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Enteroendocrine cells (EECs) are an essential interface between the gut and brain that communicate signals about nutrients, pain, and even information from our microbiome. EECs are hormone-producing cells expressed throughout the gastrointestinal epithelium and have been leveraged by pharmaceuticals like semaglutide (Ozempic, Wegovy), terzepatide (Mounjaro), and retatrutide (Phase 2) for diabetes and weight control, and linaclotide (Linzess) to treat irritable bowel syndrome (IBS) and visceral pain. This review focuses on role of intestinal EECs to communicate signals from the gut lumen to the brain. Canonically, EECs communicate information about the intestinal environment through a variety of hormones, dividing EECs into separate classes based on the hormone each cell type secretes. Recent studies have revealed more diverse hormone profiles and communication modalities for EECs including direct synaptic communication with peripheral neurons. EECs known as neuropod cells rapidly relay signals from gut to brain via a direct communication with vagal and primary sensory neurons. Further, this review discusses the complex information processing machinery within EECs, including receptors that transduce intraluminal signals and the ion channel complement that govern initiation and propagation of these signals. Deeper understanding of EEC physiology is necessary to safely treat devastating and pervasive conditions like irritable bowel syndrome and obesity.

•An infant showing signs of congenital sodium diarrhea including early-onset diarrhea, gaseous distention, dehydration, and electrolyte disturbances.•Hospital timeline of an infant born with confirmed heterozygous GUCY2C gene associated with autosomal dominant congenital sodium diarrhea.•Treatment course over a period of 100 days including parenteral and enteral titration of sodium, potassium, chloride, acetate, and bicarbonate replacement.•Patient was successfully transitioned from parenteral to enteral management which provided symptomatic control through the first year of life. Congenital sodium diarrhea (CSD) is a rare disorder causing electrolyte imbalances due to excessive diarrhea. In pediatric literature, common practice for treating CSD includes parenteral nutrition (PN) for fluid, nutrient, and electrolyte support through the first year of the patient's life. The aim of this study was to report a neonate who showed common symptoms of CSD, including a distended abdomen, large amounts of clear, yellow fluid draining from the rectum, dehydration, and electrolyte abnormalities. A diagnostic gene panel was completed and confirmed heterozygous variant GUCY2C gene associated with autosomal dominant CSD. The infant was initially treated with PN to maintain fluid, nutrient, and electrolyte status, but was subsequently transitioned to full enteral feeds, showing improvement in symptoms. Frequent therapy adjustments were required to maintain appropriate electrolyte levels during the duration of the hospital stay. At discharge, the infant followed an enteral fluid maintenance plan that provided symptomatic control through the first year of life. This case demonstrated the ability to maintain electrolyte levels in a patient through enteral means while avoiding long-term use of intravenous access.

The Gram-positive bacterium Listeria monocytogenes (Lm) is an emerging platform for cancer immunotherapy. To date, over 30 clinical trials have been initiated testing Lm cancer vaccines across a wide variety of cancers, including lung, cervical, colorectal, and pancreatic. Here, we assessed the immunogenicity of an Lm vaccine against the colorectal tumor antigen GUCY2C (Lm-GUCY2C). Surprisingly, Lm-GUCY2C vaccination did not prime naïve GUCY2C-specific CD8 + T-cell responses towards the dominant H-2K d -restricted epitope, GUCY2C 254-262 . However, Lm-GUCY2C produced robust CD8 + T-cell responses towards Lm-derived peptides suggesting that GUCY2C 254-262 peptide may be subdominant to Lm-derived peptides. Indeed, incorporating immunogenic Lm peptides into an adenovirus-based GUCY2C vaccine previously shown to induce robust GUCY2C 254-262 immunity completely suppressed GUCY2C 254-262 responses. Comparison of immunogenic Lm-derived peptides to GUCY2C 254-262 revealed that Lm-derived peptides form highly stable peptide-MHC complexes with H-2K d compared to GUCY2C 254-262 peptide. Moreover, amino acid substitution at a critical anchoring residue for H-2K d binding, producing GUCY2C F255Y , significantly improved stability with H-2K d and rescued GUCY2C 254-262 immunogenicity in the context of Lm vaccination. Collectively, these studies suggest that Lm antigens may compete with and suppress the immunogenicity of target vaccine antigens and that use of altered peptide ligands with enhanced peptide-MHC stability may be necessary to elicit robust immune responses. These studies suggest that optimizing target antigen competitiveness with Lm antigens or alternative immunization regimen strategies, such as prime-boost, may be required to maximize the clinical utility of Lm-based vaccines.

