Summary

Bowel involvement is a severe manifestation of deep endometriosis that affects approximately 8–12% of women with endometriosis. Bowel endometriosis is most commonly localised in the rectosigmoid colon and frequently coexists with other pelvic lesions. The pathogenesis of bowel endometriosis is multifactorial, involving hormonal, inflammatory, immune, genetic, and anatomical factors. Clinical presentation ranges from asymptomatic disease to severe gastrointestinal and pelvic symptoms, which can mimic other digestive disorders such as irritable bowel syndrome and inflammatory bowel disease. Diagnostic delays frequently exceed 7–10 years. Transvaginal ultrasound and MRI are the main non-invasive tools for the diagnosis and preoperative assessment of rectosigmoid endometriosis. First-line medical therapy with combined oral contraceptives or progestogens might provide symptom control but is not curative, whereas surgery is reserved for bowel obstruction or severe or refractory symptoms, with surgical approach tailored to disease characteristics and patient needs. Fertility outcomes remain uncertain, and the complexity of long-term management, including the rare risk of malignant transformation, supports the need for multidisciplinary follow-up.

Abstract

Of all the organ systems in the body, the gastrointestinal tract is the most complicated in terms of the numbers of structures involved, each with different functions, and the numbers and types of signaling molecules utilized. The digestion of food and absorption of nutrients, electrolytes, and water occurs in a hostile luminal environment that contains a large and diverse microbiota. At the core of regulatory control of the digestive and defensive functions of the gastrointestinal tract is the enteric nervous system (ENS), a complex system of neurons and glia in the gut wall. In this review, we discuss 1) the intrinsic neural control of gut functions involved in digestion and 2) how the ENS interacts with the immune system, gut microbiota, and epithelium to maintain mucosal defense and barrier function. We highlight developments that have revolutionized our understanding of the physiology and pathophysiology of enteric neural control. These include a new understanding of the molecular architecture of the ENS, the organization and function of enteric motor circuits, and the roles of enteric glia. We explore the transduction of luminal stimuli by enteroendocrine cells, the regulation of intestinal barrier function by enteric neurons and glia, local immune control by the ENS, and the role of the gut microbiota in regulating the structure and function of the ENS. Multifunctional enteric neurons work together with enteric glial cells, macrophages, interstitial cells, and enteroendocrine cells integrating an array of signals to initiate outputs that are precisely regulated in space and time to control digestion and intestinal homeostasis.

CLINICAL HIGHLIGHTS

How gastrointestinal homeostasis is controlled is fundamental to understanding the etiology of gastrointestinal diseases. This review addresses how the digestive and defensive functions of the gastrointestinal tract are regulated by the enteric nervous system. Enteric neurons function in circuits together with enteric glial cells, macrophages, interstitial cells, and enteroendocrine cells to initiate outputs (e.g., motility, secretion) that are precisely regulated in space and time to control intestinal homeostasis. A deep understanding of how enteric neural control is regulated will guide future investigations into pathophysiological conditions and gastrointestinal diseases.

Abstract

Background: The Rome V criteria for irritable bowel syndrome (IBS) were proposed in May, 2026. Their performance for the diagnosis of IBS in clinical practice is as yet unknown. We aimed to conduct a diagnostic accuracy study to examine this issue.

Methods: This diagnostic accuracy study was conducted in the specialist IBS clinic in Leeds Teaching Hospitals National Health Service Trust, Leeds, UK. Consecutive adults aged 16 years and older who were referred with suspected IBS between Sept 22, 2016, and June 18, 2024, provided complete symptom data. We applied standardised investigations (including full blood count, C-reactive protein, and coeliac serology), with assessors masked to symptom status. We assessed performance of the Rome V criteria, compared with the previous iterations, Rome IV and Rome III. The reference standard used to confirm IBS was the presence of lower abdominal pain or discomfort in association with altered stool form or frequency combined with no evidence of organic gastrointestinal disease after standardised investigations. Sensitivity, specificity, and positive and negative likelihood ratios were calculated for each of the diagnostic criteria, with 95% CIs.

Findings: Of the 745 eligible patients recruited, 726 patients had complete Rome V symptom data (546 [75%] were female, 180 [25%] were male, and mean age was 36·9 years [SD 14·0]). 417 (57%) patients met Rome V criteria for IBS. The level of agreement between the Rome V and either the Rome III or Rome IV criteria was fair to moderate (κ=0·36-0·55). Of patients with complete Rome V symptom data, 590 had IBS according to the reference standard, of whom 390 met Rome V criteria for IBS. Sensitivity of the Rome V criteria was therefore 66·1% (95% CI 62·1-69·9) and specificity was 80·1% (72·4-86·5). Positive likelihood ratio for the Rome V criteria was 3·33 (95% CI 2·40-4·74) and negative likelihood ratio was 0·42 (0·37-0·49). The Rome III and Rome IV criteria for IBS performed differently, with sensitivities of 87·5% (95% CI 84·4-90·3) and 78·9% (75·4-82·1) and specificities of 75·0% (66·3-82·4) and 81·0% (73·4-87·2). Positive and negative likelihood ratios for the Rome III criteria were 3·50 (2·61-4·84) and 0·17 (0·13-0·21) and for the Rome IV criteria were 4·16 (2·98-5·95) and 0·26 (0·22-0·31).

