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.

Abstract

Inhibitors of voltage-gated sodium channel 1.8 (NaV1.8) are anticipated to provide opioid-free treatment for acute pain and potentially chronic neuropathic pain. Herein, we report on the discovery of a novel series of NaV1.8 inhibitors characterized by high selectivity over other sodium channels. Utilizing a pharmacophore model trained on literature data, we identified the initial hit compound 1 through virtual screening. During the hit-to-lead optimization phase, we improved the potency and clearance of the lead compounds. Structural modifications and control of lipophilicity and other physicochemical parameters resulted in a favorable in vitro safety and drug–drug interaction profile for compound 24. Key to optimizing the clearance was the identification of a metabolic hotspot via metabolite identification (MetID) experiments. The lead compound 24 exhibited a long in vivo half-life and high exposure (Kp,uu) in the pain-relevant target tissue (DRG) in rat PK studies. These findings highlight potential of these compounds for further optimization as nonopioid therapeutics.

Highlights

• Alternatives to opioids in pain medication are urgently needed.
• Ion channels, GPCRs, and transporters are potential new analgesic targets.
• Multitarget molecule-rich approaches may be the best alternative.

Despite their efficacy, opioids have long been associated with risks of addiction, tolerance, and dependence, leaving an unmet clinical need for pain treatment. Efforts have been devoted to developing novel classes of pain-relieving medication that outperform current options in terms of pain relief, side-effect profiles, and potential for abuse, but with limited success. Recent advances in the neurobiology of pain have shed light on the potential of targeting non-opioid receptors involved in pain processing. In this review, we identify avenues, ranging from molecular-based approaches to molecule-rich solutions, for effectively identifying non-opioid analgesics free from the side effects associated with opioids.

Abstract

Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly encountered in pain practice, but reported pain improvement may reflect direct antinociception, weight loss, metabolic change, or disease-specific effects. This structured narrative review examined these possibilities and relevant safety issues. 

Methods: PubMed/MEDLINE, Embase, and Web of Science Core Collection were searched through 15 May 2026. Peer-reviewed human studies, key mechanistic preclinical studies, systematic reviews and meta-analyses, and professional guidance relevant to pain outcomes or procedural safety were considered. Metabolic-only and non-peer-reviewed reports were excluded, and human pain-primary evidence was prioritized. 

Results: Preclinical data support plausible mechanisms involving spinal microglia, interleukin-10, beta-endorphin, neuroinflammation, and sensory-neuron signaling, but direct analgesic efficacy at systemic clinical doses has not been demonstrated. In STEP 9 (n = 407), mean WOMAC pain scores at 68 weeks changed from baseline by −41.7 points with semaglutide 2.4 mg and −27.5 points with a placebo; body weight changed by −13.7% and −3.2%, respectively. Liraglutide produced additional weight loss without superior knee-pain reduction. Diabetic peripheral neuropathy evidence was mainly structural or neurophysiologic; idiopathic intracranial hypertension and ROSE-010-treated irritable bowel syndrome showed disease-specific signals, whereas fibromyalgia- and opioid-related findings remained observational or hypothesis-generating. Gastrointestinal dysmotility, reduced intake, and lean-mass loss may offset functional benefits. 

Conclusions: GLP-1RAs are not established analgesics. Current human signals are best interpreted as indirect metabolic–functional or disease-specific effects. Future trials should use validated pain-primary outcomes, control for weight loss, and monitor treatment-related harms.

Abstract

Background: Fructanase, an enzyme that hydrolyzes dietary fructans to fructose in vitro, may reduce gastrointestinal (GI) microbial fermentation in vivo by breaking down fructans before transit to the colon.

Objective: This study evaluated the effects of a microbial fructanase on GI symptoms and intestinal fermentation in men and women after inulin-type fructan ingestion.

Methods: A randomized, double-blind crossover study design was used with 30 healthy adults [mean (standard deviation) age 38.6 (7.3) y and BMI 24.5 (3.0) kg/m^(2)] who consumed 25 g inulin mixed into 40 g oatmeal with either one capsule containing fructanase or placebo maltodextrin. GI symptoms and fatigue were assessed using visual analog scales at baseline and postprandially for 24 h. Breath hydrogen and methane concentrations were measured postprandially hourly for 8 h. A Wilcoxon signed-rank test was used to compare paired differences between fructanase and placebo conditions.

