GI Symptoms May Be Characteristic of a Multiple Sclerosis Prodrome, Study Suggests

Individuals with multiple sclerosis (MS) had more clinical visits for gastrointestinal (GI) symptoms and filled more prescriptions for drugs that treat GI-related disorders during the 5 years prior to an MS diagnosis than a matched population without MS, suggesting that gut-related issues may be a prodromal feature of the disease, according to authors of a new study published in Annals of Clinal and Translational Neurology.

A strong body of evidence suggests a prodromal phase associated with MS that presents as a range of nonspecific “nonclassical” symptoms, investigators wrote. Recent studies have demonstrated a connection between the gut microbiome and the development of MS, they explained, leading the GI community to question the potential for GI symptoms as characteristic of the prodromal phase. There is little published research on the relationship between GI symptoms and MS onset and beginning to fill this void would provide novel insights into the pathology of the disease as well as evidence to support earlier diagnosis and treatment.

Canadian investigator Fardowsa LA Yusuf, University of British Columbia, and colleagues investigated GI-related physician visits and drug dispensation during the 5 years before an initial recorded demyelinating event or onset of MS symptoms.

Yusuf et al tapped linked health administrative and clinical data from April 1991 through December 2013 for individuals residing in British Columbia to identify 2 study cohorts: Primary analysis focused on an administrative cohort of MS cases based on a first demyelinating disease claim (n=6836) and secondary analysis evaluated a smaller clinical cohort of cases diagnosed at an MS clinic (n=966). Up to 5 controls were matched to each MS case by age, sex, calendar year and geography for a matched administrative cohort of 31 865 individuals and a matched clinical cohort of 4534.

FINDINGS

Primary analysis

In the administrative cohort, women comprised 73% of MS cases and controls and the mean age at index date was 44 years. The investigators found that gastritis and duodenitis were the GI-related conditions most frequently associated with a clinical visit in the 5 years leading to an initial demyelinating event (52.3 visits per 1000 person-years) followed by esophageal disorders (23.3 visits per 1000 person-years). When they compared number of physician visits between MS cases and controls, the former were 42% higher for gastritis and duodenitis and 46% higher for disorders of the esophagus. Even higher among individuals with MS vs matched controls were visits for a range of other intestinal or peritoneal disorders (eg, constipation, irritable bowel syndrome), at 74%, according to the findings.

The research team's analysis of drug classes revealed that among individuals with MS, the highest risk was for prescriptions to treat gastroesophageal reflux disease (GERD) and peptic ulcer (46 prescriptions per 1000 person-years [PY] vs 33.9 for controls), a rate 35% higher for MS cases.

Secondary analysis

The clinical cohort (966 individuals with MS matched with 4534 controls) was also approximately 75% women, however the average age at index date was 37 years, 7 years younger than those in the administrative cohort. Similar to the findings in the latter cohort, Yusuf and colleagues reported gastritis and duodenitis as the GI-related events most frequently associated with a physician visit (26.1 visits/1000 PY) in the 5 years before symptom onset in MS cases and agents indicated for the treatment of GERD and peptic ulcer disease the most frequently dispensed medications (124.7 prescriptions/1000 PY).

Writing in the conclusion, Yusuf and colleagues noted other neurologic conditions, and specifically Parkinson disease (PD), known to be preceded by "gut-related issues." "Constipation can occur 5–10 years before classical motor onset PD and is well-recognized as a prodromal feature of PD. Combined with other observations, this has led to the suggestion of a gut origin and involvement of the gut microbiota for at least some portion of persons with PD,” wrote Yusuf and team. “Although our study did not directly examine the role of the gut microbiota in MS pathophysiology during the prodromal period, dysregulation of the gut–brain axis is one potential hypothesis for our findings.”

Among the study's limitations the authors note the small size of the clinical sample which may have limited detection of MS cases vs controls; the inability to adjust for potential confounding variables, including relevant comorbidities before the study period; and lack of access to data on use of over-the-counter GI medications.

While the investigators call for additional studies to deepen understanding of the relationships observed in their study, they believe the findings support a role for GI symptoms as disease precursors in MS.

Source: Yusuf FLA, Zhu F, Evans C, et al. Gastrointestinal conditions in multiple sclerosis prodrome. Ann Clin Transl Neurol. Published online December 19, 2023. doi:10.1002/acn3.51945