https://www.jaci-global.org/article/S2772-8293(26)00049-4/fulltext

Abstract

Background

Systemic mastocytosis (SM) is a clonal mast cell disorder driven in most cases by KIT D816V mutation. The evolution of symptoms before and after diagnosis remains poorly understood.

Objective

We sought to longitudinally describe various aspects of the real-world patient journey in the year leading up to and the year following diagnosis of SM.

Methods

This retrospective, observational study included a previously confirmed cohort of patients with SM within a large integrated health system. We assessed physician-coded diagnoses, dispensing of medications, and patient-reported symptoms during the year before and after diagnosis, supplementing manual review with natural language processing outputs to enhance accuracy of symptom identification. Findings were compared with 2 matched comparison groups: patients with chronic spontaneous urticaria (CSU) and patients without SM or CSU.

Results

Among 75 patients with SM (59 nonadvanced, 16 advanced), CSU patients with CSU, and 150 patients without SM or CSU, SM was associated with higher frequencies of cardiovascular disease, hepatosplenomegaly, osteoporosis, anemia, thrombocytopenia, eosinophilia, and elevated serum tryptase compared with both comparison groups. Gastrointestinal and neuropsychiatric symptoms were consistently more common in patients with SM, often persisting or worsening after diagnosis despite treatment. Advanced SM was distinguished by more pronounced hematologic and gastrointestinal abnormalities, whereas nonadvanced SM exhibited greater prevalence of cutaneous and neuropsychiatric symptoms.

Conclusions

Patients with SM often present with heterogeneous, nonspecific symptoms that overlap with several other conditions, contributing to substantial diagnostic delays. Our findings underscore the need for more inclusive diagnostic approaches and improved management strategies that address the full spectrum of patient experience before and after diagnosis.

URL: https://www.gastrojournal.org/article/S0016-5085(25)06149-9/abstract

DOI: 10.1053/j.gastro.2025.10.021

https://www.sciencedirect.com/science/article/abs/pii/S1877032022002378

Introduction (contexte de la recherche)

Les interactions entre polynucléaires éosinophiles (PNE) et mastocytes peuvent modifier l’évolution des pathologies impliquant ces cellules. Il peut s’agir d’une synapse immunologique favorisant les échanges et la régulation mutuelle via des médiateurs sécrétés : la tryptase et l’histamine induisent la dégranulation du PNE ; inversement le PNE peut activer le mastocyte grâce aux protéines granulaires. La mastocytose est une pathologie caractérisée par une prolifération de mastocytes anormaux. Certaines mastocytoses de mauvais pronostic peuvent s’accompagner d’hyperéosinophilie. La neurotoxine dérivée des éosinophiles (EDN) est une protéine sécrétée par le PNE, déjà utilisée comme marqueur d’activation éosinophilique dans l’asthme.

Objectif

Décrire les valeurs de l’EDN chez des patients atteints de pathologies mastocytaires.

Méthodes

Analyse rétrospective l’EDN, le taux de PNE circulants, la tryptasémie basale (Tb), les rapports EDN/PNE et EDN/Tb, sur une cohorte de 74 patients adultes, parmi lesquels 30 patients atteints de mastocytose, 8 suspicions de mastocytose avec Tb élevée, 10 urticaire chronique et 26 sujets contrôles.

Résultats

Les taux sériques d’EDN des patients atteints de mastocytose sont supérieurs à ceux du groupe contrôle (63,6 vs 46,2 μg/L, p = 0,02), avec une élévation proportionnelle à la sévérité de la maladie. Un taux d’EDN à 99 μg/L ou supérieur identifie les patients atteints de mastocytose avec une spécificité (Sp) de 92 % et une sensibilité (Se) de 38 %. Ces performances sont améliorées en utilisant le rapport EDN/Tb (Sp 94 %, Se 78 % pour un seuil de 3,8). Les valeurs d’EDN, du ratio EDN/PNE et EDN/Tb ne sont pas significativement associées à la dégranulation mastocytaire, l’infiltration mastocytaire histologique ou l’efficacité du traitement antihistaminique.