Results: The maximum 0-8 h overall abdominal symptom score was not statistically significant (P = 0.13) between groups. Compared to placebo, fructanase co-administration with inulin reduced abdominal pain (P = 0.044) and fatigue (P < 0.001). Rank-based repeated measures analysis showed that fructanase reduced burping (P = 0.040) in the 0-8 h period. Over the 8-24 h period, fructanase reduced overall abdominal symptoms (P = 0.030), bloating (P = 0.011), abdominal pain (P = 0.019), and flatulence (P = 0.044). Breath hydrogen and methane outcomes did not differ significantly between groups.

Conclusions: Fructanase co-administration with inulin reduced GI symptoms in healthy adults, suggesting that it may be a useful dietary supplement for fructan sensitivity. Further trials in a cohort with GI symptoms such as irritable bowel syndrome are warranted. Registered at ClinicalTrials.gov (NCT06628869). Clinical Trial Registry number and website where it was obtained Registered at ClinicalTrials.gov (NCT06628869) on October 3, 2024. Link: https://clinicaltrials.gov/study/NCT06628869.

Purpose of review

Tropical sprue, once a major cause of malabsorption syndromes, is declining in prevalence. As a consequence of its rarity, and the absence of specific diagnostic tests, diagnosis of this condition is often delayed or missed. The purpose of this review is to draw attention again to this condition and to its overlap with postinfectious irritable bowel syndrome.

Recent findings

Sporadic case reports of diagnosis in travelers to endemic countries as well as reports of its continuing occurrence in endemic countries indicate the need for continuing diagnosis of the disease. Most recently, the COVID pandemic saw a large number of patients with postinfection gastrointestinal symptoms that lasted longer than 6 months and were accompanied by malnutrition. These events deserve deeper investigation and resurrect coronaviruses as one possible cause of tropical sprue. Diagnosis of the disease is another evolving area and the original diagnostic criteria have to be modified in view of the lack of access to formal tests of absorption in most laboratories.

Summary

Sporadic reports of nonceliac enteropathy with response to antibiotic treatment indicate that the disease needs to be considered in the differential diagnosis of malabsorption in the appropriate clinical context.

Abstract

Background

Glucagon-like peptide-1 (GLP-1) receptor agonists are increasingly prescribed for diabetes and obesity, conditions that frequently coexist with irritable bowel syndrome (IBS). Their effects on gastrointestinal motility and visceral sensitivity raise the possibility of therapeutic benefit in IBS, but real-world evidence remains limited. This study evaluated the association between GLP-1 receptor agonist initiation and subsequent gastrointestinal outcomes in patients with IBS using a large federated electronic health records network.

Methods

We conducted a retrospective cohort study using the TriNetX Research Network. Patients with IBS (ICD-10 K58) who initiated GLP-1 receptor agonists (semaglutide, liraglutide, dulaglutide, exenatide, or tirzepatide) within 30 or 90 days after IBS diagnosis (GLP-1 group) were propensity score matched to IBS patients who did not receive GLP-1 therapy (non-GLP-1 group). Analyses were performed for the overall IBS cohort and stratified by subtype (IBS-D [K58.0] and IBS-C [K58.1]). Outcomes included coded chronic diarrhea, chronic constipation, abdominal pain, malabsorption, and abdominal bloating/distension. Incident outcomes were assessed using risk ratios, hazard ratios from Kaplan–Meier survival analysis, and log-rank tests.

Results

After matching, the 30-day landmark cohort included 4,668 patients per group and the 90-day landmark cohort included 6,665 patients per group. In the 90-day analysis, GLP-1 use was associated with significantly lower rates of chronic diarrhea (8.9% vs. 10.6%), chronic constipation (19.8% vs. 22.0%), abdominal pain (31.6% vs. 35.8%), and abdominal bloating/distension (8.3% vs. 10.9%) compared with non-GLP-1 controls (all p < 0.001). Similar reductions were observed in IBS-D and IBS-C subtypes, particularly for abdominal pain and bloating/distension. Differences in outcome recurrence (number of instances) were smaller than differences in incidence.

