scholarly journals Enteroendocrine cells couple nutrient sensing to nutrient absorption by regulating ion transport

2020 ◽  
Author(s):  
Heather A. McCauley ◽  
Andrea L. Matthis ◽  
Jacob R. Enriquez ◽  
Jonah Nichol ◽  
J. Guillermo Sanchez ◽  
...  
Keyword(s):  
Small Intestine ◽  
Peptide Yy ◽  
Therapeutic Option ◽  
Nutrient Sensing ◽  
Enteroendocrine Cells ◽  
Enteric Neurons ◽  
Essential Function ◽  
Human And Mouse ◽  
Deficient Mice ◽  
Absorptive Enterocytes

SummaryThe ability to absorb ingested nutrients is an essential function of all metazoans and utilizes a wide array of nutrient transporters found on the absorptive enterocytes of the small intestine. A unique population of patients has previously been identified with severe congenital malabsorptive diarrhea upon ingestion of any enteral nutrition. The intestines of these patients are macroscopically normal, but lack enteroendocrine cells (EECs), suggesting an essential role for this rare population of nutrient-sensing cells in regulating macronutrient absorption. We used human and mouse models of EEC deficiency to identify a new role for the EEC hormone peptide YY in regulating ion-coupled absorption of glucose and dipeptides the small intestine. We found that peptide YY is required in to maintain normal electrophysiology in the presence of vasoactive intestinal polypeptide, a potent stimulator of ion secretion produced by enteric neurons. Administration of peptide YY to EEC-deficient mice restored normal electrophysiology, improved glucose and peptide absorption, diminished diarrhea and rescued postnatal survival. These data suggest that peptide YY is a key regulator of macronutrient absorption in the small intestine and may be a viable therapeutic option to treat patients with malabsorption.

scholarly journals Enteroendocrine cells couple nutrient sensing to nutrient absorption by regulating ion transport

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Heather A. McCauley ◽  
Andrea L. Matthis ◽  
Jacob R. Enriquez ◽  
Jonah T. Nichol ◽  
J. Guillermo Sanchez ◽  
...  
Keyword(s):  
Small Intestine ◽  
Peptide Yy ◽  
Therapeutic Option ◽  
Nutrient Sensing ◽  
Enteroendocrine Cells ◽  
Enteric Neurons ◽  
Electrolyte Imbalance ◽  
Essential Function ◽  
Human And Mouse ◽  
Absorptive Enterocytes

Abstract The ability to absorb ingested nutrients is an essential function of all metazoans and utilizes a wide array of nutrient transporters found on the absorptive enterocytes of the small intestine. A unique population of patients has previously been identified with severe congenital malabsorptive diarrhea upon ingestion of any enteral nutrition. The intestines of these patients are macroscopically normal, but lack enteroendocrine cells (EECs), suggesting an essential role for this rare population of nutrient-sensing cells in regulating macronutrient absorption. Here, we use human and mouse models of EEC deficiency to identify an unappreciated role for the EEC hormone peptide YY in regulating ion-coupled absorption of glucose and dipeptides. We find that peptide YY is required in the small intestine to maintain normal electrophysiology in the presence of vasoactive intestinal polypeptide, a potent stimulator of ion secretion classically produced by enteric neurons. Administration of peptide YY to EEC-deficient mice restores normal electrophysiology, improves glucose and peptide absorption, diminishes diarrhea and rescues postnatal survival. These data suggest that peptide YY is a key regulator of macronutrient absorption in the small intestine and may be a viable therapeutic option to treat patients with electrolyte imbalance and nutrient malabsorption.

scholarly journals GPR41/FFAR3 and GPR43/FFAR2 as Cosensors for Short-Chain Fatty Acids in Enteroendocrine Cells vs FFAR3 in Enteric Neurons and FFAR2 in Enteric Leukocytes

Endocrinology ◽  
2013 ◽  
Vol 154 (10) ◽  
pp. 3552-3564 ◽  
Author(s):  
Mark K. Nøhr ◽  
Maria H. Pedersen ◽  
Andreas Gille ◽  
Kristoffer L. Egerod ◽  
Maja S. Engelstoft ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Small Intestine ◽  
Fatty Acid ◽  
Peptide Yy ◽  
Large Population ◽  
Short Chain Fatty Acids ◽  
Enteroendocrine Cells ◽  
Enteric Neurons ◽  
Short Chain ◽  
Free Fatty Acid Receptor