Interpretation: The Rome V criteria for IBS identified a different group of patients, with lower sensitivity than either Rome III or IV criteria in this single centre secondary care study. The clinical relevance of this is uncertain.

Editor’s summary

Cancer cachexia is a complex metabolic syndrome marked by reduced appetite, weight loss, and muscle wasting. Cross et al. report that a subset of Lkb1-mutant lung cancers is prone to cachexia (see the Perspective by Gültekin and Vander Heiden). When mice were fed a high-calorie, high-fat diet, reduced appetite and weight loss were observed, which was associated with reduced appetite sensing to the brain. Prostaglandin E2 (PGE2) is a lipid-signaling molecule produced by tumors that increases when animals consume fat. The authors found that PGE2 acts locally in the lung to drive decreased weight and appetite. Blocking either PGE2 production or silencing sensory nerves reduced cachexia, suggesting that the peripheral nervous system may represent a therapeutic target. The observations further suggest that tumors can trigger cachexia through local nerve signaling, as opposed to only circulating factors. —Priscilla N. Kelly

Abstract

Sickness behaviors are common in cancer-associated cachexia and affect up to half of lung cancer patients. We demonstrate that among the most common cancer mutations, loss of liver kinase B1 (Lkb1) promotes the development of cachexia in preclinical models of lung cancer. In an effort to improve caloric intake with an obesogenic high-fat diet, we paradoxically observed worsened cachexia-associated sickness. We found that local production of prostaglandin E2 (PGE2), rather than circulating factors, promotes sickness and that genetic, dietary, and pharmacological inhibition of tumor-derived PGE2 suppresses sickness and cachexia. Notably, we demonstrate that lung sensory neuron abrogation prevents PGE2-dependent cachexia. Our study establishes localized tumor-derived signals to sensory neurons, rather than circulating factors, as drivers of cachexia and highlights a previously unknown role of the peripheral nervous system in cancer cachexia.

Highlights

• Nav1.8 G1662S gain-of-function mutation was identified in humans with neuropathic pain.
• GS mutant channels amplify nociceptors excitability by enhancing Na^(+) influx and promoting repetitive AP firing.
• The biophysical mechanisms of GS-induced neuronal hyperexcitability are context-dependent.
• At low firing rates, G1662S-depolarized inactivation drives hyperexcitability.
• At high firing rates, G1662S-altered repriming kinetics become equally important.

Abstract

Voltage-gated sodium channel Nav1.8 is highly expressed in nociceptors, where it plays a critical role in sustaining repetitive action potential (AP) firing. Gain-of-function Nav1.8 mutations that increase nociceptor excitability have been identified in patients with painful peripheral neuropathy, but the biophysical mechanisms by which they confer nociceptor hyperexcitability are incompletely understood. Here we carry out a high-resolution dissection of the functional consequences of a Nav1.8 mutation (G1662S) identified in human subjects with severe neuropathic pain, using dynamic clamp modeling in small dorsal root ganglion (DRG) neurons. While Nav1.8WT/GS conductance did not alter resting membrane potential, rheobase, or single AP threshold, it produced a marked hyperexcitability during repetitive firing. Nav1.8WT/GS neurons generated nearly twice as many APs as wild-type controls in response to suprathreshold depolarization, an effect attributable to increased sodium charge transfer across successive spikes. Charge analysis revealed that the GS mutation disproportionately enhanced suprathreshold sodium influx, supporting greater AP fidelity without adaptation. Biophysical dissection showed that this excitability phenotype arises from frequency-dependent mechanisms: at lower firing frequencies, the depolarizing shift in steady-state inactivation increases channel availability and contributes to G1662S-mediated hyperexcitability, whereas at higher firing frequencies both the depolarized voltage-dependence of inactivation and the accelerated recovery from inactivation further sustain G1662S hyperexcitability. Together, these properties enable Nav1.8WT/GS neurons to maintain enhanced firing across a broad range of frequencies, in contrast to wild-type nociceptors that typically adapt faster. These findings provide mechanistic insight into Nav1.8-driven hyperexcitability and highlight Nav1.8 as a therapeutic target for genetic and acquired pain syndromes.