Background Parkinson’s disease is characterized by a progressive loss of dopaminergic neurons in the nigrostriatal pathway, leading to dopamine deficiency and motor impairments. Current treatments, such as L-DOPA, provide symptomatic relief but result in off-target effects and diminished efficacy over time. This study explores an alternative approach by investigating the activation of tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. Specifically, we explore the effects of phosphodiesterase (PDE) inhibition and guanylate cyclase-C (GUCY2C) activation on tyrosine hydroxylase Ser40 phosphorylation and their impact on motor behavior in a 6-hydroxydopamine (6-OHDA) Parkinson's disease model. Results Our findings demonstrate that increasing cyclic nucleotide levels through PDE inhibition and GUCY2C activation significantly enhances tyrosine hydroxylase Ser40 phosphorylation. In a Pitx3-deficient mouse model, which mimics the loss of dopaminergic neurons seen in Parkinson’s disease, Ser40 phosphorylation remained manipulable despite reduced tyrosine hydroxylase protein levels. Moreover, we observed no evidence of tyrosine hydroxylase degradation due to Ser40 phosphorylation, challenging previous reports. Furthermore, both PDE inhibition and GUCY2C activation resulted in improved motor behavior in the 6-OHDA Parkinson’s disease mouse model, highlighting the potential therapeutic benefits of these approaches. Conclusions This study underscores the therapeutic potential of enhancing tyrosine hydroxylase Ser40 phosphorylation to improve motor function in Parkinson’s disease. Both PDE inhibition and GUCY2C activation represent promising non-invasive strategies to modulate endogenous dopamine biosynthesis and address motor deficits. These findings suggest that targeting cyclic nucleotide pathways could lead to novel therapeutic approaches, either as standalone treatments or in combination with existing therapies like L-DOPA, aiming to provide more durable symptom relief and potentially mitigate neurodegeneration in Parkinson's disease.

Background The colorectal cancer antigen GUCY2C exhibits unique split tolerance, evoking antigen-specific CD8 + , but not CD4 + , T-cell responses that deliver anti-tumor immunity without autoimmunity in mice. Here, the cancer vaccine Ad5-GUCY2C-PADRE was evaluated in a first-in-man phase I clinical study of patients with early-stage colorectal cancer to assess its safety and immunological efficacy. Methods Ten patients with surgically-resected stage I or stage II (pN0) colon cancer received a single intramuscular injection of 10 11 viral particles (vp) of Ad5-GUCY2C-PADRE. Safety assessment and immunomonitoring were carried out for 6 months following immunization. This trial employed continual monitoring of both efficacy and toxicity of subjects as joint primary outcomes. Results All patients receiving Ad5-GUCY2C-PADRE completed the study and none developed adverse events greater than grade 1. Antibody responses to GUCY2C were detected in 10% of patients, while 40% exhibited GUCY2C-specific T-cell responses. GUCY2C-specific responses were exclusively CD8 + cytotoxic T cells, mimicking pre-clinical studies in mice in which GUCY2C-specific CD4 + T cells are eliminated by self-tolerance, while CD8 + T cells escape tolerance and mediate antitumor immunity. Moreover, pre-existing neutralizing antibodies (NAbs) to the Ad5 vector were associated with poor vaccine-induced responses, suggesting that Ad5 NAbs oppose GUCY2C immune responses to the vaccine in patients and supported by mouse studies. Conclusions Split tolerance to GUCY2C in cancer patients can be exploited to safely generate antigen-specific cytotoxic CD8 + , but not autoimmune CD4 + , T cells by Ad5-GUCY2C-PADRE in the absence of pre-existing NAbs to the viral vector. Trial registration This trial (NCT01972737) was registered at ClinicalTrials.gov on October 30th, 2013. https://clinicaltrials.gov/ct2/show/NCT01972737