The expression of short-chain fatty acid receptors GPR41/FFAR3 and GPR43/ free fatty acid receptor 2 (FFAR2) was studied in the gastrointestinal tract of transgenic monomeric red fluorescent protein (mRFP) reporter mice. In the stomach free fatty acid receptor 3 (FFAR3)-mRFP was expressed in a subpopulation of ghrelin and gastrin cells. In contrast, strong expression of FFAR3-mRFP was observed in all cholecystokinin, glucose-dependent insulinotropic peptide (GIP), and secretin cells of the proximal small intestine and in all glucagon-like peptide-1 (GLP-1), peptide YY, and neurotensin cells of the distal small intestine. Throughout the colon and rectum, FFAR3-mRFP was strongly expressed in the large population of peptide YY and GLP-1 cells and in the neurotensin cells of the proximal colon. A gradient of expression of FFAR3-mRFP was observed in the somatostatin cells from less than 5% in the stomach to more than 95% in the rectum. Substance P-containing enterochromaffin cells displayed a similar gradient of FFAR3-mRFP expression throughout the small intestine. Surprisingly, FFAR3-mRFP was also expressed in the neuronal cells of the submucosal and myenteric ganglia. Quantitative PCR analysis of fluorescence-activated cell sorting (FACS) purified FFAR3-mRFP positive cells confirmed the coexpression with the various peptide hormones as well as key neuronal marker proteins. The FFAR2-mRFP reporter was strongly expressed in a large population of leukocytes in the lamina propria of in particular the small intestine but surprisingly only weakly in a subpopulation of enteroendocrine cells. Nevertheless, synthetic ligands specific for either FFAR3 or FFAR2 each released GLP-1 from colonic crypt cultures and the FFAR2 agonist mobilized intracellular Ca2+ in FFAR2 positive enteroendocrine cells. It is concluded that FFAR3-mRFP serves as a useful marker for the majority of enteroendocrine cells of the small and large intestine and that FFAR3 and FFAR2 both act as sensors for short-chain fatty acids in enteroendocrine cells, whereas FFAR3 apparently has this role alone in enteric neurons and FFAR2 in enteric leukocytes.

Targeted ablation of secretin-producing cells in transgenic mice reveals a common differentiation pathway with multiple enteroendocrine cell lineages in the small intestine

Development ◽  
1999 ◽  
Vol 126 (18) ◽  
pp. 4149-4156 ◽  
Author(s):  
G. Rindi ◽  
C. Ratineau ◽  
A. Ronco ◽  
M.E. Candusso ◽  
M. Tsai ◽  
...  
Keyword(s):  
Small Intestine ◽  
Transgenic Mice ◽  
Peptide Yy ◽  
Cell Types ◽  
Enteroendocrine Cells ◽  
Cell Type ◽  
Normal Numbers ◽  
Enteroendocrine Cell ◽  
Developmental Relationship ◽  
Ganciclovir Treatment

The four cell types of gut epithelium, enteroendocrine cells, enterocytes, Paneth cells and goblet cells, arise from a common totipotent stem cell located in the mid portion of the intestinal gland. The secretin-producing (S) cell is one of at least ten cell types belonging to the diffuse neuroendocrine system of the gut. We have examined the developmental relationship between secretin cells and other enteroendocrine cell types by conditional ablation of secretin cells in transgenic mice expressing herpes simplex virus 1 thymidine kinase (HSVTK). Ganciclovir-treated mice showed markedly increased numbers of apoptotic cells at the crypt-villus junction. Unexpectedly, ganciclovir treatment induced nearly complete ablation of enteroendocrine cells expressing cholecystokinin and peptide YY/glucagon (L cells) as well as secretin cells, suggesting a close developmental relationship between these three cell types. In addition, ganciclovir reduced the number of enteroendocrine cells producing gastric inhibitory polypeptide, substance-P, somatostatin and serotonin. During recovery from ganciclovir treatment, the enteroendocrine cells repopulated the intestine in normal numbers, suggesting that a common early endocrine progenitor was spared. Expression of BETA2, a basic helix-loop-helix protein essential for differentiation of secretin and cholecystokinin cells was examined in the proximal small intestine. BETA2 expression was seen in all enteroendocrine cells and not seen in nonendocrine cells. These results suggest that most small intestinal endocrine cells are developmentally related and that a close developmental relationship exists between secretin-producing S cells and cholecystokinin-producing and L type enteroendocrine cells. In addition, our work shows the existence of a multipotent endocrine-committed cell type and locates this hybrid multipotent cell type to a region of the intestine populated by relatively immature cells.