Abstract

Post-infectious irritable bowel syndrome (PI-IBS) is defined by persistent gastrointestinal symptoms that follow recovery from an episode of infectious enteritis, which worsen after experiencing psychological stress. Mucosal neurite outgrowth stimulated by neurotrophins and serotonin/5-hydroxytryptamine receptor subtype 7 (5-HT7) activation is linked to visceral hypersensitivity. Rifaximin (RFX) is a poorly absorbed antibiotic that improves IBS symptoms; however, the exact mechanisms remain unclear. The aims are to evaluate changes in microbiota and neuroplasticity in PI-IBS mice after RFX treatment, and the analgesic effects of combined treatment with a novel 5-HT7 antagonist CYY1005 (CYY). A mouse model with dual triggers of Giardia postinfection and water avoidance stress exhibited intestinal hyperalgesia, as measured by visceromotor responses (VMRs). Higher Shannon diversity and increased relative abundances of Lachnospiraceae, Deholobactericeae, and Ruminococcus gnavus were observed in the microbiota of PI-IBS mice, which were restored to baseline after RFX treatment. Reduced VMRs were associated with attenuated mucosal neurite outgrowth and brain-derived neurotrophic factor (BDNF) expression after RFX treatment. BDNF/TrkB activation induced mTOR-dependent nerve fiber elongation and upregulated tryptophan hydroxylase 2 and 5-HT7 expression via Rac1/ROCK pathway in SH-SY5Y neuron cultures. Combined treatment with RFX and CYY reduced VMRs to levels comparable to those of the control groups. Lastly, bacteria-free colonic mouse supernatants induced neurite elongation in SH-SY5Y cells, which was inhibited by neutralizing anti-BDNF antibodies. In conclusion, microbiota restoration by RFX treatment attenuated BDNF-induced neurite outgrowth and alleviated visceral hypersensitivity in mice. Analgesic combinations of RFX and a 5-HT7 receptor antagonist reduced intestinal nociception to baseline levels.

Abstract

M3 subtype of muscarinic acetylcholine receptors (mAChRs) is a very important drug target validated for irritable bowel syndrome (IBS), over active bladder (OAB), and chronic obstructive pulmonary disease (COPD). The M2 subtype has high sequence and structural similarity with M3. This makes it difficult to design selective inhibitors for M3 subtype. To address this problem, a three-dimensional quantitative structure–activity relationship (3D-QSAR) pharmacophore model was generated to estimate M2 specific inhibitory constant (Ki). The predictions were compared with a reported 3D-QSAR M3 pharmacophore model to calculate M3/M2 selectivity ratio. This double-pharmacophore workflow was validated over known M3 antagonists. It was then applied to virtually screen a focused PubChem library with ‘piperazine–triazole’ scaffold. The top-ranked M3 selective candidates (10673583 and 46934496) were further studied for their molecular interactions at the orthosteric binding pocket of both M2 and M3 in silico, such as Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) and, Molecular Mechanics/Generalized Born Surface Area (MM/GBSA). The results predicted strong hydrogen bonding along with hydrophobic, hydrophilic, and π–π interactions of the M3 receptor–ligand complexes over M2.

Graphical abstract

Abstract

Ketamine offers rapid relief for treatment-resistant depression and severe pain in the clinic, providing immediate benefits that traditional medications often fail to deliver. While its antagonistic action at the N-methyl-D-aspartate receptor (NMDAR) is a key mechanism, ketamine’s dual nature as both a promising treatment and a drug with abuse potential suggests its therapeutic effects extend beyond NMDAR inhibition. Here we provide structural evidence of human opioid receptors bound to ketamine and its parent analog phencyclidine (PCP), supporting that both ligands can directly bind and activate opioid receptors. The structures, together with site-directed mutagenesis and structure–activity relationship studies, identify key motifs involved in ketamine and PCP recognition and efficacy modulation. Furthermore, we determine the structure of the ligand-free state of human κ opioid receptor, revealing molecular details before ligand engagement. Compared to PCP, ketamine displays more notable binding dynamics in the orthosteric site that may contribute to its unique pharmacology at opioid receptors. Our findings highlight the importance of including opioid receptors to fully understand ketamine’s versatility in clinical settings.

These data showed that the majority of patients (90.9%) in the study were opioid free through the end of treatment (up to 14 days), demonstrating the potential for JOURNAVX as a core element of opioid-free multimodal treatment for moderate-to-severe acute pain after aesthetic and reconstructive procedures. In contrast, the literature shows opioid-free rates of less than 10% with multimodal treatment without JOURNAVX.

Abstract

The clinical management of chronic pain has long relied on conventional medications, including drugs such as opioids, anti-inflammatory drugs and anticonvulsants, which are universally associated with inadequate efficacy and prominent adverse effects. This highlights an urgent need for novel therapeutic strategies targeting the underlying mechanisms of pain. Recent studies have demonstrated that T-type calcium channels play a pivotal role in the pathogenesis and progression of neuropathic and inflammatory pain, with their expression and function being significantly up-regulated in neurons of the dorsal root ganglion (DRG) and spinal dorsal horn neurons, emerging as a highly promising yet clinically unvalidated analgesic target. However, the development of blockers directly targeting the Cav3.2 subtype is still confronted with major translational challenges, such as low subtype selectivity, as well as adverse effects in the central nervous system and cardiovascular system. Repeated clinical setbacks of candidate drugs like ABT-639 have highlighted the gap between preclinical potential and clinical efficacy, and to date, no ideal clinical candidate has been identified. This review integrates structural biology insights, lessons from clinical failures and pharmacological advances to guide the research and development of safe, highly selective Cav3.2-targeted analgesic agents.