Conclusions

Initiation of GLP-1 receptor agonists was associated with significantly lower rates of several coded gastrointestinal symptoms in patients with IBS across multiple landmark periods and subtypes. While these observational findings are hypothesis-generating and require confirmation in prospective studies, they suggest potential benefit of GLP-1 therapies on IBS-related outcomes.

Abstract

Background

This study explored the regulatory effects of hypoxia-inducible factor-1α (HIF-1α) on the TLR4/NF-κB pathway and intestinal flora in diarrhea-predominant irritable bowel syndrome (IBS-D).

Methods

Twenty-eight Wistar rats were randomized into four groups: model (n = 13), blank control (n = 5), HIF-1α upregulation (n = 5), and HIF-1α downregulation (n = 5). The IBS-D model group received combined acute and chronic stress stimulation for disease induction. On the basis of identical stress intervention, the HIF‑1α upregulation group was additionally exposed to a hypobaric hypoxic chamber, while the HIF‑1α downregulation group underwent intraperitoneal administration of the HIF‑1α antagonist 2‑methoxyestradiol to achieve targeted modulation of HIF‑1α expression.the control group was fed conventionally. Two model rats were euthanized on days 0, 7, 14, 21 to analyze colonic HIF-1α, TLR4 and NF-κB, and feces from the remaining 5 model rats were gathered on days 0, 7, 14, 21, 28 for 16S rRNA sequencing. Gastrointestinal symptoms, mucosal integrity and molecular expression were assessed after 28 days.

Results

An IBS-D model was successfully established. HIF-1α expression in the model group increased progressively, while TLR4/NF-κB levels fluctuated but showed an overall increase. The levels of all three markers were significantly higher than those in the control group(P < 0.05). The HIF-1α downregulation group exhibited more severe IBS-D symptoms and higher TLR4/NF-κB expressions than the upregulation group (P < 0.05). At the genus level, the abundance of Lachnospiraceae NK4A136 decreased, whereas the abundance of the Prevotellaceae NK3B31 group, Clostridia UCG − 014, UCG − 005, and Prevotellaceae UCG − 001 increased (P < 0.05).

Conclusion

Under systemic hypobaric hypoxic stress, HIF-1α suppresses the TLR4/NF-κB signaling pathway and alleviates intestinal inflammatory responses. Concurrent intestinal hypoxia and inflammatory injury jointly interfere with normal commensal colonization, accompanied by altered gut microbial composition in IBS-D model rats. Changes in HIF-1α levels are biologically correlated with shifts in intestinal microbiota, though direct causal regulation of gut flora by HIF-1α remains to be verified in further experiments.

Abstract

Background

Diarrhea-predominant irritable bowel syndrome (IBS-D) is characterized by diarrhea and is often accompanied by depression, abdominal symptoms, and emotional comorbidities. Preclinical and clinical studies have shown that dysfunction of the brain–gut axis is a key pathogenic factor in IBS-D, yet the specific mechanisms remain unclear. Saikosaponin D (SSD), a major bioactive component of Bupleurum chinense DC., exhibits anti-inflammatory, antidepressant, and antitumor activities, with multi-target and multi-pathway interactions.

Methods

Acetic acid and restraint stress induced an IBS-D mouse model. SSD (purity ≥ 98%, Macklin Inc.) was administered orally at low, medium, and high doses (5, 10, 20 mg/kg). Visceral sensitivity, inflammatory status, intestinal barrier function, HPA axis activity, and gut microbiota composition were systematically evaluated using behavioral tests, Western blot, qRT-PCR, and 16S rRNA sequencing.

Results

SSD significantly alleviated visceral hypersensitivity and depression-like behavior, inhibited the peripheral HMGB1-TLR4/NF-κB inflammatory pathway, and restored intestinal barrier integrity. SSD also downregulated hypothalamic Nesfatin-1/CRH/p-CREB expression, suppressed hyperactivation of the stress-related HPA neuroendocrine axis, and reshaped the gut microbial community structure (β-diversity). Network pharmacology analysis suggested that SSD targets were significantly enriched in brain–gut axis-related pathways.

