TOPLINE:

Salcaprozate sodium (SNAC), the absorption enhancer present in oral semaglutide, was associated with reduced abundance of certain fiber-fermenting gut bacteria, lower fecal butyrate levels, elevated circulating inflammatory markers, decreased levels of a brain-derived neurotrophic factor, and increased liver weight, according to a preclinical analysis.

METHODOLOGY:

• Oral semaglutide is paired with SNAC to protect the drug in the stomach and enhance absorption. Rates of gastrointestinal side effects — the leading cause of discontinuation — are higher with oral vs injectable semaglutide.
• Researchers conducted an in vivo study to evaluate the effects of chronic SNAC exposure on gut microbiota composition, function, and host metabolic outcomes.
• Healthy male Sprague-Dawley rats were randomized to receive oral gavage of semaglutide alone, SNAC alone, semaglutide plus SNAC, or phosphate-buffered saline (control) daily for 21 days.
• Fecal microbiota composition was analyzed at baseline and day 21 using 16S ribosomal RNA gene sequencing; fecal short-chain fatty acids (acetic, propionic, and butyric) were measured using gas chromatography-mass spectrometry.
• Plasma levels of interleukin-6 (IL-6), TNF-alpha, and brain-derived neurotrophic factor were quantified using enzyme-linked immunosorbent assay.

TAKEAWAY:

• SNAC monotherapy vs control treatment was associated with significant reductions in key fiber-fermenting bacterial families — Muribaculaceae (-62%; P = .0011) and Bacteroidaceae (-77%; P = .0027) – and a sevenfold increase in Desulfovibrionaceae (P = .039), taxa previously linked to inflammatory conditions.
• After 21 days, fecal butyric acid concentrations were reduced by 77% with SNAC alone (P = .010) and by 75% with SNAC plus semaglutide (P = .018), consistent with the loss of key butyrate-producing bacteria.
• Compared with controls, SNAC exposure was associated with a 70% increase in plasma TNF-alpha levels (P = .0009); in the SNAC plus semaglutide, IL-6 levels increased and brain-derived neurotrophic factor levels decreased.
• Liver weight increased by 12.9% in the SNAC group compared with control group (P = .029).

IN PRACTICE:

“Given that oral [semaglutide] requires daily SNAC exposure over extended periods, these findings highlight the importance of evaluating microbiome and inflammatory marker changes in patient populations receiving oral GLP-1 receptor agonist therapy,” the authors of the study wrote.

SOURCE:

The study was led by Amin Ariaee, Translational Nanomedicines and Biotherapeutics, University of South Australia, Adelaide, Australia. It was published online in the Journal of Controlled Release.

LIMITATIONS: 

The findings were derived from a short-term preclinical study in healthy animals and may not reflect responses in patients with disease states (obesity or type 2 diabetes) where oral semaglutide is clinically used. The 21-day treatment duration did not address the persistence or reversibility of observed associations after discontinuation.

DISCLOSURES:

The study was financially supported by The Hospital Research Foundation Group. The authors disclosed having no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.