Abstract

Objective: Irritable bowel syndrome (IBS) presents with symptoms of pain, abdominal discomfort, and altered bowel habits. Changes in the intestinal microbiota, including an increase in Enterobacteriaceae like E. coli, have been associated with IBS. The aim of this study was to evaluate the effects of IBS-associated E. coli strains on epithelial inflammatory responses, tight junction-related gene expression, and Toll-like receptor regulation in Caco-2 cells.

Results: Results showed that IBS-associated E. coli strains exhibited significantly higher invasion activity and increased production of IL-8 and TNF-α compared to H-E. coli. Furthermore, IBS-associated E. coli strains upregulated TLR-4 and TLR-5 expression and reduced the expression of tight junction proteins.

Abstract

Background: The intestinal microbiome is essential for maintaining a balanced and healthy gut environment. Certain Escherichia coli strains can disrupt it through various pathogenic factors and have been linked to gastrointestinal diseases. In this study, E. coli strains were isolated from individuals with irritable bowel syndrome (IBS) and healthy controls. Identification was performed using microbiological and molecular methods. The presence of key virulence factors, including adhesins (iha, lpfA, afaC, sfaDE, papC, focG, aafII), iron acquisition systems (chuA, iroN, fepC, irp2, iutA, ireA), hemolysin (hlyA), microcins and colicins (cva, colY), and multifunctional factors (malX, yajQ), was assessed by polymerase chain reaction.

Results: The genes lpfA, papC, iroN, ireA, cva, and malX were found to be significantly more prevalent in IBS-associated isolates following Bonferroni correction (p < 0.0031). A higher prevalence of sfaDE, focG, chuA, and hlyA was also observed, though these differences were not statistically significant. Conversely, the genes iha and irp2 were significantly more common in E. coli isolates from healthy individuals. Notably, none of the isolates harbored the afaC and aafII genes. This study demonstrates significant differences in the distribution of specific virulence genes between E. coli isolates from IBS patients and healthy individuals. The higher prevalence of specific genes in IBS isolates may contribute to their pathogenic potential, whereas the frequent occurrence of iha and irp2 in healthy individuals may suggest a role in maintaining a balanced gut microbiome. These findings highlight distinct virulence gene profiles, suggesting a potential association between these E. coli factors and IBS disease status.

Abstract

The aryl hydrocarbon receptor (AHR) plays a central role in orchestrating gut barrier and mucosal immune functions in the pathogenesis of inflammatory bowel disease (IBD). Nevertheless, activation of the AHR by diverse ligands yields varied outcomes, and the downstream pathways responsible for these effects remain unknown. Here, we report that selective activation of AHR in mouse intestinal epithelial cells (IEC) by the microbial metabolite, urolithin A (UroA), triggers the Nod-like receptor pyrin domain-containing protein 6 (NLRP6) inflammasome, resulting in the release of interleukin (IL)−18 but not IL-1β. Further, we show that UroA-induced IL-18 in IECs is critical for IL-22, mucin 2 and REG3γ production, as well as protection against colitis. Moreover, UroA significantly upregulates IL-18 and IL-22 levels in IECs and type-3 innate lymphoid cells, respectively, in intestinal biopsies from patients with IBD patients. These results demonstrate that activation of AHR by UroA modulates intestinal barrier function through an NLRP6-IL-18-IL-22 pathway in both healthy and IBD conditions.

Highlights

•Liraglutide’s antidepressant effects persist in Glp1r^(−/−) mice

•Liraglutide indirectly promotes 2-AG synthesis by enriching L. delbrueckii

•Gut-derived 2-AG suppresses stress-induced neuronal hyperactivation in the BLA and DMH

Summary

Despite widespread clinical use of glucagon-like peptide-1 receptor (GLP-1R) agonists for metabolic disease, their neuropsychiatric effects remain poorly understood and controversial. Here, we demonstrate that liraglutide alleviates depression through a gut-brain pathway that operates independently of GLP-1R. Using both pharmacological and genetic approaches, we demonstrated that liraglutide retained antidepressant efficacy in GLP-1R antagonist-Exn9-treated mice or in Glp1r^(−/−) mice, whereas gut microbiota depletion abolished its effects. Multi-omics analyses revealed that liraglutide increased the abundance of Lactobacillus delbrueckii, which in turn restored the levels of the endocannabinoid 2-arachidonoylglycerol (2-AG). The elevation of 2-AG mediated the antidepressant effects by normalizing excessive neuronal activity in emotional processing brain regions. Importantly, fecal microbiota transplantation from liraglutide-treated mice or Lactobacillus delbrueckii colonization replicated the antidepressant effects. These findings uncover a non-canonical mechanism of action for GLP-1 analogs, highlighting a specific microbiota-endocannabinoid metabolic pathway as a potential therapeutic target for depression.

Graphical abstract

Source: https://onlinelibrary.wiley.com/doi/10.1111/nmo.70382

ABSTRACT

Objective

Irritable bowel syndrome (IBS) is the most frequent abdominal-pain–predominant disorder of gut–brain interaction (DGBI). Because the pediatric Rome IV criteria require abdominal pain and stool changes for at least 4 days per month over 2 months, adolescents whose pain coincides with menstruation may be misclassified as IBS. We aimed to determine whether menstrual-associated gastrointestinal symptoms contribute to the reported IBS prevalence.