Conclusions

L’EDN et le ratio EDN/Tb permettent d’identifier les patients atteints de mastocytose systémique. Des études longitudinales sur des cohortes plus importantes sont nécessaires afin d’évaluer les performances de l’EDN et du ratio EDN/Tb comparées à la numération des PNE dans le suivi des mastocytoses.

https://rcseng.ovidds.com/discover/result?logSearchID=164773675&pubid=solr_6057-medline%3A37466184

Description

BACKGROUND

Exosomes are applied as biomarkers in several diseases according to their disease-specific profiles. However, the exosomes effects in functional dyspepsia (FD) are still fragmentary. Here we examined the role of Eosinophil and mast cell derived-exosomes in FD progression.

METHODS

Fifty FD subjects and age- and sex-matched healthy controls were included in this retrospective cohort study. Duodenal mucosa and gastric juice were collected to analyze molecular difference. Eosinophil and mast cell were evaluated by immunofluorescence and microarray was subjected to examine the expression levels of NEAT1, miR-211-5p, and glial cell line-derived neurotrophic factor (GDNF), which were subsequently were tested by quantitative reverse transcription PCR (RT-qPCR) validation cohorts. CCK-8 assays, and wound healing assays were used to evaluate integrity of intestinal mucosal barrier in vitro. Rats' weights and gastric emptying rates were used as evaluation of FD severity in vivo.

RESULTS

Eosinophil and mast cell were enriched and secreted more exosomes in duodenal mucosa of FD patients. We identified differential lncRNAs that were consistently and significantly up regulated in FD cases. Of these, NEAT1 was further validated by RT-qPCR and had closely relationship with GDNF. MiR-211-5p level was found to be reduced in FD and negatively related with NEAT1 and GDNF. Furthermore, NEAT1and GDNF relived FD while miR-211-5p made symptoms worse. The NEAT1/miR-211-5p/GDNF axis had a good predictive ability for FD.

CONCLUSIONS

The NEAT1/miR-211-5p/GDNF could be a potential FD biomarker.

URL: https://fg.bmj.com/content/early/2026/06/22/flgastro-2026-103767

DOI: https://doi.org/10.1136/flgastro-2026-103767

https://clinicaltrials.gov/study/NCT07655375?cond=Irritable%20Bowel%20Syndrome&viewType=Card&rank=4

Study Overview

Brief Summary

Study evaluating the effect of UCB8600 on mast cell activation in the human gut:

IBS is a disease characterized by abdominal pain and a change in stool. Treatment is limited to an adapted life style, dietary changes and medication to lessen cramps (spasmolytica), all of which have seen limited to no clinical success.

Recently, we were able to demonstrate that mast cells play an active role in IBS symptoms. More specifically, they set histamine free when activated which heightens nerve sensitivity in the intestines which probably contributes to the abdominal pain. A new product called "UCB8600" is hypothesized to be able to counteract this by causing less mast cells to be activated. In this study we'll test this by administering UCB8600 on intestinal tissue and see if there is less mast cell activation. If the study produces good results, this new product could potentially be used as a treatment for IBS in the future.

https://preview.redd.it/3oul4czknfah1.png?width=919&format=png&auto=webp&s=ce6adc8de56fae5e99ad455f1444acbf9449b8a3

URL: https://gut.bmj.com/content/early/2026/06/25/gutjnl-2026-339311

doi: 10.1136/gutjnl-2026-339311

https://www.biorxiv.org/content/10.64898/2026.06.17.732993v1 [Preprint]

One Sentence Summary Synaptic vesicle endocytosis in nociceptors is a critical mechanism driving ongoing pain and targeting this process with intrathecal LNP-delivered CRISPR/dCas9-mediated gene repression produces durable, non-opioid analgesia across multiple chronic pain models.