scholarly journals Expression of RAD21 immunoreactivity in myenteric neurons of the human and mouse small intestine

2018 ◽  
Vol 30 (9) ◽  
pp. e13429
Author(s):  
F. Bianco ◽  
S. T. Eisenman ◽  
M. G. Colmenares Aguilar ◽  
E. Bonora ◽  
P. Clavenzani ◽  
...  
Keyword(s):  
Small Intestine ◽  
Myenteric Neurons ◽  
Mouse Small Intestine ◽  
Human And Mouse

scholarly journals Genetic background-dependent abnormalities of the enteric nervous system and intestinal function in Kif26a-deficient mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yukiko Ohara ◽  
Lisa Fujimura ◽  
Akemi Sakamoto ◽  
Youichi Teratake ◽  
Shuichi Hiraoka ◽  
...  
Keyword(s):  
Genetic Background ◽  
Survival Rates ◽  
Gastrointestinal Diseases ◽  
Negative Regulator ◽  
Enteric Neurons ◽  
Enteric Neuron ◽  
Protein Coding ◽  
Underlying Mechanisms ◽  
Functional Gastrointestinal Diseases ◽  
Deficient Mice

AbstractThe Kif26a protein-coding gene has been identified as a negative regulator of the GDNF-Ret signaling pathway in enteric neurons. The aim of this study was to investigate the influence of genetic background on the phenotype of Kif26a-deficient (KO, −/−) mice. KO mice with both C57BL/6 and BALB/c genetic backgrounds were established. Survival rates and megacolon development were compared between these two strains of KO mice. Functional bowel assessments and enteric neuron histopathology were performed in the deficient mice. KO mice with the BALB/c genetic background survived more than 400 days without evidence of megacolon, while all C57BL/6 KO mice developed megacolon and died within 30 days. Local enteric neuron hyperplasia in the colon and functional bowel abnormalities were observed in BALB/c KO mice. These results indicated that megacolon and enteric neuron hyperplasia in KO mice are influenced by the genetic background. BALB/c KO mice may represent a viable model for functional gastrointestinal diseases such as chronic constipation, facilitating studies on the underlying mechanisms and providing a foundation for the development of treatments.

scholarly journals Mast cell-specific receptor/corticotropin-releasing factor axis regulates alcohol withdrawal-associated headache

2021 ◽  
Author(s):  
Hyeonwi Son ◽  
Yan Zhang ◽  
John Shannonhouse ◽  
Hirotake Ishida ◽  
Ruben Gomez ◽  
...  
Keyword(s):  
Mast Cell ◽  
Dura Mater ◽  
Alcohol Withdrawal ◽  
Therapeutic Option ◽  
Corticotropin Releasing Factor ◽  
Trigeminal Ganglia ◽  
Specific Receptor ◽  
Pain Mechanisms ◽  
Deficient Mice

Rehabilitation from alcohol addiction or abuse is challenging due to alcohol withdrawal symptoms. Headache is a severe alcohol withdrawal symptom that frequently contributes to rehabilitation failure. Despite the need for treating alcohol withdrawal-induced headache, there is no appropriate therapeutic option available. Development of improved therapeutics will depend on obtaining a clearer understanding of alcohol withdrawal-induced headache pain mechanisms. Here, we show that the mast cell-specific receptor MrgprB2 controls development of alcohol withdrawal-induced headache. Withdrawing alcohol from alcohol-acclimated mice induces strong headache behaviors, including facial allodynia, facial pain expressions, and reduced walking movement, symptoms often observed in humans suffering from headache. Observed pain behaviors were abolished in MrgprB2-deficient mice. We observed in vivo spontaneous activation and hypersensitization of trigeminal ganglia neurons in alcohol withdrawal mice, but not in MrgprB2-deficient mice. Corticotropin-releasing factor (CRF) was increased in dura mater after alcohol withdrawal. Injection of CRF into dura mater resulted in activation of trigeminal ganglia neurons and vasodilation, which was accompanied by headache behavior. In cells, CRF evoked Ca2+ transients via MrgprB2 or human MrgprX2. The results indicate that alcohol withdrawal causes headache via mast cell degranulation in dura mater. The process is under control of MrgprB2/MrgprX2, which would appear to represent a potential target for treating alcohol withdrawal-related headache.