Methods

We conducted a cross-sectional study of 3521 school-aged females (10–16 years) from public and private schools in Colombia. Participants completed the validated Spanish Rome IV Pediatric Questionnaire for Gastrointestinal Symptoms, which included questions on temporal relation between pain, bowel habits, and menstruation. These symptoms were defined as occurring during days of active bleeding, without inclusion of a pre- or postmenstrual window.

Results

Of 3336 analyzable surveys (mean age 13.3 ± 1.8 years), 2926 (87.7%) were postmenarcheal. Overall, 609/2926 (20.8%) met criteria for ≥ 1 DGBI, including 45 participants (1.5%) who met criteria for IBS. Among postmenarcheal participants with IBS, 62.2% reported abdominal pain and bowel-habit changes exclusively during menstruation.

Conclusions

A substantial proportion of adolescents meeting pediatric Rome IV criteria for IBS reported symptoms confined to menstruation, demonstrating a clinically relevant diagnostic overlap between dysmenorrhea and IBS. Because the Rome IV pediatric algorithm does not distinguish menstrual-only pain from chronic abdominal pain, menstrual-associated gastrointestinal symptoms may resemble those of IBS and complicate diagnostic decision-making. Further studies are needed to clarify whether these presentations reflect menstrual-related gastrointestinal symptoms alone or a distinct subset of DGBI.

Key Points

• Irritable bowel syndrome (IBS) is a common condition that causes recurrent abdominal pain and changes in bowel habits such as diarrhea, constipation, or both.
• Dysmenorrhea and IBS can cause very similar gastrointestinal symptoms, and the current pediatric Rome IV criteria do not exclude symptoms that occur only during menstruation.
• In our study, 62% of postmenarcheal adolescents who met IBS criteria reported symptoms only during menses, emphasizing that symptom timing in relation to the menstrual cycle is critical for improving diagnostic accuracy.

ABSTRACT

Objective

Irritable bowel syndrome (IBS) is the most frequent abdominal-pain–predominant disorder of gut–brain interaction (DGBI). Because the pediatric Rome IV criteria require abdominal pain and stool changes for at least 4 days per month over 2 months, adolescents whose pain coincides with menstruation may be misclassified as IBS. We aimed to determine whether menstrual-associated gastrointestinal symptoms contribute to the reported IBS prevalence.

Methods

We conducted a cross-sectional study of 3521 school-aged females (10–16 years) from public and private schools in Colombia. Participants completed the validated Spanish Rome IV Pediatric Questionnaire for Gastrointestinal Symptoms, which included questions on temporal relation between pain, bowel habits, and menstruation. These symptoms were defined as occurring during days of active bleeding, without inclusion of a pre- or postmenstrual window.

Results

Of 3336 analyzable surveys (mean age 13.3 ± 1.8 years), 2926 (87.7%) were postmenarcheal. Overall, 609/2926 (20.8%) met criteria for ≥ 1 DGBI, including 45 participants (1.5%) who met criteria for IBS. Among postmenarcheal participants with IBS, 62.2% reported abdominal pain and bowel-habit changes exclusively during menstruation.

Conclusions

A substantial proportion of adolescents meeting pediatric Rome IV criteria for IBS reported symptoms confined to menstruation, demonstrating a clinically relevant diagnostic overlap between dysmenorrhea and IBS. Because the Rome IV pediatric algorithm does not distinguish menstrual-only pain from chronic abdominal pain, menstrual-associated gastrointestinal symptoms may resemble those of IBS and complicate diagnostic decision-making. Further studies are needed to clarify whether these presentations reflect menstrual-related gastrointestinal symptoms alone or a distinct subset of DGBI.

Key Points

• Irritable bowel syndrome (IBS) is a common condition that causes recurrent abdominal pain and changes in bowel habits such as diarrhea, constipation, or both.
• Dysmenorrhea and IBS can cause very similar gastrointestinal symptoms, and the current pediatric Rome IV criteria do not exclude symptoms that occur only during menstruation.
• In our study, 62% of postmenarcheal adolescents who met IBS criteria reported symptoms only during menses, emphasizing that symptom timing in relation to the menstrual cycle is critical for improving diagnostic accuracy.

