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.

I've continued to go down the rabbit hole on IBS-D and I think I've found a way to tie together a lot of the stuff that gets discussed here. I posted a while back about the mast cell theory and how treatments like ketotifen might be targeting that pathway. But after digging deeper, I noticed that nobody seems to mention GABA in these discussions, and I think it might actually be the missing link that explains why so many of these treatments work.

The basic idea is that GABA is the main inhibitory neurotransmitter in the nervous system. It's what calms things down. In IBS, there's evidence that GABA signaling is disrupted. Some studies have found lower GABA levels in IBS patients, and animal models show that enhancing GABA reduces visceral hypersensitivity. There's also work showing that GABA receptors are present on mast cells and that GABA can actually suppress histamine release from mast cells directly. So GABA isn't just a brain thing. It's working right there in the gut, potentially putting a brake on the very mast cell activation that seems to drive symptoms in a lot of IBS-D patients.

If that's the case, then a lot of the treatments people are using might be working through GABA even if that's not how they're marketed.

Take low-dose amitriptyline. It's one of the most prescribed drugs for IBS and it works well for pain and diarrhea. One of its mechanisms is that it enhances GABA release and blocks GABA reuptake, which means more GABA is available to calm down overactive pain pathways. It also stabilizes mast cells, but that might just be part of the same story. More GABA equals less mast cell degranulation equals less histamine and tryptase irritating the gut.

Ketotifen and famotidine. These are antihistamines, and they work by blocking histamine receptors. But if GABA is what naturally suppresses histamine release, then these drugs are essentially doing what GABA is supposed to be doing when the system isn't working right. They're compensating for a GABA deficit by mopping up the excess histamine that gets released when mast cells aren't being properly inhibited.

Glutamine is interesting because it's literally a precursor to GABA. It gets converted to glutamate and then to GABA. So when people take glutamine for gut barrier repair, they might also be providing raw material for the brain and gut to make more GABA. That could explain why some trials show benefits beyond just barrier function. One study even looked at glutamine and GABA together and found that the combination worked better than either alone for reducing visceral pain in animal models.

Probiotics like Bifidobacterium adolescentis have been shown to produce GABA directly in the gut. A recent pediatric trial found that this strain significantly reduced abdominal pain in kids with IBS, and they attributed part of the effect to its GABA-producing ability. So if you're taking a probiotic that produces GABA, you're essentially introducing a local source of the neurotransmitter right where it's needed most.

Now here's something that I think hasn't been discussed much. Modafinil. We all know it as a wakefulness drug, but its mechanism is actually quite relevant here. Modafinil inhibits GABA release and enhances glutamatergic transmission in certain brain regions. At first glance that seems like the opposite of what you'd want for IBS. But if you look at the brain imaging studies, IBS patients show reduced glutamatergic activity in pain-processing areas like the anterior insula. That deficiency correlates with pain severity. So modafinil might actually restore the balance by boosting the system that's underactive, rather than just piling on more GABA everywhere. It's a different approach to the same problem. Restoring the excitation-inhibition balance rather than just adding inhibition across the board.

I'm not saying modafinil is a treatment for IBS. I don't think anyone has studied it for that. But if the problem is a dysregulated GABA-glutamate balance in the brain-gut axis, then drugs that modulate that balance in either direction could theoretically be useful depending on the specific deficit in each patient. It might explain the weird anecdotal reports of people who say stimulants or wakefulness drugs somehow help their gut symptoms.

I don't have IBS-D myself so this is all just from reading. But it seems like the mast cell research is telling us what's going wrong, and the GABA research is telling us why it hurts and how to fix it. Curious if anyone else has thought about this or tried targeting GABA directly with supplements like picamilon or with drugs like gabapentin or pregabalin. Also curious if anyone with IBS has accidentally noticed changes in their symptoms when using modafinil or other drugs that hit the GABA system.

https://link.springer.com/article/10.1007/s10620-026-10143-0

Note: This is an excerpt from an article by Talley celebrating the most cited 1993 article in this scientific journal, "US householder survey of functional gastrointestinal disorders. Prevalence, sociodemography, and health impact." Talley concludes with an assessment of the Rome Foundation's criteria for DGBIs.

Rome V: Challenges Ahead

There are a number of criticisms of the Rome criteria and Delphi process that need to be acknowledged. While these do not detract from the intrinsic value of having internationally recognized diagnostic guidance, the concerns should provide room for a pause in those over-enthusiastically promoting Rome criteria as the “gold standard” (despite being largely expert based, the lowest form of evidence).

