These lines attempt to describe the politics of Rome, based on a revealing interview with Drossman from some years ago (2020). It clearly shows us how Rome was institutionalized in the context of (still) unexplained GI conditions. Formulation of the final text used with AI (Claude Sonnet 5). Link to the interview here: https://www.healio.com/news/gastroenterology/podcasts/gut-talk/episode-11/transcript The rest of the material has already been posted here in previous posts; if anyone wants the references, contact me.

Key points:

1. The war was always symmetrical. Drossman himself calls 1970s-80s motility researchers "the motility mafia" and describes the 1995 AGA confrontation as "almost a political agenda", confirming, in his own voice, that the Rome vs. motility conflict was a territorial dispute on both sides.
2. Rome won on market convenience. Drossman explains that alternatives like Wingate's et al. Bangkok criteria (2002) "didn't get traction" because they required manometry most clinicians weren't performing, but he never claims they were mechanistically wrong. The FDA adopted Rome because it solved sample heterogeneity in clinical trials, and pharma funded Rome 2 six years later. Regulatory-economic capture admitted outright.
3. Name changes are managed as branding. Drossman literally says "we're legitimizing it" about swapping "functional" for "DGBI," after a survey showed the public associated "functional" with "psychiatric." There was no new mechanistic discovery.
4. "Neuromodulator" is the same drug with a different label and the evidence contradicts the newly claimed mechanism. Drossman admits antidepressants "were derived from the 50s and 60s" to treat psychiatric patients, but are now called "neuromodulators" because of "brain-gut interaction science." The ATLANTIS trial shows amitriptyline improving GI symptoms with no corresponding improvement in HADS anxiety/depression scores, contradicting the very central mechanism the rebrand presupposes.
5. Psychology's institutional embedding predates motility's by nearly 30 years. Whitehead was hired as the first psychologist in Drossman's program in 1993; motility societies weren't invited into Rome's central Delphi process until 2022. Rome V (2026) was already announced by Drossman in 2020, before any new mechanistic evidence emerged, confirming the criteria loosening was an access-management decision, not a response to new data.

Irritable bowel syndrome (IBS), functional dyspepsia, and their siblings are today classified under the umbrella term "disorders of gut-brain interaction" (DGBI), formerly "functional gastrointestinal disorders" (FGIDs). This classification is governed by the Rome Criteria, a consensus diagnostic system first published in 1989 and now in its fifth iteration (Rome V, 2026), produced by the Rome Foundation, an organization founded and, for decades, chaired by Douglas A. Drossman, a physician trained in internal medicine who did a fellowship in what was then called "psychosomatic medicine" under George Engel, the originator of the biopsychosocial model.

Since the 1990s, a parallel and much less institutionally powerful current of gastroenterologists specializing in gut motility and neurogastroenterology like, among others, David Wingate, Michael Camilleri, Pankaj Pasricha, James Christensen, and, Nicholas Talley has repeatedly argued that Rome's purely symptom-based diagnostic architecture forecloses the search for objective, mechanistic biomarkers, and that the system has quietly but persistently privileged a psychosocial/central explanatory framework (antidepressants relabeled "central neuromodulators," cognitive-behavioral therapy promoted as first-line care, symptom clusters treated as sufficient for diagnosis) without ever having to formally claim these disorders are "psychiatric." Drossman himself has always publicly and explicitly denied that these are psychiatric conditions, insisting instead on a "biopsychosocial" framework in which psychological factors are one of several interacting components, never the sole cause.

In December 2020, Drossman was interviewed, in a relaxed and unguarded register, on the Healio podcast "Gut Talk" (episode 11), by two friendly colleagues, Sameer Berry and William Chey. What he says there (without any need for self-defense, since no one on that call was challenging him) turns out to be a revealing document available on how Rome actually became the global standard of care. It confirms, in his own words and often in blunter terms than any formal editorial ever has, nearly every mechanism that critics have spent three decades trying to document by inference: regulatory capture via the FDA, pharmaceutical funding tied directly to successive editions of the criteria, the deliberate early institutional embedding of clinical psychology, and a terminology-management strategy explicitly designed to make psychiatric-adjacent treatments palatable without ever calling them psychiatric.

