Came across a very interesting approach to treat pain, a so called pan-TRK degrader (CG001419) by Gyre Pharmaceuticals, previously owned by Cullgen.

TRK receptors are really important for the detection of pain, TrkA especially being well known in connection with one of its main ligands NGF which we've seen covered much across human and animal pain studies including IBS and early mast cell papers. TrkB bind BDNF which has also been linked to some IBS pain albeit less well studied. NGF and TRK mutations are associated with insensitivity to pain. Companies have previously developed NGF antibodies which have worked quite well in animals. Biology being what it is there seem to be peculiar side effects in humans limiting its dose and use. Drug developers have since moved to the TRK protein and mechanisms surrounding it. As with most pain treatments we're looking for better ways to target a protein for a hedge. As the life sciences are advancing we're getting to see new tools in clinical trials and this time it's a protein degrader. What we're looking for is the first NGF or TRK targeting painkiller to make a reliable difference across pain conditions, phase 2 trials are next.

Presentation by Gyre Pharmaceuticals: https://ir.gyretx.com/static-files/26e29d50-abdb-4511-b752-a650d2676341 (Page 12)

Some links to take a look at:

https://www.reddit.com/r/IBSResearch/comments/1vwb7ro/first_protein_map_of_neurons_that_initiate_pain/

https://pubmed.ncbi.nlm.nih.gov/41979621/

https://pmc.ncbi.nlm.nih.gov/articles/PMC3121917/

https://www.nature.com/articles/nrrheum.2016.224

https://www.cell.com/cell-reports/fulltext/S2211-1247%2816%2931274-8

https://www.sciencedirect.com/science/article/pii/S2667242125000958

https://pmc.ncbi.nlm.nih.gov/articles/PMC7154558/

https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2026.1827148/full

https://www.sciencedirect.com/science/article/pii/S1526590024005820

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1934162/full

https://pmc.ncbi.nlm.nih.gov/articles/PMC9286860/

Alternative (TrkA-NAM) https://www.alzecurepharma.se/sv/wp-content/uploads/sites/3/2026/05/trka-nam-in-pain-management-major-unmet-medical-needs-indication-areas-m-segerdahl-may-26-2026.pdf

Abstract

Non-infectious diarrhea constitutes a prevalent gastrointestinal pathology that severely compromises patient well-being. Its etiology is progressively associated with gut-liver axis dysfunction, although exact molecular pathways remain undefined. This narrative review consolidates the existing research to investigate 5 distinct bile acid-activated receptors: farnesoid X receptor (FXR), Takeda G protein-coupled receptor 5 (TGR5/GPBAR1), pregnane X receptor (PXR), vitamin D receptor (VDR), and retinoid-related orphan receptor gamma t (RORγt). These molecules function as pivotal hubs linking bile acid metabolism, microbial community structure, and intestinal homeostatic balance. Synthesized hepatically and biotransformed by commensal bacteria, bile acids signal through these receptors; specifically, FXR governs bile acid biosynthesis and epithelial barrier strength, TGR5 modulates motility and inflammatory responses, and PXR and VDR attenuate inflammation via nuclear factor-kappa B (NF-κB) suppression, while RORγt regulates immunity through T helper 17 (Th17) cell modulation. Perturbations within this axis—manifesting as defective bile acid reclamation, microbiota dysbiosis, or receptor malfunction—compromise intestinal permeability, provoke electrolyte imbalances, and disrupt immune equilibrium, thereby driving bile acid diarrhea, diarrhea-predominant irritable bowel syndrome, and post-surgical diarrheal conditions. Current data suggest FXR activation is essential for driving bile acid diarrhea management, whereas TGR5 overactivation underlies the hypermotility observed in diarrhea-predominant irritable bowel syndrome. Additionally, rifaximin, acting as a PXR agonist, provides therapeutic benefit. This manuscript evaluates bile acid receptor contributions to non-infectious diarrhea, emphasizing the translational potential of targeting these signaling cascades.

1. Introduction

For more than 100 years, major efforts have been undertaken to obtain potent, effective analgesics without the drawbacks of tolerance and addiction seen with opioids.^(43,64,108) Several new approaches such as intrathecal ziconotide for severe pain, calcitonin gene-related peptide antagonists for migraine, and most recently suzetrigine for acute pain have been developed and approved for use. However, they have various constraints regarding routes of administration, side effects, and the pain indications for which they are appropriate; therefore, the need for new non-opioid agents continues.^(45,73,124,136,159) One challenge to achieving this goal is identifying the most tractable strategies for analgesic drug development. Sites in brain, spinal cord, dorsal root ganglia, primary afferent fibers and terminals, and peripheral tissues are all being investigated for potential molecular analgesic targets.^(49,56,109,127,157) The basic question is: What areas and what neurons can be operationalized to obtain analgesic efficacy and avoid adverse side effects?