Abstract

Endocytosis replenishes synaptic vesicle (SV) pools that are required for persistent transmission of chronic pain signals within nociceptive spinal circuits. The nociceptor-specific contribution of SV endocytosis to pain and the therapeutic potential of endocytosis inhibitors are unclear. We identified SV endocytosis in nociceptors as a critical driver of ongoing pain and developed a gene-based strategy to target this mechanism. Nociceptor-specific adeno-associated virus-mediated knockdown of adaptor-associated kinase 1 (AAK1) or dynamin 1 (Dnm1) in dorsal root ganglia Nav1.8-positive neurons inhibited postoperative and neuropathic hypersensitivity without affecting baseline mechanical or thermal sensitivity, locomotion or spontaneous behavior. Electrophysiological recordings from spinal neurons combined with optogenetic activation of nociceptor afferents showed that AAK1 or Dnm1 downregulation blocked the sustained synaptic transmission between nociceptors and dorsal horn neurons by disrupting SV recycling and reducing neurotransmitter release probability. Lipid nanoparticle (LNP)-encapsulated CRISPR/dCas9-repressor mRNA constructs (dCas9-R) were engineered to achieve sustained and reversible transcriptional and epigenetic repression of Aak1 or Dnm1 following intrathecal delivery. LNP-mediated gene modulation produced sustained downregulation of Aak1 or Dnm1 mRNA in sensory neurons and resulted in robust and long-lasting analgesia in preclinical models of postoperative, inflammatory, neuropathic and osteoarthritis pain without impairing acute nociception or locomotor activity. Mechanistically, targeting endocytic machinery disrupted SV recycling at nociceptor terminals, thereby reducing excitatory neurotransmission within spinal pain circuits. Together, these findings establish presynaptic endocytic regulation as a convergent mechanism underlying chronic pain and demonstrate the translational potential of LNP-delivered CRISPR/dCas9-R as a durable, non-opioid pain therapy that surmounts inherent redundancy of pain signaling mechanisms.

https://www.thelancet.com/journals/langas/article/PIIS2468-1253(26)00116-0/fulltext

Summary

Background

Eosinophilic gastritis currently has no approved treatments and is postulated to be driven by type 2 inflammation. Dupilumab blocks type 2 cytokines IL-4 and IL-13 and has efficacy in multiple diseases characterised by type 2 inflammation, including eosinophilic oesophagitis. We aimed to assess the efficacy and safety of dupilumab in patients with eosinophilic gastritis.

Methods

DEGAS was a proof-of-concept, phase 2, multicentre, randomised controlled trial consisting of a 12-week, double-blind, placebo-controlled period, followed by a 24-week open-label extension period. Patients aged 12–70 years from 11 hospitals in the USA with histologically active eosinophilic gastritis (≥30 eosinophils per high-power field [HPF] in at least five HPFs in the gastric antrum and/or body) and moderate-to-severe symptoms occurring at least 2 days per week in the 2 weeks before screening were recruited. Patients with current or recent use of any biologic or current use of systemic steroids at a dose of more than 10 mg/day (prednisone) were excluded. Eligible patients were individually randomised (1:1) to parallel groups and received six injections over 12 weeks: subcutaneous dupilumab (600 mg once followed by 300 mg every 2 weeks) or subcutaneous placebo. Randomisation was performed using a central variable block (block sizes permuted between 2 and 4), with stratification by age (12–17 years or ≥18 years) and use (yes or no) of either systemic corticosteroids, swallowed corticosteroids for eosinophilic gastritis, or non-steroidal systemic immunosuppression therapy. Throughout the duration of the study, patients were expected to maintain their treatments or diets for eosinophilic gastritis. All patients who completed the double-blind period could enter the open-label extension at week 12, during which both groups received dupilumab until week 34. The primary endpoint of relative change from baseline in mean gastric eosinophil count from the five most eosinophil-dense HPFs in the gastric antrum and/or body was analysed at week 12 using linear regression. Secondary endpoints included absolute changes from baseline in Eosinophilic Gastritis Histologic Scoring System (EoS-HSS) total score, mean gastric eosinophil count from the five most eosinophil-dense HPFs, and Eosinophilic Gastritis Endoscopic Reference System (EoG-REFS) total score. All randomly assigned patients who received at least one dose of study drug were included in the safety analysis and efficacy analyses were done in all randomly assigned patients who received at least one dose of study drug and had outcome data available at week 12 (complete case). This study is registered with ClinicalTrials.gov (NCT03678545) and is now complete.