scholarly journals Multiple mechanisms limit the accumulation of unesterified cholesterol in the small intestine of mice deficient in both ACAT2 and ABCA1

2010 ◽  
Vol 299 (5) ◽  
pp. G1012-G1022 ◽  
Author(s):  
Stephen D. Turley ◽  
Mark A. Valasek ◽  
Joyce J. Repa ◽  
John M. Dietschy
Keyword(s):  
Small Intestine ◽  
Mrna Level ◽  
Cholesterol Absorption ◽  
Cholesterol Homeostasis ◽  
High Cholesterol Diet ◽  
Unesterified Cholesterol ◽  
Compensatory Mechanisms ◽  
Niemann Pick ◽  
Sterol Excretion ◽  
Deficient Mice

Cholesterol homeostasis in the enterocyte is regulated by the interplay of multiple genes that ultimately determines the net amount of cholesterol reaching the circulation from the small intestine. The effect of deleting these genes, particularly acyl CoA:cholesterol acyl transferase 2 (ACAT2), on cholesterol absorption and fecal sterol excretion is well documented. We also know that the intestinal mRNA level for adenosine triphosphate-binding cassette transporter A1 (ABCA1) increases in Acat2−/− mice. However, none of these studies has specifically addressed how ACAT2 deficiency impacts the relative proportions of esterified and unesterified cholesterol (UC) in the enterocyte and whether the concurrent loss of ABCA1 might result in a marked buildup of UC. Therefore, the present studies measured the expression of numerous genes and related metabolic parameters in the intestine and liver of ACAT2-deficient mice fed diets containing either added cholesterol or ezetimibe, a selective sterol absorption inhibitor. Cholesterol feeding raised the concentration of UC in the small intestine, and this was accompanied by a significant reduction in the relative mRNA level for Niemann-Pick C1-like 1 (NPC1L1) and an increase in the mRNA level for both ABCA1 and ABCG5/8. All these changes were reversed by ezetimibe. When mice deficient in both ACAT2 and ABCA1 were fed a high-cholesterol diet, the increase in intestinal UC levels was no greater than it was in mice lacking only ACAT2. This resulted from a combination of compensatory mechanisms including diminished NPC1L1-mediated cholesterol uptake, increased cholesterol efflux via ABCG5/8, and possibly rapid cell turnover.

scholarly journals Ligneous Conjunctivitis in Plasminogen-Deficient Mice

Blood ◽  
1998 ◽  
Vol 91 (5) ◽  
pp. 1616-1624 ◽  
Author(s):  
A.F. Drew ◽  
A.H. Kaufman ◽  
K.W. Kombrinck ◽  
M.J.S. Danton ◽  
C.C. Daugherty ◽  
...  
Keyword(s):  
Genetic Background ◽  
Direct Evidence ◽  
Therapeutic Strategies ◽  
Pathological Changes ◽  
Rare Form ◽  
Lesion Development ◽  
Ligneous Conjunctivitis ◽  
Plasminogen Deficiency ◽  
Human And Mouse ◽  
Deficient Mice

Abstract Ligneous conjunctivitis is a rare form of chronic pseudomembranous conjunctivitis that is associated with systemic membranous pathological changes. A probable link between plasminogen and ligneous conjunctivitis has been indicated by the recent diagnoses of plasminogen deficiency in five patients suffering from ligneous conjunctivitis. The current study reports that plasminogen-deficient mice develop conjunctival lesions indistinguishable from human ligneous conjunctivitis in both appearance and histology. Both human and mouse lesions contain acellular material rich in fibrin, and aberrant or disrupted epithelium. The incidence of lesion development in mice increases with age and is strongly influenced by genetic background. Interestingly, ligneous conjunctivitis was not observed in plasminogen-deficient mice simultaneously lacking fibrinogen. This study provides direct evidence that plasminogen deficiency is one cause of ligneous conjunctivitis and suggests that plasminogen-deficient mice may be an excellent model for the development of therapeutic strategies for the treatment of this debilitating disease.

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