A successful approach to analgesia is to prevent nociceptive input from entering the central nervous system.^(21,26,33,51,143,145) This has several advantages. One is the efficacy achieved by selectively blocking nociceptive signals from reaching the spinal cord. Another is avoiding unfavorable or dangerous central side effects as can occur with systemic opioids.^(3,91,146,153,158)

In this topical review, we examine recent research on nociceptors and how their algesic and analgesic molecular composition shapes a key proposition: That concentrating pain research on the molecular repertoire of vulnerable nociceptive neuronal populations may be an advantageous path to developing effective analgesic agents. This does not exclude other approaches or other neuronal populations and, in fact, comment from other groups is invited to articulate these directions.

Tokyo, Japan, July 6, 2026 – Toray Industries, Inc., announced today that it has developed KSB-200, a candidate compound for postoperative pain and other conditions. In exploratory preclinical assessments, KSB-200 demonstrated analgesic activity and suggested improved separation between analgesic and sedative effects. The compound exhibits agonist activity at the kappa opioid receptor (κOR). KSB-200 is expected to have the potential to be developed as a novel oral analgesic with a low risk of side effects.

μ-Opioid receptor agonists have traditionally been used for the management of postoperative pain because of their potent analgesic effects. However, μ receptor agonists can cause respiratory depression, dependence, and other serious side effects, creating a need for safer analgesics.

These risks are lower with existing κOR agonists. To develop them as analgesics, however, it became necessary to reduce central nervous system side effects, such as sedation and dysphoria. Leveraging the extensive experience and expertise gained through the research and development of TRK-820 (nalfurafine hydrochloride; marketed as REMITCH®, see note 1), which has been approved in Japan for the treatment of intractable pruritus associated with dialysis and chronic liver disease, Toray identified a novel κOR agonist designed to retain potent analgesic efficacy while reducing central nervous system side effects.

KSB-200 is a novel compound designed based on signaling bias at the κOR (see note 2). It was designed to selectively elicit the analgesic effects associated with κOR activation while aiming to minimize central nervous system side effects. In a mouse model of postoperative pain, oral administration of KSB-200 demonstrated analgesic activity. The results also suggested improved separation between analgesic and sedative effects compared with TRK-820, a compound with agonist activity at κOR.

Toray plans to present its findings at the International Narcotics Research Conference 2026, which will be in Denver, Colorado, from July 13 to 16. The company will seek partners to advance KSB-200 program under its early partnership strategy (see note 3) and contribute to improving medical care.

Source: French et al., Pharmacol Res. 2022, 177, 106091： An updated assessment of the translational promise of G-protein-biased kappa opioid receptor agonists to treat pain and other indications without debilitating adverse effects:

https://images.microcms-assets.io/assets/fa7ebd3c9a484c6197223084f64eb8d7/497d4d985a3c409ebb3b8ed237e6b5aa/corp_20260706_en.png

Abstract

P2X receptors are cation channels that sense extracellular ATP. Many therapeutic candidates targeting P2X receptors have begun clinical trials or acquired approval for the treatment of refractory chronic cough (RCC) and other disorders. However, the present negative allosteric modulation of P2X receptors is primarily limited to the central pocket or the site below the left flipper domain. Here, we uncover a mechanism of allosteric regulation of P2X3 in the inner pocket of the head domain (IP-HD), and show that the antitussive effects of quercetin and PSFL2915 (our nM-affinity P2X3 inhibitor optimized based on quercetin) on male mice and guinea pigs were achieved by preventing allosteric changes of IP-HD in P2X3. While being therapeutically comparable to the newly licensed P2X3 RCC drug gefapixant, quercetin and PSFL2915 do not have an adverse effect on taste as gefapixant does. Thus, allosteric modulation of P2X3 via IP-HD may be a druggable strategy to alleviate RCC.

Short story:

• Sodium channel NaV1.7 is a powerful protein to control pain, as demonstrated by humans who can't feel any pain
• Blocking NaV1.7 in the sympathetic nervous system leads to side effects
• Targeting NaV1.7 selectively is very hard, sodium channels look alike
• Encoded has developed a treatment which knocks-down the gene coding for NaV1.7 in pain sensing neurons only, using viral delivery of miRNA

There are ever new ways to target proteins central to pain control, which can deliver both strong analgesia and fewer central side effects. The cool story here is just their technology and that we are seeing ever more ways of achieving it. The fact that private money is funding it is really good news. Even when these companies fail, the fact that the money is there to do the research means we are heading into new territory where a successful new pain therapy isn't decades away anymore.