Findings

Between May 14, 2021, and Nov 10, 2023, we randomly assigned 41 patients, of whom 21 (51%) received dupilumab and 20 (49%) received placebo during the double-blind period and were included in the safety analysis. Patients were aged 12–59 years (mean 30·5 years [SD 13·2]; seven [17%] aged <18 years), 37 (90%) were White, one (2%) was Asian, one (2%) was Black or African American, two (5%) were of multiple races, 25 (61%) were female, and 16 (39%) were male. One patient from the placebo group withdrew before week 12; the remaining 21 patients treated with dupilumab and 19 patients treated with placebo had available data and were assessed for the primary endpoint. At week 12, the relative reduction in the primary endpoint was greater with dupilumab (estimated mean change –50% [95% CI –66 to –34]) than with placebo (–4% [–20 to 13]; difference –47 percentage points [–70 to –24]; p<0·0001). Significant differences between groups were noted for the secondary endpoints of absolute change from baseline in EoS-HSS total score (difference –0·10 [95% CI –0·18 to –0·03]; p=0·0055), absolute change from baseline in mean gastric eosinophil count (–38·8 [–75·6 to –17·8]; p=0·0008), and absolute change from baseline in EoG-REFS total score (–3·42 [–6·18 to –0·65]; p=0·016). At week 12, the incidence of treatment-emergent adverse events was similar between dupilumab (17 [81%]) and placebo (17 [85%]). The most common adverse event was blood eosinophilia, with similar incidence in the dupilumab (six [29%]) and placebo (six [30%]) groups. No serious adverse events or treatment-related deaths were reported.

Interpretation

The improvement of histological outcomes of eosinophilic gastritis with dupilumab in this proof-of-concept study shows type 2 inflammatory involvement in the disease and the potential value of dupilumab for the treatment of eosinophilic gastritis.

https://research.kuleuven.be/EU/p/he/p1/erc/macpain

About the project

Chronic abdominal pain is a major symptom of irritable bowel syndrome (IBS), a gastrointestinal disorder that, depending on the diagnostic criteria used, affects 4 to 20% of the population, with a female to male ratio of 2. It is characterized by altered bowel habits associated with abdominal pain in the absence of an organic cause. Despite its high prevalence and significant impact on quality of life, insight in its pathophysiology is rather limited. Consequently, treatment is disappointing and restricted to efforts aimed at correcting altered defecation, however this approach leaves abdominal pain largely unaffected. Pain arising from the gastrointestinal tract is detected by afferent nerve fibres with their cell bodies located in the dorsal root ganglia (DRG). My team recently discovered that mast cell activation in response to food intake results in the release of histamine, which renders DRG neurons more excitable leading to increased pain signalling, also referred to as visceral hypersensitivity (VHS). The clinical relevance of this finding is supported by the observation that treatment with antihistamines improves abdominal pain in about 50% of IBS patients. In MACPAIN, I aim to discover new therapeutic targets to treat the remaining 50%. Of interest, DRG neurons are surrounded by resident macrophages with which they closely interact. I hypothesize that repetitive peripheral activation of DRG neurons leads to the release of macrophage modulating mediators ultimately leading to persistent alterations in resident macrophage function and chronic VHS. Using state-of-the-art methods, we will first interrogate the impact of repetitive afferent nerve activation on the DRG macrophage population to subsequently unravel the mechanisms leading to chronic VHS. These groundbreaking insights will allow us to identify novel therapeutic targets to treat chronic VHS and will pave the way for the development of new therapeutic compounds for IBS.

Main funding info

• Programme Funding: Horizon Europe
• Sub Programme Area: ERC-2025- AdG
• Project Reference: 101265243
• From: in grant preparation
• Budget: 2.151.250 EUR
• Contract type: ERC-AdG

There’s been a wave of new research on mast cells in irritable bowel syndrome, and the picture is becoming remarkably consistent across independent labs in Europe and the US. If you follow this field, you know mast cells have been discussed for years, but the recent data move them from “maybe involved” to a central mechanistic player, at least in a significant subset of patients. Please, see the prints of the IBS Days 2026 abstracts in the end. For full download of the abstracts book, please see: https://ibsdays.com/abstract/ (note: some very interesting abstracts). Summary of findings done with the help of deepseek (AI).