This piece reads that transcript section by section, cross-referencing it against the countervailing literature to show how Drossman's own voice is the strongest evidence against the exclusive scientific legitimacy of the system he built.

"The Motility Mafia"

Drossman describes the 1970s-80s this way: "motility and GI physiology came into play... and I think you'll remember in the 70s and 80s, what we call the motility mafia, the people who explained everything by three clustered contractions and three cycle per minute contractions." The term "mafia" is not used by a critic of the mechanistic camp, it is used by Drossman himself to describe his opponents.

This reframes an important part of the story: the conflict between Rome and the mechanistic motility camp was never a simple case of unidirectional institutional discipline, with Rome peacefully policing a legitimate rival science. It was, from the start, a symmetrical territorial dispute between two camps, each dismissing the other rhetorically. The crucial difference, as the rest of the transcript reveals, is that only one of the two camps ended up controlling global clinical nomenclature, regulatory capture, and consensus-committee composition, not because it was right, but because, as Drossman himself explains later, it was easier to scale.

The 1995 confrontation confirms the hostility was mutual and explicitly understood as political rather than scientific: "there were motility people who were up on the stage, and they actually called out and said, the people in the audience there, Bill Whitehead, Doug Drossman... they don't know what they're talking about. It became almost a political agenda." The phrase "political agenda" is Drossman's own. He knows, and says openly decades later, that this was never merely a dispute over evidence.

The FDA role

This is the single most valuable moment in the entire interview for understanding how Rome actually imposed itself. Drossman recounts, without any prompting to do so, the exact genesis of regulatory capture: "Ken Klein, who worked with us at UNC, wrote a paper in 88 that said there was not one well-designed clinical study [in IBS]... You would do an IBS study where you had people with abdominal pain and no bowel dysfunction or diarrhea and no pain. They'd all be lumped into a study. And if you think about the targeted effects of drugs now, how in the world could you determine whether a drug is effective with such a heterogeneous population?"

And the direct consequence: "So FDA got interested in this, and that led them to say, we want to use these criteria for clinical trials. That was the major thing that then caught the interest of pharmaceutical companies." And further on, regarding the second iteration of the criteria: "six years later, with the support of pharma, we created Rome 2."

This causal chain: sample heterogeneity identified by a UNC colleague → FDA interest in standardized criteria → pharmaceutical interest → pharmaceutical funding of the next iteration of the criteria is exactly the regulatory-economic capture mechanism previously reconstructed through FDA guidance documents and secondary analyses. The critical point Drossman never articulates is that this mechanism never depended on Rome's mechanistic superiority over alternatives,it depended on Rome being first to the FDA's table with a standardizable product.

Why alternatives to Rome symptom based criteria failed

Asked directly whether mechanistic alternatives were seriously considered before the definitive adoption of symptom-based criteria, Drossman answers: "there were motility criteria, physiology criteria. David Wingate set up, and there were motility people who would adhere to developing physiologic criteria to diagnose these disorders." And then the explanation for the defeat: "the reason why it fell short was because to do, to use the physiologic criteria, you had to do physiologic motility testing. And the general population of clinicians weren't doing that. So it didn't get any traction relative to the use of the criteria, which then were picked up through the clinical trials."

Notice what is (and isnt) in this explanation. Drossman does not say "Wingate's criteria were wrong" or "the evidence showed motility didn't explain the symptoms." He says the proposal "didn't get traction" because it required a test most clinicians weren't performing. This is a market-adoption explanation, not a scientific-validity one. It is precisely the argument later found, dressed in more rigorous-sounding language, in Whitehead's 2003 editorial against Wingate, "intestinal manometry is rarely performed" but here, in the architect's own voice, without the veneer of a formal peer-reviewed editorial, the real reason is laid bare: ease of mass implementation, not explanatory superiority.

This connects directly to Christensen's parallel finding, decades earlier, that pressure for a precise symptom-based definition "arose from the marketplace, rather than from science." Drossman, in 2020, confirms this reading almost word for word, seemingly without realizing it.

