Physical capacity modulates intestinal barrier dysfunction in functional disorders: phenotype-specific patterns in [FM] and [IBS] 2025 Russo et al

[Andy]

Background: Intestinal barrier dysfunction is increasingly implicated in the pathophysiology of fibromyalgia (FM) and irritable bowel syndrome (IBS), particularly in their comorbid form. Physical capacity (PC) influences systemic inflammation and metabolic resilience, but its relationship with gut barrier integrity in these conditions remains poorly defined.

Methods: We conducted a cross-sectional study of 56 patients with FM (n = 14), IBS (n = 23), or both (FM + IBS, n = 19). Intestinal barrier function was assessed using serum and fecal zonulin, intestinal fatty acid-binding protein (I-FABP), and the lactulose/mannitol (Lac/Man) urinary excretion test. PC was quantified using the Global Physical Capacity Score (GPCS). Clinical symptoms were evaluated using the Fibromyalgia Impact Questionnaire–Revised (FIQ-R) and IBS Severity Scoring System (IBS-SSS).

Results: FM + IBS patients exhibited the greatest barrier dysfunction, with elevated fecal zonulin and Lac/Man ratio. IBS patients showed increased I-FABP, consistent with epithelial injury, whereas FM patients had milder gastrointestinal symptoms and less pronounced biomarker alterations. Although overall PC scores did not significantly differ across groups, serum zonulin levels showed a strong inverse correlation with GPCS. When stratified by GPCS (cut-off ≥6), patients in the high PC group exhibited significantly lower (p = 0.01) serum zonulin concentrations (48.23 ± 12.44 ng/mL) compared to those in the low PC group (57.63 ± 9.69 ng/mL). Multiple regression analysis confirmed GPCS as an independent predictor of serum zonulin (β = −9.67, p = 0.01), while BMI was not a significant contributor (p = 0.79). Furthermore, urinary indole levels correlated positively with both lactulose excretion and the Lac/Man ratio, supporting the existence of a dysbiosis-permeability feedback loop in these disorders.

Conclusion: Intestinal barrier dysfunction in FM and IBS displays phenotype-specific patterns and is significantly modulated by PC. These findings support the integration of PC assessment into clinical phenotyping and highlight potential targets for personalized management of chronic overlapping pain syndromes.

Open access

 

[Andy]

From the discussion,

"Physical exercise can be viewed as a pathogenically targeted intervention, akin to pharmacological agents, with dose-dependent and phenotype-specific effects. Its ability to modulate intestinal, inflammatory, and functional biomarkers positions it as both a preventive strategy and a primary therapeutic approach, particularly when tailored to individual patient characteristics. This aligns with the principles of precision medicine, which aim to tailor interventions based on individual biological and functional profiles. Integrating non-invasive biomarkers (e.g., zonulin, I-FABP) with physical performance indices, such as the GPCS, could facilitate a shift from symptom-based management to mechanism-driven stratification and care. Phenotypic stratification guided by such biomarkers may enable a precision medicine approach. For example, a patient with FM + IBS, high zonulin, and low GPCS might receive a combined regimen of graded exercise, probiotics targeting zonulin production (e.g., Lactobacillus rhamnosus GG, which has shown efficacy in modulating gut permeability (Chen et al., 2019), and gut-directed nutrients. In contrast, an IBS patient with elevated I-FABP may initially benefit from mast cell modulation and epithelial repair agents, such as zinc carnosine (Mahmood et al., 2007). This paradigm shift from symptom management to mechanistic targeting aligns with emerging frameworks for complex chronic disorders (Clauw, 2014).

While we advocate for the integration of PC assessment and exercise-based interventions, it is imperative to acknowledge that fatigue is a core and often debilitating symptom of FM. Any exercise program must be carefully graded and individualized, starting at a very low intensity and gradually increasing, to avoid exacerbating fatigue and pain. Patient education on pacing and energy conservation strategies is equally crucial to ensure adherence and prevent symptom flare-ups."

 

[Utsikt]

Without longitudinal data, there is no way of knowing which came first, the change in zonulin or the change in physical capacity.

As usual, they don’t care and interpret correlation as one-way causation in favour of the current dogma.

 

[bicentennial]

Zonulin is worth exploring, so let us get back to it, but this paper also reveals something else.

This is the 2nd paper I came across saying a dose of exercise can be prescribed like a drug, if adhered to. How many more?

This paper shows a perseverant determination, to append exercise programs in all the "emerging frameworks for complex chronic conditions": which all such authors know will turn out to be bio-chemically corrected, putting them out of the business.

They cite a 10 year-old paper to "align" this aspirational combo with their high-faluting "paradigm shift from symptom management to mechanistic targeting".

This comes from the same hymn book so lazily incorporated by BACME.

As BACME says, a la BACME:

Here's what the document says about their theoretical basis:

Making sense of the diagnosis, based on the history

Other hypotheses about the underlying mechanisms ... are being developed... new treatments may be developed...

Does supported self-management seem the best way forward... ?

... we may need to consider if they are complimentary and can run in parallel, or perhaps one approach may need to be delayed to a different time so that they run in series.

- we can see the cautiously "adjusted" re-iteration of this hymn book, a la BACME, still pestering a National Health Service, here:

UK BACME ME/CFS Guide to Therapy 2025

It was brought to my attention that BACME have apparently produced a new version of their "guide to therapy" (used by some of the NHS clinics) recently...

... Adobe Acrobat's PDF comparison tool on the 2022 and 2025 versions indicates there are a significant number of changes.

Furthermore, there has been a concerted European effort to mount this combo, aspiring to renew very many obsoleted contracts, eg as referenced by these Italian authors, Russo et al (including their own run-up paper of 2023):

3. Aya V., Flórez A., Perez L., Ramírez J. D. (2021).

Association between physical activity and changes in intestinal microbiota composition: a systematic review.

PloS one 16 (2), e0247039. 10.1371/journal.pone.0247039 DOI PMC PubMed

4. Bianco A., Russo F., Franco I., Riezzo G., Donghia R., Curci R., et al. (2023).

Enhanced physical capacity and gastrointestinal symptom improvement in Southern Italian IBS patients following three months of moderate aerobic exercise.

J. Clin. Med. 12 (21), 6786. 10.3390/jcm12216786 DOI PMC PubMed

5. Bilski J., Mazur-Bialy A., Magierowski M., Kwiecien S., Wojcik D., Ptak-Belowska A., et al. (2018).

Exploiting significance of physical exercise in prevention of gastrointestinal disorders.

Curr. Pharm. Des. 24 (18), 1916–1925. 10.2174/1381612824666180522103759 DOI PubMed

There are 62 references altogether, so I have still to find out if the authors also referenced the real zonulin researchers in Spain and the USA: eg as found in the MISC - C children who were not amenable to exercise, being hospitalised, at the time

The link above to the current exercise promotion yields Frontiers in Physiology's unhandled error, so I used another link which my bolshy browser is allowed to access, except for the link to 62 references - so i only got the 1st 5 references for Physical Capacity Modulates.....(everything, forever and a day, any where, any way, rah rah rah)

Maybe - during the preparation for some Clinical Knowledge Summary (belatedly outsourced by NICE) - maybe it was this kind of promotion that persuaded NICE to silently remove from the British National Formulary: all the life-saving special medical feeds for all the unspecified conditions.

And maybe it persuaded NICE to simultaneously decline a Review of their ME / CFS Nutrition & Dietetic Recommendation, leaving BACME to trip up all over the floor, instead.

While the hymn book began to advise its own version is nearly ready for a NICE ME / CFS Guideline Review - I read it somewhere, not long ago.