Here are the key takeaways from several 2024/2025 abstracts and papers:

1. It’s not the number of mast cells, it’s their activation state and location.
Multiple studies (Balsiger et al., DISCOvERIE project, Monti et al.) show that the sheer count of mast cells in the colonic or duodenal mucosa often does not differ between IBS patients and healthy controls. Instead, mast cell activation (measured by tryptase release, piecemeal degranulation on electron microscopy, or the percentage of tryptase-stained area) is consistently increased. The spatial position is crucial: mast cells found within 5 µm of nerves (DISCOvERIE, Yuan et al.) or of leaky blood vessels (Monti et al.) are significantly more common in IBS, and this proximity correlates with symptom severity.

2. Mast cells interact with nerves and contribute to pain.
The UCLA group (Yuan et al.) used high-resolution 3D imaging to quantify nerve fibre densities and mast cell proximity in sigmoid biopsies. IBS patients showed reduced densities of cholinergic and intrinsic sensory nerve fibres (especially in constipation-predominant IBS), while vasoactive intestinal peptide (VIP) fibres were higher in diarrhoea-predominant IBS. Crucially, the proximity of mast cells to substance P- and calbindin-containing nerve fibres correlated positively with abdominal pain scores, while lower densities of VIP and NPY fibres correlated with worse symptoms. This suggests that mast cell mediators are directly sensitising pain-sensing nerves, and that there may be a low-grade enteric neuropathy driven by chronic mast cell activation.

3. A microbiota-mast cell-barrier axis has been defined mechanistically.
The most compelling causal evidence comes from a clinical trial by Gao et al. (USA) in diarrhoea-predominant IBS. Patients improved colonic barrier function and reduced mast cell activation after a low-FODMAP diet. Fecal supernatants taken before the diet caused barrier dysfunction in mice; those taken after did not. The effect was shown to depend on lipopolysaccharide (LPS) activating the TLR4 receptor directly on colonic mast cells. Removing LPS, blocking TLR4, or using mast cell-deficient mice abolished the barrier damage. Reconstitution with normal mast cells restored it, but reconstitution with TLR4-knockout mast cells did not. So we now have a clear chain: dietary fermentable substrates → microbiota-derived LPS → TLR4 on mast cells → barrier disruption.

4. Mast cell activation is most pronounced in patients with mental and somatic comorbidities.
The European multicentre DISCOvERIE project stratified IBS patients into those without comorbidities, those with mental comorbidities (anxiety/depression), and those with both mental and somatic comorbidities (fibromyalgia, chronic fatigue). Mast cell activation (tryptase area, degranulation profiles) and mast cell proximity to nerves increased progressively with comorbidity burden. Proteomic analysis of colonic mucosa revealed 271 differentially expressed proteins in the most severely affected group, enriching for pathways related to extracellular matrix interactions, oxidative phosphorylation, and thermogenesis, giving a molecular substrate to fatigue and widespread symptoms.

5. Vascular permeability is part of the story too.
Monti et al. (Bologna) showed that mast cells are not only close to nerves but also closely apposed to PV1-positive blood vessels, which are vessels with increased permeability. The density of these leaky vessels is higher in IBS, (and mast cells within 5 µm of them are significantly increased across all IBS subtypes with the most dramatic rise (177%) seen in IBS-D). This suggests mast cells contribute to vascular barrier dysfunction, potentially creating a vicious cycle of immune cell recruitment and mucosal oedema.

What this all means

Across these independent studies, a consistent model is emerging:

• Mast cells are strategically positioned as sensors and effectors at the neuro‑immune‑vascular interface of the gut mucosa.
• They can be triggered by microbial products (LPS/TLR4), dietary components (via changes in microbiota), and likely by stress mediators (CRH, substance P) in a bidirectional loop.
• Their activation results in epithelial and vascular barrier disruption, sensitisation of pain-sensing nerves, and ultimately the cardinal symptoms of IBS – pain, altered bowel habits, and even the systemic symptoms of fatigue and somatisation seen in patients with comorbidities.