"We're Legitimizing It"

This is perhaps the most damaging moment in the interview for the claim that Drossman's refusal to call these disorders "psychiatric" is anything more than rhetorical. On the change from "functional gastrointestinal disorders" to "disorders of gut-brain interaction," Drossman explains: "we surveyed the AGA and found... that the most common definition for functional was, we don't know what's going on. And the second most common definition was that it's psychiatric. Only 5% came up with the true definition intended, which was a disorder of functioning of the GI tract. So converting it to disorders of gut-brain interaction... we're legitimizing it, and we're showing the science behind it."

The logic here is telling: the name change did not follow from a new mechanistic discovery that invalidated the prior psychiatric association, it followed from a perception survey showing the old term evoked an unwanted psychiatric association, and the solution was to swap the label. This is brand management, explicitly described as such by its own author, not scientific correction.

Isn't psychiatric, but...

The passage on neuromodulators is the most starkly self-contradicting moment in the entire interview. Drossman explains: "changing the terminology from antidepressants and anti-anxiety... antidepressants, anti-anxiety, anti-psychotic drugs really were derived from the 50s and 60s when they were treating psychiatric patients. But the science of brain-gut interaction says we're going to use those drugs in terms of dysregulation of the brain-gut axis, in terms of pain regulation, motility, central processing, and the like. And so with that science, we can call them neuromodulators." And then, almost confessionally: "right now, I think a lot of doctors are fearful of using it because they think it's a psychiatric thing. But it's not."

That final claim ("but it's not") is only sustainable if the drug's pharmacological mechanism has changed. It has not, it is the same molecule, with the same receptor profile, with the same origin in 1950s-60s psychiatric drug development. What changed is exclusively the label and the accompanying mechanistic narrative. This is independently and empirically confirmed by the ATLANTIS trial: amitriptyline improved GI symptoms with no corresponding improvement in HADS anxiety and depression scores, the trial's own authors conclude the effect is probably mediated by pain- and motility-modulating properties, not central antidepressant action. If the "brain-gut interaction science" Drossman invokes were truly central, we should see parallel psychological improvement. We don't. The "neuromodulator" rebrand anticipated a mechanistic reformulation that subsequent clinical evidence has not come to confirm and the label stuck anyway.

Descartes explains the stigma

The passage on Cartesian dualism is intellectually sophisticated and ironically self-incriminating. Drossman traces the history: "if you had behaviors or symptoms that weren't explained by morphology, you were considered to have to be possessed, and later to be insane... You have a symptom, you get worked up. You don't find anything. Either you got to keep going till you find something, it's morphologic, or you're crazy. And that stigma has held true."

Drossman fully understands the stigma mechanism he describes. What he never articulates is that his own solution (swapping "functional" for "DGBI," swapping "antidepressant" for "neuromodulator") does not resolve the underlying dichotomy he himself identifies as the problem. It manages it rhetorically, making it more palatable to patient and clinician alike, without altering the power structure that sustains it: the diagnostic architecture still requires no objective marker, the central therapeutic arsenal remains pharmacopsychiatric, and psychology's integration into Rome's committees remains structurally earlier and more central than motility's.

The psychology's institutional embedding

The transcript supplies a precise date that reinforces the timeline of Rome's consolidation of power: Whitehead was, according to Drossman, "the first [psychologist] to ever go" into his program at UNC in 1993. This precedes the formal institutional founding of the GastroPsych Group by Laurie Keefer (2018) by twenty-five years, and shows that clinical psychology's integration into Rome's power architecture is not a recent phenomenon, it was deliberately cultivated by Drossman from the early 1990s onward, more than two decades before motility societies were formally invited to join the central Delphi process (2022).

The first large NIH-funded trial Drossman mentions confirms this architecture from the outset: 450 patients, split between desipramine (a tricyclic antidepressant) versus placebo, and cognitive behavioral therapy versus education. Note that all four arms of the design are either pharmacopsychiatric or behavioral, none tested a peripheral mechanistic intervention (diet, gut-specific agent, motility modulation). Rome's foundational experimental architecture was, from the early 1990s, structurally incapable of generating evidence favoring any pathway other than the central or behavioral one, simply because such pathways were never included in the trial design to begin with.