Abstract

Irritable bowel syndrome (IBS) is a chronic disorder of gut–brain interaction characterized by abdominal pain and altered bowel habits. Short-chain fatty acids (SCFAs), microbial metabolites of dietary fiber, play key roles in gut physiology and have been implicated in IBS pathogenesis. Propionate, acetate, and butyrate are of particular interest as potential biomarkers for diagnosis and subtype differentiation. A systematic search of PubMed, Web of Science, and Embase identified studies reporting fecal SCFA concentrations in IBS patients versus healthy controls (HCs). Adult cohorts diagnosed by Rome criteria, case–control or randomized designs, and sufficient SCFA data for effect size calculation were included. Data were harmonized to mean ± SD and analyzed; pooled standardized mean differences (SMDs) with 95% confidence intervals (CI) were calculated, with subgroup analyses for IBS-D and IBS-C. Methodological quality was assessed using the Newcastle–Ottawa Scale (NOS). Eleven studies met inclusion criteria. Across all IBS cohorts, propionate was significantly elevated compared to HCs, while acetate and butyrate showed no differences. In IBS-D, propionate was consistently higher. In IBS-C, total SCFAs were significantly reduced, with negligible heterogeneity. Acetate, propionate, and butyrate remained non-significant, with moderate to substantial heterogeneity. NOS assessment indicated that most studies were of good quality, with one rated moderate. This meta-analysis highlights propionate elevation as a biomarker for IBS, particularly IBS-D, and reduced total SCFAs as a distinct metabolic signature in IBS-C. Variability in individual metabolites reflects dietary and methodological influences. The absence of Indian cohorts limits generalizability; future studies integrating SCFA profiling with microbiome analysis in Indian populations are needed to validate biomarker utility and support precision management of IBS.

Highlights

• • Irritable bowel syndrome lacks causal therapy, and current symptomatic treatment is often unsatisfactory.
• • Visceral pain and motility disorders are core distressing symptoms of irritable bowel syndrome.
• • Serotonin type 7 receptor modulates gastrointestinal motility, visceral pain and immune response in irritable bowel syndrome.
• • Links between microbiota and serotonin type 7 receptor might be crucial in irritable bowel syndrome pathogenesis.
• • Targeting serotonin type 7 receptor is a promising therapeutic strategy for irritable bowel syndrome.

Abstract

Irritable bowel syndrome (IBS) affects up to 9% of the population worldwide, but current therapies benefit only 25–30% of patients. Disrupted serotonin (5-HT) signaling alters gut microbiota, permeability and immunity, driving IBS pathogenesis. The serotonin type 7 receptor (5-HT7R), which is widely expressed in both central and peripheral tissues, has emerged as a promising therapeutic target. 5-HT7R regulates peristalsis, modulates dendritic cell morphology and drives anti-inflammatory responses. Furthermore, 5-HT7R antagonists induce analgesia and reduce mucosal innervation. This review summarizes the crucial role of 5-HT7R in the gastrointestinal tract and highlights its potential for future IBS therapy.

Graphical abstract

Abstract

The Rome-V criteria represent a major evolution in the conceptualization and clinical application of disorders of gut-brain interaction (DGBIs). Building upon the biologically grounded framework established in Rome IV, Rome V moves beyond rigid symptom-based definitions toward a multi-dimensional, clinically operational model that integrates symptom patterns, temporal characteristics, physiological testing and psycho-social context. A central advance is the transition from categorical classification to dimensional phenotyping, recognizing the continuum and overlap inherent to DGBIs. The recalibration of diagnostic thresholds, most notably the re-introduction of abdominal discomfort and the requirement for symptom intermittency in irritable bowel syndrome, restores diagnostic sensitivity while improving mechanistic specificity. Rome V further introduces Rome Clinical Criteria, addressing the substantial sub-diagnostic population and enabling earlier, context-driven diagnosis in routine practice. Across organ systems, diagnostic definitions are refined to align more closely with underlying pathophysiology and clinical decision-making. This is exemplified by the integration of physiological frameworks in esophageal disorders, temporal stratification in gastroduodenal syndromes, the redefinition of centrally mediated abdominal pain and the incorporation of motor-sensory phenotyping in anorectal disorders. In parallel, Rome V emphasizes harm reduction in biliary disorders and introduces greater continuity across pediatric and adult frameworks. Despite these advances, challenges remain, including the absence of validated biomarkers, variability in global applicability and the need for further validation of new constructs. Overall, Rome V represents a shift from static diagnostic criteria to dynamic clinical pathways, providing a robust platform for mechanism-informed and increasingly individualized care in DGBIs.

Highlights

•σ1R antagonism reduces spontaneous visceral pain in capsaicin-treated mice.

•σ1R blockade potentiates morphine, oxycodone, and fentanyl analgesia.

•Potentiation is strongest at subanalgesic opioid doses.

•Effects are opioid- and σ1R-dependent, and fully reversed by naloxone.