For a substantial subgroup, particularly IBS-D, post-infectious IBS, and IBS with mental/somatic comorbidities, mast cell activation is a replicable, molecularly defined pathophysiological pathway. The challenge now is to translate this into clinical biomarkers and targeted treatments (mast cell stabilisers, TLR4 antagonists, dietary interventions).

https://preview.redd.it/rj1w2ob2pg8h1.png?width=788&format=png&auto=webp&s=08320aa3b68819fb1270913a00c4ca51b727676e

https://preview.redd.it/pg2hlgx3pg8h1.png?width=561&format=png&auto=webp&s=9e029a3a81fcf50f82bac86dcb5b95f345b985ce

https://preview.redd.it/jv92b6g6pg8h1.png?width=813&format=png&auto=webp&s=9abdfd918d3e2524f3a70e17e0bfac40c68a601a

https://preview.redd.it/hjzqcxz9pg8h1.png?width=816&format=png&auto=webp&s=c2924594d0ec267310187c548696d92977c4cbc0

https://preview.redd.it/k43o5h6ipg8h1.png?width=794&format=png&auto=webp&s=c555f8030fc62b048ee3605705f66b8672947108

https://www.sciencedirect.com/science/article/pii/S1878747926000565

Abstract

Migraine is a complex neurologic disorder with a significant global burden. Mast cells, a type of immune cell residing in the meninges and in close contact with dural afferent neurons, have been proposed to play an important role in the pathophysiology of migraine. While mast cells have been studied in the context of migraine for decades, more recent work has begun to investigate how the mast cell-specific receptor Mas-related G protein-coupled receptor X2/B2 (MRGPRX2/B2) may be an important contributor to neuroimmune interactions in migraine. Neuropeptides released from meningeal sensory neurons such as substance P and pituitary adenylate cyclase-activating polypeptide (PACAP), can induce mast cell degranulation via MRGPRX2/B2, leading to neurogenic inflammation and peripheral neuronal sensitization. In this review, we discuss recent findings on how MRGPRX2/B2 may contribute to mast cell and sensory neuron interactions in the meninges and could serve as a novel target for new migraine therapeutics.

URL: https://physoc.onlinelibrary.wiley.com/doi/10.1113/JP290947

DOI: https://doi.org/10.1113/JP290947Digital Object Identifier (DOI)

URL: https://www.cell.com/trends/neurosciences/abstract/S0166-2236(26)00114-1

DOI: 10.1016/j.tins.2026.05.006

https://www.neurotherapeuticsjournal.org/article/S1878-7479(25)00134-5/fulltext

4E Therapeutics is focused on developing innovative non-opioid therapeutics for various types of pain. The scientific foundation of the company is centered on the idea that pain can be effectively and safely treated by targeting the activity of a signaling axis called MNK-eIF4E, which plays a key role in regulating the activity of pain-sensing neurons in the peripheral nervous system called nociceptors. eIF4E is phophorylated by the kinase mitogen activated protein kinase interacting kinase (MNK). Inflammatory mediators and injury to nociceptors causes MNK-eIF4E signaling to increase, resulting in rapid changes in gene expression that drive pain. Genetic or pharmacological inhibition of MNK prevents and reverses these effects, suggesting small molecule MNK inhibitors have great potential as first-in-class pain therapeutics. Through extensive medicinal chemistry optimization and efficacy testing, collections of proprietary small molecule MNK inhibitors with exceptional potency and selectivity were identified. 4ET1103 was ultimately selected as a clinical candidate for neuropathic pain, low back pain, migraine, and rheumatoid arthritis due to its strong effect on human nociceptors, efficacy across multiple disease models, exceptional safety profile and ease of synthesis. 4ET1103 has completed IND-enabling studies and is poised to begin first-in-human Phase 1 clinical trials to determine safety, tolerability, pharmacokinetics and target engagement. This presentation will provide an overview of the development of 4ET1103 and will highlight key factors that have contributed to the success of the program.

UPDATE: Lilly has acquired this company (4E Therapeutics)

Press release: https://www.prnewswire.com/news-releases/4e-therapeutics-acquired-by-lilly-to-advance-non-opioid-approach-to-chronic-pain-302800631.html

Source: https://www.linkedin.com/in/markfield10/recent-activity/all/