal repair through compromising the ability of epithelial cells to aid in intestinal proliferation., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

This study aimed to investigate responsible mechanisms for rapid intestinal catch-up growth in intrauterine growth restriction (IUGR) pups via analysis of autophagy, apoptosis and proliferation in a rat model. Twenty primiparous dams were assigned into two groups as 1) dams with feed ad libitum (Adlib) and 2) dams with 50% feed restriction from gestational day 10 to 21 to achieve normal birth weight (NBW) and IUGR pups, respectively. Litter size and pup weight were recorded at parturition and 8 pups were kept in each litter to have sufficient colostrum for 24 h. Subsequently, 2 pups from each litter were decapitated. Results indicated that feed restriction dams had similar litter size with rats in Adlib group although produced IUGR pups. Histological analysis indicated that IUGR rats had decreased villus height and surface area in jejunum. There was an accumulation of autophagosomes in jejunal mucosa of IUGR pups, however, the mitochondria and microvilli were unaffected. mRNA expressions of WIPI1, MAP1LC3B, Atg13, ULK1 and Beclin1 were increased, and mTOR expression was decreased in jejunum of IUGR, which also had lower Bcl-2 mRNA expression, increased caspase 9 and relative increased ki67 mRNA expression. Results suggested that after feeding colostrum, IUGR pups had impaired jejunum with unaffected mitochondrial histology. Enhanced intestinal autophagy under low-stress conditions might improve intestinal proliferation, which may be contributed to the rapid intestinal catch-up growth.

This study aimed to investigate responsible mechanisms for rapid intestinal catch-up growth in intrauterine growth restriction (IUGR) pups via analysis of autophagy, apoptosis and proliferation in a rat model. Twenty primiparous dams were assigned into two groups as 1) dams with feed ad libitum (Adlib) and 2) dams with 50% feed restriction from gestational day 10 to 21 to achieve normal birth weight (NBW) and IUGR pups, respectively. Litter size and pup weight were recorded at parturition and 8 pups were kept in each litter to have sufficient colostrum for 24 h. Subsequently, 2 pups from each litter were decapitated. Results indicated that feed restriction dams had similar litter size with rats in Adlib group although produced IUGR pups. Histological analysis indicated that IUGR rats had decreased villus height and surface area in jejunum. There was an accumulation of autophagosomes in jejunal mucosa of IUGR pups, however, the mitochondria and microvilli were unaffected. mRNA expressions of WIPI1, MAP1LC3B, Atg13, ULK1 and Beclin1 were increased, and mTOR expression was decreased in jejunum of IUGR, which also had lower Bcl-2 mRNA expression, increased caspase 9 and relative increased ki67 mRNA expression. Results suggested that after feeding colostrum, IUGR pups had impaired jejunum with unaffected mitochondrial histology. Enhanced intestinal autophagy under low-stress conditions might improve intestinal proliferation, which may be contributed to the rapid intestinal catch-up growth. [ABSTRACT FROM AUTHOR]

The sepsis caused by Vibrio vulnificus is characterized by an average incubation period of 26 h and a high mortality rate exceeding 50%. The fast growth and dissemination of V. vulnificus in vivo lead to poor clinical outcomes in patients. Therefore, elucidation of the proliferation mechanisms of this organism in vivo may lead to the development of an effective therapeutic strategy. In this study, we focused on the low oxygen concentration in the intestinal milieu because of its drastic difference from that in air. Fumarate and nitrate reduction regulatory protein (FNR) is known to be a global transcriptional regulator for adaptation to anaerobic conditions in various bacteria. We generated a strain of V. vulnificus in which the fnr gene was replaced with an erythromycin resistance gene (fnr::erm mutant). When the fnr::erm mutant was tested in a growth competition assay against the wild-type (WT) in vivo, the competitive index of fnr::erm mutant to WT in the intestinal loop and liver was 0.378 ± 0.192 (mean ± SD) and 0.243 ± 0.123, respectively. These data suggested that FNR is important for the proliferation of V. vulnificus in the intestine to achieve a critical mass to be able to invade the systemic circulation. [ABSTRACT FROM AUTHOR]

The effects of chronic fat overconsumption on intestinal physiology and lipid metabolism remain elusive. It is unknown whether a fat-mediated adaptation to lipid absorption takes place. To address this issue, mice fed a high-fat diet (40%, w/w) were refed or not a control diet (3%, w/w) for 3 additive weeks. Despite daily lipid intake 7.7-fold higher than in controls, fecal lipid output remained unchanged in mice fed the triglyceride (TG)-rich diet. In situ isolated jejunal loops revealed greater [1-14C]linoleic acid uptake without TG accumulation in mucosa, suggesting an increase in lipid absorption capacity. Induction both in intestinal mitotic index and in the expression of genes involved in fatty acid uptake, trafficking, and lipoprotein synthesis was found in high-fat diet mice. These changes were lipid-mediated, in that they were fully abolished in mice refed the control diet. A lipid load test performed in the presence or absence of the LPL inhibitor tyloxapol showed a sustained blood TG clearance in fat-fed mice likely attributable to intestinal modulation of LPL regulators (apolipoproteins C-II and C-III). These data demonstrate that a chronic high-fat diet greatly affects intestinal physiology and body lipid use in the mouse.