First, the current criteria are dominated by expert-derived symptom-only-based diagnoses, including IBS and functional dyspepsia, and the criteria have often been altered with each iteration. For example, the current criteria for IBS have again been revised going back in Rome V to essentially the Rome III criteria (because abdominal discomfort was omitted in Rome IV), which will change the most updated prevalence numbers considerably [22]. Notably, most patients with IBS report bloating and many abdominal distension; while the original Manning criteria included distension and despite its validation by others, the Rome committee still consider functional bloating and distension to be a separate entity from IBS although the validity of this is yet to be robustly confirmed [23, 24].

If symptom-based clusters accurately reflected the underlying pathophysiology, we would expect to observe more diagnostic convergence, rather than the reclassification seen across sequential iterations of the Rome criteria. Further, factor and cluster analysis studies have failed to independently replicate a number of the currently identified Rome diagnoses, raising questions about the validity of some entities [25, 26]. On the other hand, the factor and cluster studies have not all identified the same groupings either, reflecting symptom heterogeneity. Combining psychological factors and symptoms provides more robust separation from health as does adding in biological markers, but psychological factors are still considered comorbidities (not disease characteristics) by Rome V [27, 28]. The absence of robust biomarkers (although some may be emerging) limits advancing diagnosis in the field, so further work is essential [29].

Second, the very high prevalence rates reported in the Rome IV epidemiology survey has raised concerns about the normal thresholds being applied. Notably 40% of the world has a DGBI by Rome IV criteria if the internet survey data are accepted, and 25% in addition just miss meeting criteria (termed subthreshold DGBI) [16, 30]. Therefore, only about one third of humanity is healthy in terms of not having a DGBI based on Rome criteria; it’s abnormal to be normal! Surely, this cannot be correct, and the Rome thresholds for true disease may be set too loosely. It is also apparent that only a subset of those with symptoms will ever consult a physician and thus become patients despite meeting Rome criteria suggesting some non-consulters may be misclassified [31, 32]

Third, there are an increasing number of Rome diagnoses with each iteration, and many patients with DGBI by Rome IV or V meet criteria for more than one syndrome [33]. This challenges the concept of dividing by anatomical location into multiple discrete syndromes.

Fourth, DGBI symptoms are not confined to the alimentary tract; abdominal symptoms in IBS are often associated with multiple somatic symptoms including nausea, migraine headaches, backaches, and other pain syndromes, myalgias, fatigue, and sleep disturbances [34, 35]. As a rule of thumb, the more somatic symptoms that are present, the less likely it is that the symptoms reflect an underlying medical disease. Applying the Rome criteria the opposite is true; the more gut symptoms that are present, the more Rome diagnoses that will be identified. Another risk of having so many Rome diagnostic categories is misdiagnosing somatic symptom disorder as IBS or another DGBI [36].

A fifth issue is potentially confusing or even pejorative nomenclature. Functional is still applied for some disorders in Rome V such as functional dyspepsia but not in others (e.g., functional was dropped from constipation). Not all adult and pediatric criteria and terms align, which is odd. Further, the term DGBI introduced in Rome IV has been criticized because some clinicians feel it overemphasizes the brain–gut axis (despite gut coming before brain in DGBI) and because patients and clinicians outside of GI often have little clue what we are talking about as yet [37]. Whether better terminology can be created and accepted is under debate [38].

Finally, journal reviewers often now identify as a major criticism any absence of use of the Rome criteria in DGBI studies, even when this may artificially group patients or does not impact study validity. Such narrow thinking by experts needs to be challenged if the field is to evolve.

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.

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.

Hi everyone,

I’m 20 years old from Hong Kong, and I have been dealing with functional dyspepsia (FD) since 2021.

I wanted to ask if anyone with FD also experiences other symptoms beyond digestive issues, such as headaches, muscle pain, fatigue, or other unexplained body sensations.

One of the hardest things for me is explaining FD to doctors because it fluctuates so much. Sometimes I can be stable for weeks or months, but then suddenly experience a flare-up. By the time I see my doctor, I may already be improving, so it feels difficult to explain how severe it was and what the pattern looked like.

Over the years, I have tried different treatments, including acid suppression medications, gastrointestinal medications, and neuromodulators/psychiatric medications. These included medications such as PPIs, peppermint oil, Buscopan, antidepressants, and other medications sometimes used for gut-brain interaction symptoms.

Some treatments helped certain aspects, but I still find that FD is difficult to monitor because symptoms can change over time.

For people who have lived with chronic FD:

• How do you explain your symptoms to your doctor?
• Do you keep a symptom diary or track your symptoms?
• Do you also experience non-digestive symptoms like headaches, muscle tension, fatigue, or anxiety-related physical symptoms?

I sometimes compare FD with conditions like hypertension, where treatment response can often be monitored through measurable numbers. With FD, symptoms can fluctuate a lot, and there is no single measurement that fully shows how someone is doing.

I would really like to hear how others manage FD long term.

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.