Conclusion

The present results indicate that SSD could ameliorate IBS-D by synergistically regulating peripheral inflammation, central stress, and intestinal microbes via the brain–gut–microbiota axis, providing experimental evidence for its potential application in TCM-based treatment.

Highlights

• Normal imaging does not imply the absence of nociceptive biology

• Structural diagnostics poorly match nociceptive physiology

• Nociceptive dysfunction often occurs at the molecular and network levels

• Emerging imaging technologies can detect hidden nociceptive mechanisms

• Diagnostic pipelines should align with underlying nociceptive biology

Abstract

Pain is the leading reason people seek medical care. Yet, the diagnosis of acute and chronic pain states remains tied to a structural paradigm that equates real disease with visible anatomical abnormality on imaging or systemic laboratory changes. When scans are normal and routine lab tests are unremarkable, patients with severe pain are often labeled nonspecific or functional, as if the absence of structural findings implied an absence of underlying biology. This approach ignores convergent evidence that nociception, the neural process required for pain, operates through molecular, cellular, and network-level mechanisms within a distributed apparatus spanning peripheral nociceptors, dorsal root ganglia, spinal circuits, and supraspinal networks, at scales and in compartments that conventional diagnostics were never designed to detect. Mechanistic studies already demonstrate microstructural, neuroimmune, electrophysiological, and metabolic abnormalities in people with chronic pain whose imaging and systemic laboratory results appear normal. Current policies that discourage imaging in conditions such as low back pain correctly recognize the weak correlation between structural findings and pain but mistakenly treat this as evidence that imaging has no diagnostic role, rather than that structural imaging is poorly matched to nociceptive physiology. We argue that chronic pain diagnostics should be realigned with nociceptive biology, using existing and emerging tools to detect physiologic nociceptive pathology even when structural imaging is normal.

Perspective

This paper challenges the structural paradigm for diagnosing painful states, arguing that normal imaging does not imply normal biology. It calls for aligning diagnostics with nociceptive physiology, recognizing molecular, cellular, and network mechanisms of pain, and advancing emerging imaging technologies to detect nociceptive pathology currently invisible to conventional structural imaging.

Abstract

Background Luminal proteases have been implicated in epithelial barrier dysfunction and visceral hypersensitivity in irritable bowel syndrome (IBS), yet their impact on the enteric nervous system (ENS), the principal regulator of gastrointestinal function, remains unknown.

Objective To investigate whether faecal mediators differentially activate enteric neurons across IBS subtypes and whether proteolytic and proteomic profiles explain neuronal phenotypes.

Design The effects of faecal supernatants (FSN) from 21 IBS-D (diarrhoea-predominant), 9 IBS-C (constipation-predominant) and 18 healthy control (HC) patients recruited across centres in three countries on guinea pig distal colon submucous plexus neurons were assessed using a neuroimaging technique. Faecal proteolytic activities and proteomic profiles were analysed.

Results IBS-D and IBS-C supernatants evoked significantly stronger neuronal activation than HC, demonstrating that FSN directly modulate ENS. In IBS-D, but not IBS-C, effects were mediated by serine and cysteine proteases and PAR-1. Proteome analysis revealed a significant difference in 47 proteins between IBS-D and HC, including several immunoglobulin components, underlying the role of microinflammation in IBS-D. A combination of amylases, trypsin-2 and an immunoglobulin protein demonstrated high diagnostic performance to distinguish IBS-D from HC.

Conclusion These findings uncover a previously unrecognised luminal–ENS axis in IBS and reveal fundamentally different pathological mechanisms between IBS-D and IBS-C. IBS-D is characterised by proteases and PAR-1-dependent neuronal activation and a distinct immune-enriched faecal proteome, whereas mediators in IBS-C act independently of these factors. These findings establish a functional link between faecal protease activity, ENS signalling and molecular biomarkers, highlighting new therapeutic and diagnostic avenues for subtype-specific management of IBS.

WHAT IS ALREADY KNOWN ABOUT THIS TOPIC

• Diarrhoea-predominant (IBS-D) and constipation-predominant (IBS-C) irritable bowel syndrome patients exhibit elevated faecal serine and cysteine protease activity, respectively.
• Increased faecal serine and cysteine protease activity triggers visceral hypersensitivity and disrupts the intestinal barrier in animal models.
• Enteric submucous neurons are strategically located at the interface between lumen and effector cells in the gut wall, yet the effect of IBS faecal supernatants on enteric neuronal activation remains unexplored.