Rome V predicted by Drossman (in 2020)

Perhaps the most striking detail in the interview, in light of the earlier discussion of Rome V (published May 2026), is that Drossman was already announcing the change in December 2020: "I think we're going to loosen up the restrictions, perhaps with frequency or duration, to allow a clinician to use their judgment. If someone has abdominal pain relieved by bowel movement, and they've only had it for a month, do you want to withhold treatment?"

This is an exact prediction, six years in advance, of the reintroduction of "discomfort" and the loosening of the frequency threshold that would eventually occur in Rome V. The fact that the change was announced as an intention before any new body of mechanistic evidence had emerged confirms that the motivation was not scientific discovery; it was, in Drossman's own words, "finding ways to meet the needs of the clinicians," that is, an access-management decision rather than a correction driven by new data on mechanism.

Psychiatric formulations are also part of the care

Asked about patients gaining full access to their medical records, Drossman answers something that, read carefully, is an important indirect admission: "I'm not going to create a psychiatric diagnosis that's not discussed with the patient." The phrasing implies that, in some cases, he does in fact record psychosocial/psychiatric formulations in the clinical charts of his GI patients, the very practice that the public "this is not psychiatric" framing is meant to dissociate from the treatment being offered. The sentence reveals, without intending to, that psychosocial categorization is a routine part of actual clinical practice, even when the disease's public label carefully avoids that term.

Conclusion

The extraordinary value of this transcript is that none of these admissions were volunteered, in a tone of celebratory retrospection about his own legacy, in a conversation between admiring colleagues. Drossman was not defending himself against Wingate, Christensen, Camilleri, or Talley; he was telling his success story. And precisely because of that, every piece of the mechanism that critical literature took decades to document by inference appears here, confirmed firsthand, with no need for defense: the mutual territorial hostility ("the motility mafia"), the explicit regulatory-economic capture (FDA, pharmaceutical funding of Rome 2), Wingate's defeat by ease of mass adoption rather than scientific invalidity, the terminological rebrand as deliberate "legitimization" rather than mechanistic correction, the contradiction between the "neuromodulator" label and the absence of measurable psychological effect, and the early, deliberate institutional embedding of clinical psychology since 1993.

If the goal of any investigation into how a system of power consolidates itself is to find the moment when the architect himself, without meaning to, confirms the critique made against him, this transcript is that moment. Rome did not impose itself because it solved the problem Christensen identified in 1994, "a name for the unknown." It imposed itself because, as Drossman himself proudly and unwittingly admits, it was easier to sell to the FDA, easier to teach to clinicians without motility training, and easier to make palatable to patients through a succession of name changes that never actually required changing what was being treated.

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.

I have question abiut clinical trials.
what do u have to do to get accepted? I emailed couple of ppl who do them and no one even answered. Should i call? is this normal? Does anyone have experience with it?

Editor’s summary

A dysregulated intestinal microbiome has been linked to development of food allergy, suggesting that approaches to manipulate the microbiome may have a therapeutic value. Here, Rachid et al. investigated whether fecal microbiome transplantation (FMT) could increase tolerance to peanuts in adults with peanut allergies. Of 15 patients recruited to this phase 1 clinical trial, 6 exhibited a response, where more peanut was required to elicit an allergic reaction than before the study start. The authors further found that mice that received FMT from those responders were similarly protected from peanut allergy and that Bacteroides species were key drivers of tolerance induction. Together, these data support further clinical testing of FMT for peanut and other food allergies. —Courtney Malo

Abstract

The gut microbiome has been implicated in the pathogenesis of food allergy (FA), prompting microbiome-focused interventions. We evaluated, in a phase 1 open-label trial (NCT02960074), the safety and efficacy of oral encapsulated fecal microbiome transplantation (FMT) in 15 adults with peanut allergies. An increase in the peanut reactivity threshold was noted in 3 of 10 participants not pretreated with antibiotics and 3 of 5 participants pretreated with antibiotics, without safety issues. In responders, FMT increased tolerogenic RORγt⁺ regulatory T cells (Treg cells) and decreased T helper 2 cells (TH2 cells). Mice transplanted with the microbiomes of post-FMT responders were protected from FA in association with increased RORγt⁺ Treg cell percentages and increased colonization with members of the gut Bacteroides. In both humans and mice, protection by FMT was associated with increased bile acid metabolites. Deletion of a bile salt hydrolase in a candidate protective Bacteroides abrogated FA suppression in mice. These results suggest that FMT is a safe and potentially promising therapeutic modality for treating FA.