A 3-year-old male patient with recurrent hospitalizations due to diarrhea, fever, vomiting, and seizures was discovered to have a GUCY2C gene mutation, inherited from his asymptomatic father. Despite antibiotics and supportive therapy, the patient continued to suffer from persistent secretory diarrhea, recurrent febrile seizures, and features of atypical Kawasaki disease. This case describes a rare presentation of early onset diarrhea and systemic inflammation associated with a gain-of-function mutation. The GUCY2C mutations are known to dysregulate intestinal fluid homeostasis, through excessive CFTR-mediated chloride secretion causing recurrent diarrhea. Additionally, this case suggests a potential link between gut barrier dysfunction and systemic inflammation, contributing to recurrent febrile episodes and KD-like manifestations. Standard antidiarrheal therapy was ineffective, highlighting potential roles for CFTR inhibitors and immune modulation. This case highlights the interplay between genetic mutations, gastrointestinal dysfunction, and systemic inflammation, underscoring the importance of a multidisciplinary approach in managing rare genetic enteropathies with immune involvement.

There is a geographic inequality in the incidence of colorectal cancer, lowest in developing countries, and greatest in developed countries. This disparity suggests an environmental contribution to cancer resistance in endemic populations. Enterotoxigenic bacteria associated with diarrheal disease are prevalent in developing countries, including enterotoxigenic E. coli (ETEC) producing heat-stable enterotoxins (STs). STs are peptides that are structurally homologous to paracrine hormones that regulate the intestinal guanylyl cyclase C (GUCY2C) receptor. Beyond secretion, GUCY2C is a tumor suppressor universally silenced by loss of expression of its paracrine hormone during carcinogenesis. Thus, the geographic imbalance in colorectal cancer, in part, may reflect chronic exposure to ST-producing organisms that restore GUCY2C signaling silenced by hormone loss during transformation. Here, mice colonized for 18 weeks with control E. coli or those engineered to secrete ST exhibited normal growth, with comparable weight gain and normal stool water content, without evidence of secretory diarrhea. Enterotoxin-producing, but not control, E. coli, generated ST that activated colonic GUCY2C signaling, cyclic guanosine monophosphate (cGMP) production, and cGMP-dependent protein phosphorylation in colonized mice. Moreover, mice colonized with ST-producing E. coli exhibited a 50% reduction in carcinogen-induced colorectal tumor burden. Thus, chronic colonization with ETEC producing ST could contribute to endemic cancer resistance in developing countries, reinforcing a novel paradigm of colorectal cancer chemoprevention with oral GUCY2C-targeted agents.

For the last decade, we have focused on guanylyl cyclase C (GUCY2C) as a potentially ideal target antigen for colorectal cancer immunotherapy. GUCY2C is expressed only in intestinal epithelial cells and by nearly 100% of colorectal cancers. We have developed and tested a recombinant adenoviral vector possessing GUCY2C (Ad5-GUCY2C) as a candidate vaccine for colorectal cancer patients. Murine studies have revealed that this vaccine is safe and effective against GUCY2C-expressing targets, and Ad5-GUCY2C is poised for phase I clinical testing in colorectal cancer patients with minimal residual disease. Moreover, we are developing second-generation GUCY2C-targeted therapeutics, including the use of chimeric antigen receptor (CAR)-expressing T cells, for treatment of patients with advanced colorectal cancer for whom Ad5-GUCY2C immunization is not appropriate. Thus, a family of GUCY2C-targeted immunotherapeutics may bridge the gap in effective treatments for the 500,000 patients worldwide who die annually from colorectal cancer.

Perhaps most importantly, provision of help led to the generation of GUCY2C-specific memory responses and resistance to tumor challenge months after immunization [3]. [...]GUCY2C tolerance eliminating CD4+ and CD8+ T- and B-cell responses, antitumor immunity and immunological memory reflects only CD4+ T-cell tolerance, while CD8+ T- and B-cell pools remain intact [3]. [...]is a holistic, rather than lineage-specific, assessment of candidate tumor antigens required to sufficiently determine the mechanisms controlling responses to that antigen and its potential vaccine utility?