WHAT THIS STUDY ADDS

• Faecal supernatants from IBS-D and IBS-C patients both activate submucous plexus neurons, demonstrating that luminal mediators can directly influence enteric neuronal signalling.
• Only IBS-D–induced activation is protease- and PAR-1-dependent, revealing a previously unrecognised luminal–enteric nervous system (ENS) pathway specific to diarrhoea-predominant IBS.
• Human-targeted proteomics identifies both immune- and pancreas-derived proteins as discriminative markers of IBS-D, establishing a pathologically ‘irritated’ gut unseen in IBS-C.

HOW THIS STUDY AFFECTS RESEARCH, PRACTICE, OR POLICY

• Defines a mechanistic link between faecal protease activity, ENS activation and IBS subtype, advancing our understanding of luminal control of enteric function.
• Targeting luminal serine and cysteine protease pathways to reduce increased enteric neuronal activation may offer therapeutic potential in IBS.
• Provides candidate faecal protein biomarkers that could support non-invasive, subtype-specific diagnosis of IBS and its pathophysiological background.

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2602910

Abstract

Background

Nav1.8, a voltage-gated sodium channel expressed in the peripheral nervous system, has a critical role in pain signaling. Previous trials of NaV1.8 inhibitors have shown effectiveness in reducing postoperative pain.

Methods

We conducted a phase 2b, double-blind, randomized, placebo-controlled trial to evaluate LTG-001, a selective Nav1.8 inhibitor, in patients with moderate-to-severe pain after abdominoplasty. Patients were randomly assigned in a 1:1:1:1 ratio to receive a 300-mg loading dose of LTG-001, followed by 150 mg every 12 hours (low-dose group); a 450-mg loading dose of LTG-001, followed by 300 mg every 12 hours (high-dose group); hydrocodone bitartrate–acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen) every 6 hours; or placebo every 6 hours. All doses were administered orally over a 48-hour period. The primary end point was the time-weighted sum of the pain-intensity difference (SPID) over the 48-hour treatment period (SPID48), based on scores on the Numeric Pain Rating Scale (range, 0 to 10, with higher values indicating more severe pain; higher SPID48 values indicate greater pain reduction). Secondary end points included the amount of opioid rescue medication consumed in morphine milligram equivalents (MME) and no receipt of opioid rescue medication.

Results

A total of 343 patients underwent randomization. The least-squares mean SPID48 was 161.05 (95% confidence interval [CI], 142.93 to 179.16) in the low-dose group, 185.30 (95% CI, 167.26 to 203.34) in the high-dose group, 164.08 (95% CI, 146.02 to 182.14) in the hydrocodone bitartrate–acetaminophen group, and 123.22 (95% CI, 105.23 to 141.21) in the placebo group. The least-squares mean difference in the SPID48 between LTG-001 and placebo was significant for each dose (low dose: 37.82 [P=0.003]; high dose: 62.08 [P<0.001]), and that between hydrocodone bitartrate–acetaminophen and placebo was 40.86. High-dose LTG-001, but not low-dose LTG-001, was associated with significantly lower opioid use than placebo (11.00 MME vs. 18.35 MME, P=0.01), as well as a significantly higher percentage of patients who received no opioid rescue medication (52% vs. 22%, P<0.001). High-dose LTG-001 was associated with a higher incidence of pyrexia than placebo (7% vs. 2%) and a higher incidence of presyncope (6% vs. 1%).

Conclusions

LTG-001 led to significantly greater reductions in pain scores than placebo over the course of 48 hours after abdominoplasty. (Funded by Latigo Biotherapeutics; LTG-001-010 ClinicalTrials.gov number, NCT07102459.)

Research Summary

SPID48 from Suzetrigine (VX-548) clinical trials:

4 Clinical Trials of suzetrigine vs vicodin vs placebo

Source: https://onlinelibrary.wiley.com/doi/10.1111/jgh.70618

Graphical Abstract

Abstract

Background and aim: Given the prevalence and chronicity of irritable bowel syndrome (IBS), this systematic review aimed to synthesize evidence on the cost of illness of IBS, with attention to the relative contributions of direct healthcare and indirect non-healthcare costs.