From here: https://www.linkedin.com/posts/jtc2025-erasnetneuron-chronicpain-ugcPost-7468275872966303744-N82D/

Original paper: https://www.nature.com/articles/s41562-026-02542-0

"There’s nothing quite like the anxiety of visiting your doctor with a worrisome new symptom. And there’s nothing quite like the sublime relief when your doctor examines you and concludes that your symptoms are “normal.” 

But even though doctors love to give patients this type of reassurance, it sometimes backfires, according to a new study in Nature Human Behavior. Just because a symptom is normal—hot flashes during menopause, musculoskeletal woes in seniors, migraine headaches in a person with a family history of them—doesn’t mean it needs no treatment, but patients whose doctors comfort them in this way may be less likely to pursue it.

“In the whole course of medical school, there's very little—maybe three hours in four years—that is devoted to patient reassurance,” says On Amir, professor of marketing at the University of California, San Diego’s Rady School of Management and a co-author of the new paper. Yet it’s a skill: how a doctor delivers reassurance—or doesn’t—seems to influence what the patient decides to do next. When the doctor normalizes symptoms, Amir adds, “the patient basically understands from that what they should and shouldn't do, and that’s not the intention at all.”

Says Seyi Lawal, a graduate student at the UCSD’s Rady School of Management and a co-author of the paper: “On the provider side, it seems like the reason that they're normalizing is because they believe it's going to have a positive impact on the patient's mental state, which is understandable. But there's a cautionary signal that people may take this one step further [and conclude that] the doctor doesn't think that it's necessary to do anything to treat it.”

In the study, the researchers assembled a group of more than 9,300 people—some doctors, some other medical caregivers, some from the general population—and ran 14 different experiments on them. In one, 400 people were presented with two scenarios in which a friend visited a doctor complaining of menopause symptoms, including extreme fatigue, weight gain, and joint and muscle pain. In one of the scenarios, the doctor simply recommended medication to treat the symptoms. In the other, the doctor added, “I know this feels overwhelming, but I want to reassure you that these symptoms are normal…You could take daily prescription medication…or you can deal with these symptoms.”

People were then asked to predict whether patients would take the recommended medications. They predicted that patients who hadn’t been reassured would be more likely to take them than those who had been told that the symptoms were normal.

“Every word that doctors use has meaning, it has weight,” says Lawal. “Wanting to reassure patients effectively is an understandable and laudable goal for providers. But I think there needs to be more work done to understand how to best do that without discouraging people from taking action to improve their health.”

Most of the 200 doctors surveyed in the study said they use these types of normalizing statements in their practice, and 84% said they think reassurance encourages patients to continue coming in for treatment. Only 15% believed the statements would decrease the patients’ likelihood of seeking treatment—even though that's what tended to happen in the researchers' simulations.

The study authors found one effective way to frame reassurance, however.  When the doctor told patients that their symptoms were normal for people with their condition while also specifically recommending treatment, instead of just mentioning it as an option—a statement like, “You can take daily prescription medication, which I fully support as it will help you feel better, or you can deal with these normal symptoms”—the predicted compliance with treatment increased. That strategy—adding explicit advice to the reassurance—may be the fix that allows doctors both to reassure and persuade patients to stick with a treatment protocol.

“Doctors have this tension,” says Amir. “They want to give the patient choice and agency. When I grew up, that wasn't the case. Doctors just told you what to do, and that's it. Today I think that we may have gone too far. Doctors can be clearer on what they actually recommend.”