Abstract

OBJECTIVES:
Fibromyalgia (FM) is a multisystem disorder frequently associated with functional gastrointestinal disorders, particularly irritable bowel syndrome (IBS). Diet-related factors and gut microbiota alterations, key elements in IBS pathophysiology, may disrupt the gut-brain axis, promoting immune activation, altered pain processing, and peripheral nerve dysfunction, including small fibre involvement, which has been consistently reported in FM. The study investigated whether IBS symptom severity in FM is associated with clinical and psychological features and with neuropathological evidence of small fibre involvement.
METHODS:
In this monocentric cross-sectional observational study, 89 FM patients underwent clinical and psychological assessments. IBS severity was assessed using the IBS Severity Scoring System (IBS-SSS). Skin biopsy with quantification of intraepidermal nerve fibre density (IENFD) at proximal and distal sites was performed in 57 patients. Patients were classified into mild-moderate and severe IBS groups. Between-group differences were analysed using Mann-Whitney U and χ² tests. Spearman’s rank correlation served to assess associations between IBS severity, clinical variables, and IENFD.
RESULTS:
Severe IBS symptoms were present in 47.1% of patients. Compared with patients with mild–moderate IBS, those with severe IBS showed higher widespread pain index (WPI) and symptom severity scale (SSS) scores, indicating greater fibromyalgia severity, as well as increased anxiety and depressive symptoms, reduced sleep duration, and greater functional impairment (all p<0.05 after FDR correction). Skin biopsy revealed a higher prevalence of reduced IENFD, particularly at proximal sites, in severe IBS patients. Notably, IBS-SSS scores were negatively correlated with proximal IENFD (r=-0.34, p=0.01).
CONCLUSIONS:
IBS severity identifies a clinically more severe FM phenotype with small fibre pathology. These findings are consistent with a possible interaction between gastrointestinal dysfunction and peripheral nerve involvement in FM, although mechanistic pathways require further investigation.

The main focus of this series is to highlight the progress being made in ion channel clinical drug development, which is a key validation parameter for target selection along with other considerations such as human genetic data, cryo-EM structures for drug design, availability of relevant animal and iPSC models, and medical and commercial drivers in each therapeutic indication. I’d like these discussions to help overcome perceptions that ion channels are ‘difficult’ drug discovery targets, and the tendency for historical failures to get blamed on the target class rather than the discovery process itself. We all know that drug discovery is a tortuous and expensive journey regardless of target or modality, so it is important to recognise the successes (and learn from the pitfalls) of ion channel modulators as they enter clinical trials.

It was another relatively quiet quarter of news in Q4 2025 for ion channel clinical drug discovery, with a mixture of clinical trial failures and positive updates from a diverse set of peripheral and CNS programs, and moderate sized deals and funding news. The big news in terms of new drug approvals was Milestone Pharma gaining FDA marketing approval for their Cav1.x blocker Etripamil (Cardamyst) for cardiac arrythmia, and additional approval of Sage/Biogen’s GABA-A PAM zuranalone (ZURZUVAE) for post-partum depression in Canada, after EU approval last quarter and US approval in 2023. There was also very promising mid- and late-stage results for several Nav1.x programs from Praxis, Encoded, Stoke and Biogen in rare and common forms of epilepsy, and Praxis are getting close to FDA approval of their Cav3.x modulator for Essential Tremor, so the CNS space is definitely showing signs of delivering new drugs in 2026 after several drug approvals in 2025 for peripheral indications. In contrast, news was mixed for respiratory and pain programs, with Eli Lilly facing yet another failure in their pain portfolio (P2X7 ligand), but progress for a TRPM8 ligand for migraine and Xenon returning to some familiar old analgesia targets (Nav1.7 and Kv7.x). There was also a significant and positive flow of financial news for UK, US, Israeli and Asian biotechs working on therapeutic programs for pain, depression and epilepsy. Pacira Bio (US) and iN Therapeutics (Korea) signed licensing deals for Nav1.x and Nav1.7 analgesia ligands, and Chinese company Hyperway Pharma raised a decent Series B to help progress a range of clinical programs including a Nav1.8 inhibitor for acute pain. Israeli company Syremis Therapeutics was created with a $165 million Series A round to develop mAChR and NMDA-R modulators for depression, and UK academic spin-out EpilepsyGTX came out of stealth with a decent $33 million series A for their anti-convulsant Kv gene therapy, while Axsome in-licensed an old AZ GABA-A modulator for epilepsy. Finally, there is a significant M&A item I previously missed where Novartis acquired Regulus Therapeutics for $800 million upfront to access their ASO kidney disease TRPP1/2 gene therapy Farabursen.

In the peripheral disease indication section there are mixed (and delayed) updates for a diverse range of cardiac, respiratory, renal and pain ion channel programs. Mixed news for mid-stage respiratory programs as Arcturus Therapeutics revealed underwhelming interim data from the lowest dose of their CFTR mRNA gene therapy in the 1st small cohort of an ongoing Ph IIb MAD trial, and Enterprise Therapeutics and Nocion Therapeutics teasing about Ph II data on their small molecule ENaC and Nav1.x inhibitors in cystic fibrosis and chronic cough, respectively, with both companies expecting critical efficacy results to be released in 1H 2026. Maze Therapeutics feature again in the renal space after I caught up on previous news that they had already started Ph II trials for the small molecule APOL1 inhibitor MZE829, with topline data scheduled for release shortly after this blog comes out. There is also generally positive news in the pain space, with TRPM8 antagonists (Kallyope) and agonists (Dongwha Pharma)  showing good results in mid-stage trials of migraine and pruritis, respectively, and Xenon returning to some traditional analgesia ion channel targets by starting Ph I trials of both Nav1.7 inhibitors and Kv7.x openers. In contrast, Eli Lilly announced yet another failure of a program in their ‘master protocol’ pain portfolio as the last of the original ion channel programs, a P2X7 ligand licensed from Asahi Kasei back in 2021, was dropped after failing to show analgesia efficacy in Ph II trials across multiple chronic pain indications. To round up there was a major piece of positive clinical development news this quarter when Milestone Pharma received FDA approval of their Cav1.x blocker Etripamil (Cardamyst) for treating Paroxysmal Supraventricular Tachycardia (PSVT), a form of cardiac arrythmia. This marks the 3rd novel ion channel ligand approved by the FDA in 2025, making it a record year!