Methods: A systematic search of PubMed, Embase, and the Cochrane Library was conducted from inception to August 2025, following PRISMA 2020 guidelines (PROSPERO CRD420251266432). Studies were included if they primarily assessed costs of IBS with sufficiently detailed methodology. Costs were inflation-adjusted to 2024 US dollars using World Bank consumer price indices and prevailing exchange rates. Risk of bias was assessed using the Consensus on Health Economic Criteria (CHEC) list.

Results: Thirty-three studies met our inclusion criteria, spanning 14 countries from 1992 to 2022. Mean annual direct healthcare costs per patient ranged widely, from US$193 in Korea to US$31113 in the United States among patients with IBS-C. Among the 10 studies adopting a societal perspective, indirect costs such as absenteeism, presenteeism, and lost productivity frequently constituted a dominant share of total costs. In some settings, non-healthcare costs exceeded direct healthcare costs several-fold (e.g., Sweden: US$17112 vs. US$1943 for IBS-C). Treatment failure and inadequate symptom control were associated with higher expenditures. IBS-C incurred the highest subtype-specific costs, and racial and gender disparities in spending were identified.

Conclusions: IBS imposes a considerable global economic burden. When societal perspectives are adopted, indirect costs emerge as a predominant driver of total costs, necessitating holistic management strategies. Importantly, assessments limited to direct healthcare expenditures underestimate the true economic impact of IBS.

Abstract

Osteoarthritis (OA) affects 600 million individuals globally, pain being a hallmark symptom. Emerging clinical evidence supports the use of mesenchymal stem cells (MSCs) and their extracellular vesicles (MSC-EVs) for pain relief in knee OA. In mice, MSC-EVs ameliorate OA-induced pain and normalize knee-innervating neuron excitability. Moreover, it has been shown that overnight incubation of sensory neurons with MSC-EVs prevents the OA-associated mediator nerve growth factor (NGF) sensitizing sensory neurons. Here, conducting experiments with male and female C57BL/6J mice, we found that protease-mediated MSC-EV ‘shaving’ inhibited MSC-EV internalization into sensory neurons and the ability of MSC-EVs to prevent NGF-induced sensitization. In addition, acute, 10-minute, exposure of sensory neurons to MSC-EVs was also insufficient to counteract NGF. We hypothesized that MSC-EVs trigger transcriptional changes and found that inhibiting transcription prevented NGF-induced sensitization. MicroRNAs (miRNAs) can be delivered to cells by MSC-EVs, and certain miRNAs regulate transcription and pain; small RNA-sequencing of our MSC-EVs identified three candidate miRNAs, miR-21-5p, miR-148a-3p and miR-451a. Using gold nanoparticle delivery, each miRNA was able to prevent NGF sensitization of sensory neurons, a combination of all three showing the most pronounced effect. These findings demonstrate that MSC-EVs prevent NGF-induced sensory neuron sensitization via cellular uptake and transcriptional regulation that is mediated by miRNAs.

Significance statement Mesenchymal stem cell extracellular vesicles (MSC-EVs) contain a complex biomolecular cargo and modulate cellular activity through diverse signaling mechanisms. MSC-EVs alleviate pain in osteoarthritis (OA) through direct activity of sensory neurons whereby they prevent OA-induced hyperexcitability, as well as sensitization induced by nerve growth factor (NGF). Here, we show that MSC-EV internalization and induction of transcription is required to prevent NGF-induced sensitization. Using gold nanoparticle delivery, we further demonstrate that a cocktail of microRNAs (miRNA) enriched in MSC-EVs can recapitulate the ability of MSC-EVs to counteract NGF, miR-21-5p being most potent when administered alone.