Abstract

Visceral pain remains a major clinical challenge, often resistant to conventional analgesics. Sigma-1 receptor (σ1R) antagonists enhance opioid antinociception in somatic and neuropathic pain, yet their role in visceral nociception remains unclear. Here we investigated whether σ1R blockade potentiates the antinociceptive effects of µ-opioid agonists in a well-established model of capsaicin-induced visceral pain in mice. To this end, female wild-type (WT) and σ1R-knockout (σ1R-KO) mice received intracolonic capsaicin (0.1%). Visceral pain-related behaviors and referred mechanical hyperalgesia were quantified after subcutaneous administration of morphine, oxycodone, or fentanyl, alone or combined with selective σ1R antagonists (S1RA, NE-100, BD-1063, BD-1047). Opioid specificity was assessed using naloxone, and σ1R dependence using σ1R-KO mice and the σ1R agonist PRE-084. We found that σ1R-KO mice and WT animals treated with σ1R antagonists exhibited reduced spontaneous visceral pain. Morphine, oxycodone, and fentanyl produced dose-dependent inhibition of both pain-related behaviors and referred hyperalgesia. Genetic deletion or pharmacological inhibition of σ1R significantly potentiated these opioid-induced antinociceptive effects, especially at sub-antinociceptive opioid doses. This potentiation was absent in σ1R-KO mice, confirming receptor specificity. Naloxone fully reversed both the antinociceptive effects of all opioids and the potentiation induced by σ1R antagonists, whereas PRE-084 did not modify opioid efficacy. Taken together, these findings demonstrate that genetic deletion or pharmacological inhibition of σ1R significantly enhances µ-opioid–induced antinociception in visceral nociception. This interaction is σ1R-dependent and requires opioid receptor activation. σ1R blockade emerges as a promising adjuvant strategy to improve opioid efficacy against visceral pain while potentially allowing lower opioid doses.

Perspective

This study demonstrates that sigma-1 receptor antagonism enhances µ-opioid–mediated antinociception in visceral nociception at sub-antinociceptive opioid doses. These findings suggest that antagonizing the sigma-1 receptor may represent a clinically relevant adjuvant strategy to shift opioid dose–response relationships toward increased apparent potency, potentially allowing reduction of opioid dose requirements in visceral pain conditions.

Graphical Abstract

Highlights

• • No robust average cortical morphometry differences were detected between irritable bowel syndrome and controls.
• • Equivalence testing provided statistical evidence of negligible effect sizes.
• • Weak brain-phenotype associations and mostly not irritable bowel syndrome-specific.

Abstract

Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction that has sparked interest in neural markers. Yet, previous neuroimaging findings remain inconsistent and often fail to replicate, likely due to small sample sizes that overestimate effects and overlook patient heterogeneity. Using normative modeling to quantify cortical deviations from MRI in a UK Biobank digestive health questionnaire (DHQ)-derived IBS phenotype and matched controls (N = 3 413 each) relative to a healthy reference sample (N = 8 661), we found no robust group differences. Further, equivalence tests provided evidence that both group and group × sex effects were statistically equivalent to negligible effect sizes across nearly all regions. Within IBS, negative associations between cortical gray matter deviations and symptom or pain severity were observed for some regions. However, no statistically meaningful IBS-specific effects and no sex moderation were detected. Overall, our findings challenge previously reported structural alterations in IBS, underscoring the need for replicability in adequately powered designs.

Graphical abstract

Abstract

Major Depressive Disorder (MDD) is a highly prevalent, severe mental health condition that constitutes one of the leading causes of disability worldwide. While recent animal studies suggest a causal role of the gut microbiome in the pathophysiology of MDD models, evidence in humans is still unclear due to small sample sizes, inconsistent clinical assessment of MDD diagnosis, and methodological limitations regarding causal inference in cross-sectional data. Here, we explicitly address these shortcomings to investigate the potential causal link between the gut microbiome and MDD: First, we replicate previously reported microbiome-depression associations using one of the largest multicenter MDD cohorts for which microbiome data and in-depth diagnostic assessment are available (N = 1,269 MDD patients and controls). We find a significant difference between healthy controls and MDD patients for the relative abundance of four taxa: Eggerthella, Hungatella, Coprobacillus, and Lachnospiraceae FCS020. Second, we employ state-of-the-art, fully data-driven causal inference tools within Judea Pearl's framework, allowing us to derive model constraints from the data rather than relying on potentially strong, unrealistic assumptions. Using this approach, we found evidence for Eggerthella and Hungatella as potential causal contributors to MDD. Furthermore, we show that the potential causal effects of Eggerthella and Hungatella on MDD persist beyond the influence of body mass index, revealing two distinct potential causal pathways linking the gut microbiome to MDD. Finally, the difference in relative abundance of these taxa between healthy and MDD patients was independent of antidepressant medication. Our study provides the first data-driven evidence for a potential causal role of gut microbiota in the pathophysiology of depression in humans.

ABSTRACT

Hirschsprung disease (HSCR) is a deadly congenital disorder where the enteric nervous system (ENS) is absent from the distal bowel. Current surgical treatment is generally life-saving but is often accompanied by long-term bowel problems and comorbidities. As alternative, we are developing a regenerative therapy based on rectal administration of Glial cell-derived neurotrophic factor (GDNF). We previously showed that administering GDNF enemas to HSCR mice soon after birth is sufficient to permanently induce a new ENS from tissue-resident neural progenitors. Here, we elucidate the underlying mechanism using single-cell transcriptomics, signal transduction inhibitors and genetic cell lineage tracing tools. We found that the neurogenic effect of GDNF is mediated by NCAM1 (Neural cell adhesion molecule 1), rather than by its canonical signaling receptor RET (Rearranged during transfection). We also unveiled the existence of multiple neuronal differentiation pathways that involve a larger than expected repertoire of tissue-resident neural progenitors, including a surprising one not derived from the usual neural crest. These data support feasibility of GDNF-based therapy in most human patients, even those bearing a RET variant. This work also has far-reaching implications for the choice of ENS progenitor source to use when developing cell transplantation-based therapeutic approaches.