In the CNS section there was a lot of positive progress for epilepsy programs, but mixed updates for ion channel ligands in depression and other CNS indications. Interim results from early Ph I/II safety and efficacy trials of Nav1.1 gene therapies in young Dravet epilepsy patients from Stoke and Biogen (Zorevunersen) and Encoded Therapeutics (ETX101) were very promising, with testing continuing in Ph III and Ph II studies, respectively.  Praxis Precision Medicines are also making great progress with two Nav1.x small molecule inhibitor programs that aced Ph II trials for common focal onset (Vormatrigine) and rare developmental Nav1.2 and Nav1.6 epilepsies (Relutrigine), with the latter result setting up a potential NDA for 2026. Xenon also started Ph I testing of a mixed Nav1.6/Nav1.2 small molecule blocker in collaboration with Neurocrine Biosciences, a follow-up to a Nav1.6-selective ligand that failed to deliver in a previous Ph II trial. The Canadian company also provided updates on their Kv7.2/7.3 opener Azetukalmer which completed enrolment in a Ph III study in patients with focal onset seizures (and delivered very promising results at time of writing in March 2026 as I was finishing up this blog). In contrast there was mixed news for depression programs after Neurocrine Biosciences and Biohaven both revealed failures in Ph II trials of their NMDA NAM and Kv7.x PAM ligands, respectively. On the plus side, new Welsh biotech Draig Therapeutics announced the start of a Ph II study of their AMPA PAM in patients with major depression. Sadly here was also more bad news for Neuphoria Therapeutics after their nAChR ligand failed again in social anxiety at the Ph III stage, and despite it living on in mid-stage testing for PTSD and the company receiving a milestone from Merck for another nAChR program, the company (previously Bionomics) seems to once again be facing down investors and looking for another financial survival strategy. In contrast, QurAlis published promising data from a Ph IIb biomarker trial showing that their Kv7.2/7.3 opener could reduce motoneuron hyperexcitability in a small cohort of ALS patients. Finally, Praxis finally brought their Cav3.x blocker Ulixacaltamide through some unremarkable Ph II and interim Ph III readouts in patients with Essential Tremor to reveal very positive results from the completed Ph III trial, which enabled favourable discussions with the FDA that may shortly lead to drug approval, marking the end of a long journey from when PRAX-944 was developed in the 2010s by UBC academic spin-out NeuroMed and then Zalicus as an analgesia candidate.

Abstract

Background

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem illness marked by fatigue, cognitive impairment, and post-exertional malaise. Gastrointestinal (GI) symptoms are frequently reported, yet their relationship to central features of the illness and biological correlates remains poorly understood.

Objectives

We aimed to characterize GI symptom burden in ME/CFS and evaluate its associations with core clinical features and specific immune and inflammatory markers, with attention to potential gut-related contributions to disease expression.

Methods

GI symptoms and 49 additional symptoms across nine domains were assessed in 116 ME/CFS patients and 80 matched controls. Plasma C-reactive protein (CRP) and antibodies against dietary and microbial antigens were measured as indicators of systemic inflammation and putative gut-derived antigen exposure.

Results

ME/CFS patients reported significantly elevated GI symptom frequency and severity compared with controls, with 53% of ME/CFS patients versus 8% of controls reporting a prior diagnosis of irritable bowel syndrome. GI symptom burden correlated with fatigue, cognitive difficulties, flu-like symptoms, pain, sleep disturbances, neurological complaints, and sensory sensitivities, independent of illness duration. CRP levels were higher in patients with greater GI symptoms and correlated with GI, fatigue, musculoskeletal pain, and flu-like symptom burden. Patients with greater flu-like symptom expression exhibited higher IgM responses to dietary gliadin and bacterial lipopolysaccharide. These associations were not detected in controls.

Conclusions

GI symptoms are a prominent, clinically relevant dimension of ME/CFS, associated with broader symptom burden and inflammatory heterogeneity. These findings highlight the relevance of gut-related and immune processes in ME/CFS and underscore the value of incorporating GI symptom assessment in translational studies to help refine mechanistic understanding and improve therapeutic stratification.

Abstract

In neuron-specific ovalbumin-transgenic CKTAC mice, antigen-specific OT-I CD8 T cells home to the enteric nervous system, where they attack and destroy neurons of the myenteric and submucosal plexus. Clinically, experimental autoimmune enteric ganglionitis (EAEG) manifests with gastrointestinal dysmotility and rapidly progresses to lethal ileus. Although interferon-γ has been identified as capable of damaging neurons in EAEG, the role of perforin, Fas/FasL, and tumor necrosis factor-α (TNF-α) in this disease is still a matter of debate. Thus, CKTAC mice were adoptively transferred with either perforin^(−/–) or wild-type OT-I CD8 T cells. In addition, CKTAC mice that had received wild-type OT-I CD8 T cells were treated by either anti–TNF-α or anti-FasL. Furthermore, wild-type OT-I CD8 T cells were adoptively transferred into CKTAC mice with neuron-specific deletion of Fas. Although neither inactivation of enteric neuronal Fas nor anti-FasL treatment improved the disease, the absence of perforin from OT-I CD8 T cells and anti–TNF-α treatment significantly ameliorated EAEG and prevented lethal ileus by rescue of enteric neurons. Thus, these experiments identify perforin and TNF-α as important in the pathogenesis of EAEG.