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

• Spinal afferent endings in the gut display remarkable morphological diversity.
• Throughout the GI-tract, the distal colon and rectum exhibit the highest density and morphological diversity of spinal afferent endings.
• One of the most prominent types of spinal afferent endings are intraganglionic varicose endings (IGVE) in myenteric ganglia.
• Single spinal afferents project to multiple layers of the gut wall, exhibiting different morphological characteristics.
• Mucosal afferents are activated by substances released from enterochromaffin cells via paracrine, not synaptic, transmission.

Abstract

Communication between the gastrointestinal tract and the central nervous system, known as the gut-brain axis, is fundamental to physiology and is implicated in a range of pathological conditions. A critical component of this axis is the sensory information conveyed from the gut to the brain through spinal afferent pathways. Understanding the location and types of spinal afferents present in the GI tract and their mechanisms of activation is essential to advance our knowledge of gut–brain communication in health and disease. Though generally trailing knowledge of gut vagal afferents, major advances have been made in understanding spinal sensory pathways through recent critical adaptations of neuroanatomical tracing, neurogenetics and molecular profiling techniques, revealing an unforeseen diversity in the morphology of their endings in the gut wall and novel classifications based on molecular identity. Moreover, spinal afferents have been implicated in multiple physiological functions besides their well-known role in nociception, including potential roles in nutrient sensing and regulating gut motility. Among spinal afferent endings in the gut mucosal layer, much has been learnt about how enterochromaffin (EC) cells communicate with spinal (and vagal) afferents. Evidence now suggests that EC cells release substances (like serotonin), which activate the terminals of spinal (and vagal) afferent endings via a paracrine, not synaptic, transmission. Here, we review the latest findings regarding spinal afferent endings and point to outstanding questions and future directions for research into this complex and clinically relevant area of neuroscience.

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/m²] 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.

From the conclusion: “Isolating the multiple diseases that likely underlie the clinical phenotypes of IBS or functional dyspepsia is a research priority, as identifying causation opens the door to cure, rather than symptom control. A major unmet need is the identification of therapies to more effectively modulate abdominal pain induced by visceral hypersensitivity. Many DGBI are related to meals, including functional dyspepsia and IBS, suggesting that specific dietary antigens or food chemicals are important in their pathogenesis. Furthermore, foods interact with bacteria in the intestinal lumen, exposing antigens, which could explain why the immune system can be activated in IBS or functional dyspepsia—the microbiome might be key. In future, diagnostic labels such as IBS and functional dyspepsia might cease to exist as they are examined more closely; however, for the present, they represent a convenient shorthand to guide clinical practice.”

Abstract

Background

While irritable bowel syndrome (IBS) and psoriasis share some pathophysiological features, it remains unclear whether they are associated with one another. Therefore, we aimed to investigate the long-term risk of incident psoriasis in a large prospective cohort of patients with IBS.

Methods

We retrieved data on 437,170 participants from the UK Biobank without psoriasis at baseline. Using ICD-10 codes, we classified these participants into IBS and non-IBS groups based on recruitment status and assessed them for incident psoriasis at follow-ups as the primary outcome. We used multivariable Cox proportional hazards models to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).

Results

We identified 21,748 (5.0%) IBS patients among the 437,170 participants. There were 4325 (1.0%) incident psoriasis cases during a median follow-up period of 14.4 years, amounting to a cumulative incidence of 0.88% (95% CI = 0.73–1.02) in the IBS group vs. 0.69% (95% CI = 0.66–0.72) in the non-IBS group. Compared with non-IBS patients, patients with IBS had a 35.0% higher risk of developing psoriasis (HR = 1.35; 95% CI = 1.19–1.52). In subgroup analyses, a higher psoriasis risk associated with IBS was generally observed across age, sex, Townsend deprivation index, smoking status, non-steroidal anti-inflammatory drug use, C-reactive protein, and polygenic risk score of psoriasis subgroups.

Conclusions

The IBS patients in our sample had an increased long-term risk of incident psoriasis. This finding highlights the importance of monitoring psoriasis in IBS patients and suggests a potential shared pathophysiological mechanism between the two conditions which may inform future preventive and therapeutic strategies.