Graphical Abstract

Editor’s summary

Chemotherapy-induced peripheral neuropathy (CIPN), one of the most debilitating side effects of some cancer therapies, is a painful condition with no known remedy and is thus a major cause of treatment discontinuation. Heles et al. reported that prophylactic treatment with the natural psychedelic psilocybin prevented the development of CIPN in mouse models (see the Perspective by Maiarú). Mechanistically, psylocibin acted both peripherally and centrally through two independent mechanisms: reducing pain perception and protecting peripheral sensory neurons. Psychedelics might offer an effective therapeutic approach for preventing CIPN. —Mattia Maroso

Structured Abstract

INTRODUCTION

Chemotherapy-induced peripheral neuropathy (CIPN) is a common, disabling, and often irreversible complication of cancer treatment affecting many patients receiving platinum- or taxane-based regimens. Patients experience pain, cold sensitivity, numbness, and impaired touch sensation that can persist for years, frequently forcing dose reductions or discontinuation of otherwise life-saving therapy. The condition arises from injury to sensory nerves, mitochondrial dysfunction, loss of nerve endings in the skin, and maladaptive changes in central pain-processing circuits. Despite its enormous clinical burden, no proven preventive strategy exists.

RATIONALE

Psilocybin is a naturally occurring compound found in certain mushroom species that activates serotonin 2A receptors. These receptors have been linked to neuronal plasticity and mitochondrial regulation, which indicates that psilocybin could protect the sensory nervous system from chemotherapy-induced injury. Because nerve damage, once established, is often irreversible, prevention is more tractable than treatment. We therefore asked whether psilocybin administered before chemotherapy could prevent neuropathy from ever developing and used a combination of mouse behavioral models, electrophysiology, live-cell imaging, molecular profiling, and human tissue analysis to define the underlying mechanisms.

RESULTS

In mouse models, just two doses of psilocybin given before chemotherapy prevented the development of pain hypersensitivity caused by neurotoxic chemotherapies, with protection maintained across up to six consecutive chemotherapy cycles and over the course of 8 months of follow-up. Critically, psilocybin also protected tumor-bearing mice without reducing tumor growth or altering immune cytokine levels. Using highly selective pharmacological tools, we showed that serotonin 2A receptor activation is both necessary and sufficient for this neuroprotection and that the effect does not require the hallucinogenic properties of psilocybin—a nonhallucinogenic serotonin 2A agonist conferred equivalent protection. Mechanistically, psilocybin acted through two complementary pathways: Peripherally, it preserved the structure and energy supply of distal sensory nerve endings, protecting tactile function and maintaining skin nerve fiber density; centrally, it normalized cortical electrical activity disrupted by chemotherapy. Using live imaging of mitochondria in freshly isolated human peripheral nerves from surgical patients and in human stem cell–derived sensory neurons, we found that psilocybin preserved the active transport of mitochondria along axons, the process by which nerve fibers distribute energy to their most distant, vulnerable endings. Chemotherapy halted this transport and depleted energy at distal nerve endings; psilocybin prevented both effects. Molecular studies traced this protection to a signaling cascade, the TrkB-Akt-PAK5-MAP2-KIF5B pathway, that supports mitochondrial transport along sensory axons. Human donor sensory neurons and patient skin biopsies independently confirmed that this serotonin 2A–mitochondrial trafficking network is conserved in human tissue.

CONCLUSION

Psilocybin prevents CIPN by activating serotonin 2A receptors on peripheral sensory neurons, preserving axonal mitochondrial transport and the local energy supply that nerve endings require for survival. This peripheral neuroprotective mechanism, previously unrecognized for psilocybin, acts in concert with the preservation of central cortical function. Given that no effective preventive treatment currently exists and psilocybin has an established clinical safety profile, these findings position psilocybin and related nonhallucinogenic serotonin 2A agonists as a first-in-class prophylactic strategy warranting clinical evaluation to prevent one of the most common and undertreated toxicities of cancer therapy.

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling, often irreversible toxicity that affects millions of patients, limits life-saving cancer therapy, and lacks proven treatment. In this work, we show that as little as two doses of psilocybin before chemotherapy durably prevented the onset of CIPN across platinum- and taxane-based models, including repeated chemotherapy cycles, without impairing antitumor efficacy. Peripherally, psilocybin maintained tactile sensitivity and intraepidermal nerve fiber endings through axonal mitochondrial trafficking and distribution preservation, through the TrkB-Akt-PAK5-MAP2-KIF5B pathway and remobilization of syntaphilin-anchored mitochondria. Centrally, it normalized medial prefrontal cortical synaptic activity and cortical alpha and beta electroencephalography power. This stabilization of peripheral axonal energy balance establishes psilocybin as a first-in-class prophylactic agent for CIPN while also preserving central neural function. Given psilocybin’s established safety, these discoveries support clinical evaluation as a strategy to prevent CIPN.