Summary

Disorders of gut–brain interaction, such as irritable bowel syndrome and functional dyspepsia, are increasingly linked to defects in gut barrier function. Mucosal disruption, encompassing alterations in the epithelial and mucus layers, leads to enhanced intestinal permeability, microbial translocation, and aberrant immune and neuronal signalling, potentially contributing to symptom severity. Despite growing recognition of barrier dysfunction in disorders of gut–brain interaction, clinical interventions remain largely symptom-based, with few therapies designed to directly restore epithelial integrity. In this Review, we examine the cellular and molecular pathways underpinning gut barrier function and highlight evidence supporting the role of diet, microbiome-targeted interventions, stress modulation, and pharmacological agents in maintaining or restoring intestinal permeability. Mechanistic insights reveal that short-chain fatty acids, amino acids (glutamine and tryptophan), and targeted probiotics can enhance tight junction integrity and mucin secretion, whereas psychological stress, low-fibre diets, and high-fat diets disrupt these pathways. We also discuss novel therapeutics, including antihistamines, mast cell stabilisers, protease inhibitors, secretagogues, and guanylate cyclase C agonists, and emerging technologies, such as vagal nerve stimulation and barrier-protective hydrogel delivery systems. Although promising, these strategies require validation in well designed clinical trials with targeted endpoints, and patient stratification based on microbial and immune phenotypes. By integrating advances in molecular biology with translational therapeutics, interventions targeting intestinal permeability could shift the treatment paradigm for disorders of gut–brain interaction from general symptom management to personalised disease modification.

ABSTRACT

The comorbidity between irritable bowel syndrome (IBS) and anxiety arises from impaired sensory-emotional integration, yet its underlying neural circuit mechanisms remain elusive. Using a water-avoidance stress (WAS) rat model, this study identifies a glutamatergic projection from the anterior cingulate cortex (ACC^(Glu)) to the anterior insular cortex (AIC^(Glu)) that mediates stress-induced visceral hypersensitivity and anxiety. Chemogenetic or optogenetic manipulation reveals that activation of glutamatergic neurons in AIC or the ACC^(Glu)-AIC^(Glu) circuit mimics WAS-induced both visceral hypersensitivity and anxiety. Conversely, inhibition of this circuit reverses WAS-induced visceral hypersensitivity and anxiety. However, bidirectional chemogenetic manipulation of ACC^(Glu)-AIC^(Glu) circuit fails to affect ovalbumin-induced visceral hypersensitivity, indicating stress-specific modulation. Additionally, at synaptic level, WAS rats exhibit elevated synaptosomal expression of GluA1/A3-containing AMPARs and NR2B-containing NMDARs of ionotropic glutamate receptors (iGluRs) in the AIC, accompanied by enhanced AMPAR- and NMDAR-mediated currents. These alterations are alleviated by chemogenetic inhibition of the ACC^(Glu)-AIC^(Glu) pathway. Moreover, inhibition of GluA1/A3 and NR2B receptors relieved visceral hypersensitivity and anxiety in WAS rats. Taken together, these findings reveal that AMPA and NMDA receptor trafficking driven by this circuit underlies stress-induced comorbidity of visceral pain and anxiety, uncovering a circuit-to-synapse mechanism and highlighting potential therapeutic targets for circuit-based treatment of this comorbidity.

Abstract

Background/Aims: Food is thought to play a central role in the pathophysiology of disorders of gut–brain interaction (DGBI). Data on these associations come largely from Western countries. We evaluated associations between diet and common bowel DGBI using the database of the Rome Foundation Global Epidemiology Study (RFGES).

Methods: The RFGES database contains data collected via the Internet, personal interviews, or both from 33 countries, providing prevalence rates for common DGBI. Logistic regressions were used to analyze associations between DGBI and vegan, vegetarian, lactose-free and bread-, pasta-, and rice-predominant diets.

Results: 54 127 internet and 20 973 household survey subjects were included. Rates of adherence to a vegan or vegetarian diet were low in both surveys (0.4% to 9.8%) and differences in dietary preference were also noted between surveys with lactose-free and rice-predominant diets being more common among household survey respondents. While discrepancies between results from the 2 surveys limited the interpretation of the data, some trends were evident with a lactose-free diet linked to an increased prevalence and bread- and rice-predominant diets to lower prevalence rates of several bowel DGBI.

Conclusions: Though complicated by variations in results between the 2 survey populations, this global survey has revealed dietary factors that may impact, in the general population, on reported prevalence rates for DGBI.