Gastrointestinal (GI) dysmotility frequently complicates etiologically diverse GI inflammatory disorders, including ulcerative colitis, Crohn’s disease, celiac disease, and bacterial and viral infections, and may cause persistent disabling symptoms. In Western countries, approximately 30% of the general population has unexplained, mostly mild to moderate symptoms presumed to be of GI origin.^(1) In such patients, radiology and neurophysiology indicates abnormalities of the enteric nervous system (ENS), which regulates gut motility.^(2) In patients with histopathologic evidence of damage to the enteric neurons, the descriptive diagnosis of “enteric neuropathy” is made, which, however, is associated with a variety of clinical entities.^(1)

The remarkably exposed location of two ganglionated plexus [ie, the submucosal plexus (SP) and the myenteric plexus (MP)], extending along the entire gut close to the mucosal and the luminal surface, differs from neurons in other compartments. In contrast to the central nervous system (CNS), the intestinal barrier at the interface between the outer and inner milieu of the body is maintained by linkage of neighboring epithelial cells and the mucosal surface of the adjacent epithelial cell lining.^(3) SP neurons function as master regulator of the epithelial barrier, which regulates intestinal permeability.^(3) With these features, the intestinal barrier is very different from the unique blood–brain barrier,^(4) which strictly restricts entry of cells and soluble mediators, thus conferring protection of CNS neurons to maintain their highly specialized function in light of their limited regenerative capacity. The high incidence of GI dysmotility may, at least in part, be due to this distinct anatomic feature, as the ENS may be more easily reached by self and foreign antigens derived from the gut lumen, yielding complex interactions between the neuronal and epithelial, as well as innate and adaptive, immune compartments that may ultimately damage the ENS.

Enteric ganglionitis may underlie idiopathic GI dysmotility, as recently identified in colonic biopsy findings.^(5) In these patients, acute CD8 T cell–dominated inflammation was followed by a chronic phase characterized by a loss of the majority (74.8%) of enteric neurons in the absence of inflammation.^(5) These observations strongly suggest a CD8 T cell–mediated immune response to neurons as a key pathogenic mechanism. Despite a much more prolonged course, important aspects of human disease are well recapitulated in a murine model in which enteric neurons selectively express ovalbumin (OVA) as an autoantigen. In these neuron-specific OVA-transgenic CKTAC mice, adoptive transfer (AT) of OVA-specific CD8 T cells induces experimental autoimmune enteric ganglionitis (EAEG). Clinically, EAEG manifests with GI dysmotility rapidly progressing to fatal ileus due to OVA-specific CD8 T cell–mediated destruction of the majority (76%) of enteric neurons.^(5)

Interferon-γ (IFN-γ) neutralization hampers cytotoxic T lymphocyte (CTL) capacity to induce enteric neuronal death in CKTAC mice. Despite this prognostically important effect, CKTAC mice still develop clinical symptoms of moderate GI dysmotility and, clinically relevant, a mortality of still 20%.^(5) These observations indicate that in addition to IFN-γ, other factors also contribute to neuronal death.

Principally, CD8 T cells can destroy target cells by three major mechanisms. First, they kill other cells via perforin-mediated cytotoxicity through formation of transmembrane pores or granzyme trafficking into the target cell.^(6–9) Second, target cell apoptosis may be induced by Fas/FasL interaction with FasL on CTL engaging the Fas receptor on the target cell.^(10)^(,)^(11) Third, in addition to cell–cell contact-mediated cell destruction, soluble mediators such as IFN-γ and tumor necrosis factor-α (TNF-α) can play an important role in cell destruction.^(12) The relative, mutually not exclusive contribution of perforin, Fas/FasL, and proinflammatory cytokines to cytotoxic tissue damage is highly variable and determined by disease etiology as well as the target organ and the specific target cell population to be lysed. Interestingly, in experimental autoimmune encephalomyelitis, there is evidence that effector functions of CD8 T cells differ even between different CNS compartments, (ie, the brain and spinal cord). Myelin-specific CD8 T cells contribute to the pathogenesis of experimental autoimmune encephalomyelitis via a FasL-dependent mechanism that preferentially promotes lesion formation in the brain, where they produce higher levels of IFN-γ and TNF-α.^(13)

To decipher the mechanisms underlying CD8 T cell–mediated destruction of ENS neurons in detail, we studied the role of the three major pathways of CTL activity in EAEG. These studies identified OT-I CD8 T cell–derived perforin and TNF-α as crucial factors mediating enteric neuronal death.