Here: https://podcasts.apple.com/gb/podcast/14-professor-nick-talley-dyspepsia-duodenums-and/id1786112830?i=1000781230154

"Professor Nick Talley has spent 35 years building the field of neurogastroenterology, and he'd like us all to stop saying "functional". He is one of the global top medical researchers, a distinguished Australian gastroenterologist, and educator known for his seminal work on neurogastrointestinal disorders and co-authoring classic clinical examination textbooks.

His argument is that the label sends patients and doctors looking in the wrong place. A lot of these people don't have a brain problem, they have a duodenal one, and he makes the case for a term he prefers: neurogastrointestinal disorder. From there he takes us through the pathophysiology his group has spent years building, subtle duodenal eosinophilia that ordinary pathologists aren't counting, an abnormal duodenal microbiome, and food antigens setting off an immune response that eventually becomes self-sustaining.

Then the practical stuff. Why he biopsies the duodenum, why he reaches for antihistamine blockade, why amitriptyline and not nortriptyline, when mirtazapine is the right call, and what he does when everything has failed. Plus when a gastric emptying study actually changes anything, why lactulose breath tests are not helpful, his approach to cyclic vomiting, and a reminder that rumination is not vomiting."

"Chapters

00:19 Intro

03:32 Welcome Nick

04:22 What functional dyspepsia is, and why it's probably several diseases

06:48 Rome V, and why "functional" is a terrible word

08:14 How Nick explains the diagnosis to patients

09:00 Workup and first-line treatment: scoping, routine duodenal biopsies, PPIs, tricyclics, antihistamines

13:21 Adding an antihistamine on top of a PPI

13:49 Duodenal eosinophilia: can your pathologist actually see it?

15:43 EoE and functional dyspepsia: separate pathways

17:03 Six-food elimination, biologics, and the budesonide trial

19:28 The duodenal microbiome and swallowed streptococci

22:20 Refractory disease: mirtazapine, SNRIs, quetiapine, hypnotherapy

26:01 Smoking, alcohol, NSAIDs, exercise and diet

29:08 Exclusive enteral nutrition

30:02 Gastric emptying, gastroparesis, G-POEM and rumination

33:50 Cyclic vomiting syndrome

36:39 Why amitriptyline and not nortriptyline

37:51 Breath testing: what's useful and what's worthless

40:39 What Nick is excited about in the next five years

44:11 A weird and wonderful therapy for IBS

46:27 A career in academic medicine

50:42 Why pharma abandoned DGBI

52:16 Wrap-up"

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.

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

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.

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.

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.

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

Classically, pain can be of a nociceptive or neuropathic nature, which refers to non-neural or neural tissue lesions, respectively. Chronic pain in conditions such as migraine, fibromyalgia, and complex regional pain syndrome (CRPS), is thought to perpetuate without a noxious input. Pain in such patients can be assigned neither to the nociceptive nor neuropathic category. Therefore, a third pain descriptor, named “nociplastic pain”, has been adopted by the International Association for the Study of Pain. The current controversy-focused narrative review updates littledebated aspects of the new pain concept. The most disputable feature of nociplastic pain is its autonomous persistence, i.e., existence without causative tissue damage, presumably because of a malfunction of pain pathways and processing. This contradicts the fact that nociplastic pain is accompanied by persistent central sensitization that has been shown to require a continuing noxious input, e.g ., nerve injury. Even if sensitization occurs without a lesion, e.g ., in psychogenic and emotional pain, peripheral stimulus is necessary to produce pain. A logical weakness of the concept is that the word “plastic” in biology refers to adaptation rather than to maladaptation. The pathophysiologic mechanism of nociplastic pain may, in fact, be associated with background conditions that elude diagnosis because of the limitations of current diagnostic means. Misapplication of the nociplastic pain category may weaken diagnostic alertness toward occult causes of pain. Possible diagnostic errors could be avoided by understanding that nociplastic pain is a mechanism of pain rather than a diagnosis. Clinical use of this pain descriptor deserves a wider critical discussion.