Abstract

Background: Acute diverticulitis (AD) is a prevalent gastrointestinal disorder with a significant recurrence rate. Faecal calprotectin (FC) is a non-invasive biomarker of intestinal inflammation, but its role in diagnosing and monitoring diverticulitis remains to be fully established. Objective: This narrative review aims to evaluate the current evidence on the utility of FC in the diagnosis, severity assessment, prediction of recurrence, and monitoring of therapeutic response in patients with diverticular disease (DD) and AD. Methods: A structured literature search was conducted using PubMed, Scopus, and ScienceDirect for peer-reviewed original studies published in English between 2004 and April 2025. The search strategy combined terms related to diverticular disease and faecal calprotectin. Studies reporting original data on FC in DD were synthesised narratively. Results: FC demonstrates significant utility across multiple clinical applications in DD. For diagnosis, FC is markedly elevated in AD (mean 556–695 μg/g) and symptomatic uncomplicated diverticular disease (SUDD) (median 181 μg/g), while remaining normal in irritable bowel syndrome (mean 50 μg/g), enabling differentiation between organic and functional disorders. FC correlates strongly with endoscopic disease severity, with positivity rates increasing from 48.6% in DICA 1 to 93.2% in DICA 3 (p < 0.0001). For predicting recurrence, elevated FC identifies patients at high risk, with one study reporting 87.5% of recurrent cases showing prior FC elevation and a negative predictive value of 96.8%. FC also exhibits excellent short-term prognostic capacity (AUC 0.976 at 3 months) and responds to therapeutic intervention, with significant reductions following successful treatment with probiotics, nutraceuticals, budesonide, and other agents. Conclusions: FC is a promising non-invasive biomarker for diagnosing diverticulitis, assessing disease severity, predicting recurrence, and monitoring treatment response. Its ability to detect subclinical inflammation makes it particularly useful for risk stratification. However, the current evidence base consists predominantly of retrospective and observational studies, and standardised thresholds require further validation through prospective trials before routine clinical implementation can be recommended.

Selective glucocorticoid receptor modulator (SEGRM) Wikipedia

Grünenthal receives FDA Orphan Drug and Rare Pediatric Disease Designations for Tegacorat for the Treatment of Duchenne Muscular Dystrophy

Novel selective glucocorticoid receptor modulator GRM-01 demonstrates dissociation of anti-inflammatory effects from adverse effects on glucose and bone metabolism

Poster „EVALUATION OF THE NOVEL SEGRAM GRM-01 IN THE B10.mdx MODEL OF DUCHENNE MUSCULAR DYSTROPHY (DMD)

Grünenthal's Glucocorticoid Receptor Modulator Video

Abstract

Background and Aims

Microscopic colitis (MC) and bile acid diarrhea (BAD) are common causes of chronic watery diarrhea. Retrospective studies suggest that BAD coexists in a subset of patients with MC, but the interplay and therapeutic implications remain unclear. We aimed to determine the prevalence of BAD in patients with an MC flare using biochemical markers, to assess the effects of budesonide on BAD biomarkers, and to correlate with clinical outcomes.

Methods

In this prospective multicenter study conducted at 3 Danish secondary care outpatient clinics, 49 patients with an MC flare were treated with budesonide for 6 weeks. 7α-Hydroxy-4-cholesten-3-one (C4) levels ≥46 ng/mL defined BAD. C4 allows timely testing but has 47% sensitivity. Fecal bile acids (BAs) and fibroblast growth factor 19, stool habits, and quality of life were evaluated.

Results

BAD was diagnosed in 6 (12%; 95% confidence interval, 5%–25%) of 49 patients (C4 range 47–92 ng/mL). Three patients had a gray zone C4 between 33 and 46 ng/mL. Patients with BAD had lower fibroblast growth factor 19 and high levels of primary and total BA in spot stool samples. Budesonide significantly reduced diarrhea and improved health-related quality of life in all patients. In patients with BAD, budesonide normalized stool BA, but C4 levels remained elevated.

Conclusion

These data demonstrate that some patients with MC flare have BAD. In patients with MC and BAD, budesonide reduced diarrhea symptoms and normalized stool BA levels but did not improve an underlying dysregulation of BA homeostasis. Clinicians may consider testing for BAD in patients with recurrent MC. Trials on therapies targeting BAD in MC patients are warranted.