Abstract

Background

Recent evidence suggests an increased prevalence of irritable bowel syndrome (IBS) among individuals with allergic diseases, and several biological mechanisms have been proposed. This study aims to investigate the association between IBS and allergic diseases in a large nationwide cohort of adolescents.

Methods

This cross-sectional nationwide study included Israeli adolescents aged 16–20 years who underwent medical assessment before military service. The military database was used to identify individuals with allergic diseases (asthma, allergic rhinitis, atopic dermatitis, or ocular atopic disease) and IBS between 1998 and 2018. Logistic regression models adjusted for sociodemographic factors were applied.

Results

Of the 1,538,864 adolescents (42% women; mean age, 17.2 ± 0.5 years) included in the study, 189,806 (12.3%) were diagnosed with allergic diseases and 8,134 (0.5%) with IBS. Overall, 25.4% of adolescents with IBS had at least one concurrent allergic disease. The prevalence of IBS among adolescents with allergic diseases was 1.1%, corresponding to an adjusted OR of 2.2 (95% CI 2.1–2.4). This association remained consistent across socioeconomic groups and across all allergic diseases examined.

Conclusion

Allergic diseases in adolescents are associated with higher rates of concurrent IBS. These findings strengthen existing epidemiological evidence linking IBS and allergic diseases in adolescents and warrant further mechanistic and longitudinal studies.

Abstract presented at ESPGHAN 2026 meeting

Objectives and Study

Several studies, including our own, have shown a strong association between dysfunctional sucrase-isomaltase (SI) variants and diarrhoea-predominant irritable bowel syndrome (IBS-D). The common p.V15F variant has emerged as an important genetic marker. A multicentre study reported that the four major congenital sucrase-isomaltase deficiency (CSID) mutations, p.V557G, p.G1073D, p.R1124X, and p.F1745C, occur significantly more often in IBS patients than in healthy controls (p = 0.020; OR = 1.57), suggesting that SI polymorphisms may predispose individuals to IBS.

CSID is a well-defined genetic disorder caused by SI mutations, with symptom severity depending on the specific variant. Recent work has shown that wild-type SI can interact with pathogenic mutants, impairing trafficking and enzymatic function. This raised the hypothesis that compound heterozygosity involving p.V15F and common CSID variants may further disrupt SI function.

Methods

We therefore co-expressed SI^(V15F) with major CSID mutants (SI^(V557G), SI^(G1073D), SI^(R1124X), SI^(F1745C)) in COS-1 cells, studied SI trafficking through endoglycosidase H treatment, and assessed sucrase activity.

Results

Under normal conditions, SI^(WT) is efficiently glycosylated and trafficked to the apical membrane. In contrast, co-immunoprecipitation demonstrated direct interaction between SI^(V15F) and each CSID mutant, and endo H digestion showed markedly impaired trafficking of SI^(V15F) in all co-expression conditions. Only the partially functional SI^(C1229Y) exhibited trafficking similar to SI^(WT).

Sucrase assays revealed substantial enzymatic loss: SI^(V15F) alone showed a 35% reduction relative to SI^(WT), whereas co-expression with CSID mutants caused a 75–90% decrease. Co-expression of SI^(V15F) with SI^(WT) did not worsen activity, highlighting the dominant-negative effects of pathogenic variants.

Conclusions

In conclusion, common CSID mutations strongly impair SI^(V15F) trafficking and sucrase activity. These findings indicate that p.V15F is highly vulnerable to dominant-negative interference in compound heterozygous contexts, offering a molecular explanation for its association with IBS-D.

Original publication: https://www.nature.com/articles/s41467-026-71418-8

Helmholtz researchers have created the first detailed protein map of specific sensory neurons that trigger pain. Their study, published in ​“Nature Communications,” will help researchers better understand the molecular mechanisms of chronic inflammatory pain and identify new drug targets.

Joint press release by the Max Delbrück Center and the Helmholtz Centre for Infection Research

One in five people worldwide suffers from chronic inflammatory pain. Meanwhile, about two thirds of those affected find little relief from existing pain medications; new therapeutic approaches are urgently needed. ​“We first must understand precisely how sensory nerve cells trigger pain at the molecular level — in other words, which proteins are involved,” says Professor Gary Lewin, Group Leader of the Molecular Physiology of Somatosensory Perception lab at the Max Delbrück Center in Berlin.

To unravel these molecular processes, Lewin – who has been studying pain for four decades and recently discovered a previously unknown ion channel involved in pain perception – is working closely with systems biologist Dr. Fabian Coscia, Group Leader of the Spatial Proteomics lab at the same center. Coscia co-developed a method called Deep Visual Proteomics that makes it possible to determine the proteome — the complete set of proteins — of specific cells and to create maps detailing the spatial locations of individual proteins.

The researchers combined this technology with electrophysiological methods from Lewin’s group. This enabled them to first identify specific subtypes of pain neurons based on their function and then analyze their protein profiles. The result is a high-resolution molecular map of these nerve cells, which has been published in ​“Nature Communications.” The team also demonstrated how the technology can identify potential new drugs targets to treat chronic pain. 