Our society is aging at a rapid rate; the effects of aging on physiologic functions (e.g., small bowel adaptation) are poorly understood. The purpose of this study was to determine the ability of the aged small bowel mucosa to adapt after resection. Young (2-month-old) and aged (24-month-old) F344 rats underwent massive (70%) proximal small bowel resection (SBR) or sham operation; rats were killed at 9 or 16 days after surgery. The remnant small bowel and corresponding sham segments were harvested, weighed, and analyzed for DNA content and villus height. To determine whether the adaptive response after SBR could be enhanced, aged rats underwent SBR or sham operation and were treated with either neurotensin or saline solution (control). SBR resulted in adaptive hyperplasia in the remaining small bowel remnant in both young and aged rats at 9 and 16 days compared with sham animals. At 9 days, significant increases were noted in weight, villus height, and DNA content of the distal remnant in young and aged rats after SBR; the increases were similar in both young and aged rats. At 16 days, both young and aged rats displayed significant increases in remnant weight after SBR. Administration of neurotensin increased the weight of the remnant intestine in aged rats after SBR compared with saline treatment. Our findings demonstrate that aged small bowel mucosa exhibits a proliferative and adaptive capacity in response to SBR that was similar to that of the young animals. In addition, neurotensin administration enhanced the normal adaptive response of the small bowel in aged rats, providing further evidence that neurotensin may be therapeutically useful to augment mucosal regeneration in the early periods after massive SBR. ( J Gastrointest Surg 2003;7:88–95.) [Copyright &y& Elsevier]

The gastrointestinal tract is particularly vulnerable to off-target effects of antineoplastic drugs because intestinal epithelial cells proliferate rapidly and have a complex immunological interaction with gut microbiota. As a result, up to 40-100% of all cancer patients dosed with chemotherapeutics experience gut toxicity, called chemotherapeutics-induced intestinal mucositis (CIM). The condition is associated with histological changes and inflammation in the mucosa arising from stem-cell apoptosis and disturbed cellular renewal and maturation processes. In turn, this results in various pathologies, including ulceration, pain, nausea, diarrhea, and bacterial translocation sepsis. In addition to reducing patient quality-of-life, CIM often leads to dose-reduction and subsequent decrease of anticancer effect. Despite decades of experimental and clinical investigations CIM remains an unsolved clinical issue, and there is a strong consensus that effective strategies are needed for preventing and treating CIM. Recent progress in the understanding of the molecular and functional pathology of CIM had provided many new potential targets and opportunities for treatment. This review presents an overview of the functions and physiology of the healthy intestinal barrier followed by a summary of the pathophysiological mechanisms involved in the development of CIM. Finally, we highlight some pharmacological and microbial interventions that have shown potential. Conclusively, one must accept that to date no single treatment has substantially transformed the clinical management of CIM. We therefore believe that the best chance for success is to use combination treatments. An optimal combination treatment will likely include prophylactics (e.g., antibiotics/probiotics) and drugs that impact the acute phase (e.g., anti-oxidants, apoptosis inhibitors, and anti-inflammatory agents) as well as the recovery phase (e.g., stimulation of proliferation and adaptation)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dahlgren, Sjöblom, Hellström and Lennernäs.)

Our laboratory has shown that epidermal growth factor (EGF) and hepatocyte growth factor (HGF) can improve the function of normal rat small intestine. This study was designed to evaluate the role of these growth factors on the residual small intestine following massive (80%) small bowel resection. Our data demonstrate that EGF and HGF can enhance intestinal substrate absorption and mucosal mass beyond that which occurs with intestinal adaptation. These growth factors may be beneficial in the management of children with short bowel syndrome. [ABSTRACT FROM AUTHOR]

The sepsis caused by Vibrio vulnificus is characterized by an average incubation period of 26 h and a high mortality rate exceeding 50%. The fast growth and dissemination of V. vulnificus in vivo lead to poor clinical outcomes in patients. Therefore, elucidation of the proliferation mechanisms of this organism in vivo may lead to the development of an effective therapeutic strategy. In this study, we focused on the low oxygen concentration in the intestinal milieu because of its drastic difference from that in air. Fumarate and nitrate reduction regulatory protein (FNR) is known to be a global transcriptional regulator for adaptation to anaerobic conditions in various bacteria. We generated a strain of V. vulnificus in which the fnr gene was replaced with an erythromycin resistance gene (fnr::erm mutant). When the fnr::erm mutant was tested in a growth competition assay against the wild-type (WT) in vivo, the competitive index of fnr::erm mutant to WT in the intestinal loop and liver was 0.378 ± 0.192 (mean ± SD) and 0.243 ± 0.123, respectively. These data suggested that FNR is important for the proliferation of V. vulnificus in the intestine to achieve a critical mass to be able to invade the systemic circulation., (© FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)