Dr. Sampurna Chakrabarti is the study’s first author and a former postdoctoral researcher in the Lewin lab who now heads the Pathways in Infection and Nociception group at the Helmholtz Centre for Infection Research in Braunschweig. Nociception refers to how our nerves respond to stimuli that trigger pain. Nerves in skin and other peripheral tissues – such as muscles and joints – that detect damaging stimuli are called nociceptors; they relay signals to the brain to initiate pain. 

Undiscovered signaling pathways

All nociceptors are not alike. ​“Until now, only the transcriptome – that is, the RNA level information of the different subsets of nociceptors – was known,” says Chakrabarti. ​“However, the actual functional components of all cells are the proteins formed from these transcripts – and we have now examined them in greater detail for the first time in two subtypes of nociceptors.” Using an electrophysiological method known as the patch-clamp technique, the team first identified and characterized two nociceptor subtypes – peptidergic and non-peptidergic – in the spinal ganglia of mice. Each of these subtypes respond differently to similar stimuli and may initiate pain of different quality and duration.

Section of a mouse dorsal root ganglion with two subtypes of pain receptors marked in cyan and magenta.

The researchers used around 50 neurons of each subtype to generate a specific protein map for each of the two cell types. Deep Visual Proteomics combines mass spectrometry with microscopy, artificial intelligence and robotics. Coscia and his team have so far mainly used this methodology for proteome analyses of cancer cells. ​“We have now shown for the first time that it can also be applied to nerve cells,” he says.

The team measured more than 6,000 proteins in these 50 neurons. A comparison with existing RNA data revealed that the transcriptome and proteome of the cells differ significantly in some cases – an indication that key functional processes only become visible at the protein level. ​“We provide a unique molecular map of pain-initiating neurons,” says Coscia. ​“It enables the identification of signaling pathways in these cells that have so far remained hidden.”

In an additional step, Chakrabarti and her colleagues wanted to understand which proteins sensitize nerve cells, contributing to chronic pain. They isolated both types of nociceptors from mouse dorsal root ganglia and exposed them to a molecule called Nerve Growth Factor (NGF), which is known to trigger chronic pain both animals and humans, such as in arthritis. Using Deep Visual Proteomics, the researchers were able to precisely identify the proteins produced after the cells were exposed to NGF. 

Reduced sensitivity to pain signals

Lewin and his team had already discovered that NGF plays an important role in chronic inflammatory pain more than 30 years ago. ​“In dogs and cats, pain can now be alleviated very effectively using antibodies that inhibit NGF,” says Lewin. ​“In humans, rare side effects have unfortunately prevented their use,” he adds. ​“But now we may have found an alternative approach: targeting a downstream protein responsible for NGF’s sensitizing effect.”

“We identified several proteins that were present in higher levels in a subset of nociceptors following treatment with NGF. The higher levels of these proteins could be linked to long term pain associated with inflammation,” says Chakrabarti. One of the proteins, an enzyme called B3GNT2, stood out in particular. ​“When we knocked out the corresponding gene in the cells, the inflammation-induced hyperactivity of nociceptors was reduced. Fewer cells responded to mechanical stimulus,” she says. In other words, the neurons had become less sensitive and would elicit much less pain. 

In the future, the researchers plan to validate their findings in mice and humans. ​“More than 90 percent of all approved drugs now target proteins,” says Coscia. ​“This highlights how important it is to develop a better understanding of these molecules in order to identify new targets for more effective pain therapies and treatments for other neurological diseases.”

Abstract

Background: Irritable bowel syndrome with constipation (IBS-C) and diarrhea (IBS-D) exhibit highly divergent clinical manifestations. This study aims to investigate the correlation between IBS-C and IBS-D.

Methods: All participants provided fecal samples and completed IBS-SSS, IBS-QOL, and GSRS. Fecal bacterial composition was analyzed via custom V4-region 16S rRNA amplicon sequencing on the Illumina NovaSeq 6000 platform, while bile acids were quantified using liquid chromatography-tandem mass spectrometry (LC-MS).

Key results: Patients with IBS-D reported significantly higher frequency and severity of diarrhea and abdominal pain. Conversely, IBS-C patients experienced more severe bloating and constipation than IBS-D patients. Compared to HCs, total bile acids, primary bile acids, secondary bile acids, conjugated bile acids, and unconjugated bile acids were elevated in IBS-D but reduced in IBS-C. The gut microbiota composition of both IBS-D and IBS-C patients differed significantly from that of HCs. Differential species in the IBS-D group were primarily associated with Prevotella and Ruminococcaceae, those in the IBS-C group were mainly concentrated in Bacteroides and Clostridium, and differential species in the HCs group were primarily found in Ruminococcus. Abundances of Clostridiaceae and Bacteroides correlated negatively with plasma chenodeoxycholic acid and cholic acid, respectively, while Clostridium correlated negatively with ursodeoxycholic acid (UDCA). Ruminococcus correlated positively with isodeoxycholic acid.

Conclusions: Alterations in the bile acid-gut microbiota axis are closely related to the distinct clinical presentations of IBS-C and IBS-D. IBS-D is characterized by a decreased abundance of Ruminococcus and Clostridium, alongside increased bile acid secretion and reduced reabsorption, which primarily contribute to the observed differences.

Abstract

Objective: To describe a case of biopsy-confirmed lymphocytic microscopic colitis (MC) temporally associated with paroxetine (Paxil) therapy and to highlight psychiatric nursing implications for monitoring serotonergic adverse effects across the brain-gut interface.

Methods: This case report was developed using clinical history, diagnostic findings, treatment course, and relevant literature on selective serotonin reuptake inhibitors, MC, and serotonergic signaling in gastrointestinal function.

Results: A 27-year-old male with generalized anxiety disorder, panic disorder, agoraphobia, and irritable bowel syndrome developed chronic watery diarrhea, abdominal pain, bowel urgency, and one episode of fecal incontinence while receiving paroxetine, which had previously produced sustained psychiatric remission. Differential considerations included an irritable bowel syndrome flare, infectious diarrhea, inflammatory bowel disease, medication-associated diarrhea, and medication-associated microscopic colitis. Colonoscopy with biopsy confirmed lymphocytic MC. Paroxetine was discontinued, and the patient was treated with budesonide (Entocort EC) and adjunctive gastrointestinal therapies, leading to resolution of gastrointestinal symptoms. After recurrence of anxiety and panic symptoms and poor tolerability or inadequate response to alternative psychotropic medications, paroxetine extended-release was cautiously reintroduced with interdisciplinary monitoring. Gastrointestinal symptoms did not recur during the 1-year follow-up period.

Conclusions: This case illustrates the importance of psychiatric nursing vigilance for persistent gastrointestinal symptoms in patients receiving serotonergic antidepressants. Recognition of possible medication-associated MC may support timely referral, interdisciplinary collaboration, and individualized psychopharmacologic decision-making.

Chinese researchers are testing DREADDs, a gene therapy to turn down neuronal activity, in the clinic

“Stunned silence.”

That’s how Bryan Roth of the University of North Carolina School of Medicine described the mood at a US National Institutes of Health Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative meeting in Bethesda, Maryland, this week when he told fellow attendees about at least seven clinical trials in China that are testing chemogenetic therapies in humans.

Twenty years ago, Roth developed the chemogenetic technology the trials are using, which is based on a group of proteins called “designer receptors activated by designer drugs,” or DREADDs. Designer drug is a bit of a misnomer in this case; the receptor being used in the Chinese trials responds to a small-molecule drug, clozapine, used to treat schizophrenia. But the designer receptor is much more sensitive to the drug than any human receptor, binding to it with picomolar affinity.

A researcher can introduce the gene encoding the receptor protein to a small group of neurons using a viral vector. Then, when the receptor is expressed and binds to the drug, it suppresses neuronal signaling in those cells and any brain circuits they belong to.

Dirk Trauner, a biochemist at the University of Pennsylvania who works on optogenetics, a related technology, says that DREADDs offer “a more precise knife” that, theoretically, could have reduced side effects compared with other approaches. Small molecules targeting endogenous receptors can have off-target effects when those receptors are expressed in other parts of the brain or when the molecules trigger closely related receptors; in contrast, DREADDs appear only where they are introduced.

The designer receptors have become a widespread research tool in neuroscience, where they have enabled researchers to alter brain circuits’ activity. But until now, they have not been used in the clinic.

“Over the years, folks have approached me to commercialize the technology, but there were all these barriers,” Roth says. “I think nobody wanted to take the risk.”

About 2 months ago, a rumor about designer proteins being introduced to treat brain diseases sent Roth and a postdoctoral scholar looking in clinical trial databases in the US and China. They found seven studies, which investigate intractable epilepsy, Parkinson’s disease, and neuropathic pain.

For several of the diseases in question, the therapy of last resort is to remove a portion of the brain, Roth points out. Chemogenetic treatment might avoid that, though if the treatment ended up having unwanted side effects, trial patients might seek relief through surgery after all.

Three of the DREADD trials use an adeno-associated virus as a vector to deliver the chemogenetic therapy. Gene therapies using viruses, such as these, carry the risk of serious, sometimes fatal immune reaction. Several people died recently in early-stage gene therapy trials in China. But Roth points out that six of the studies appear to have begun some months after the first epilepsy trial began, suggesting that investigators might have started after getting some indication that the gene therapy may be safe.

Jacques Carolan, a neuroscientist at University College London who was at the BRAIN Initiative meeting, posted on X on Friday, “If we needed more evidence that China is ahead in neuro, this is it.”

C&EN has reached out for comment to the investigators of record on the clinical trials.

According to Roth, the study with the greatest potential focuses on trigeminal neuropathic pain, which can be debilitating enough that it is a risk factor for suicide. “If that trial is successful, then it opens the way basically to circuit-based therapeutics for virtually all neuropsychiatric diseases,” he says.