Oral Semaglutide Absorption Enhancer SNAC Linked to Gut Microbiota Changes in Animal Study

Researchers at Adelaide University have identified potential biological effects associated with salcaprozate sodium (SNAC), the absorption-enhancing compound used in oral formulations of semaglutide, the active ingredient in Wegovy and Ozempic. The findings, published in the Journal of Controlled Release, represent the first in vivo study to systematically investigate how repeated exposure to SNAC affects gut microbiota, metabolic function, and related health markers.

Using an animal model over a 21-day period, scientists observed several notable changes. SNAC monotherapy 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 group, 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). Additionally, researchers observed a smaller cecum — the part of the intestine where gut bacteria break down fiber and produce protective compounds.

The study does not prove that SNAC is harmful. However, the results indicate that the absorption enhancer may influence the body in ways that go beyond simply allowing semaglutide to function as a pill. Semaglutide depends on SNAC to shield it from being broken down by stomach enzymes and to help it pass into the bloodstream. Without SNAC, oral semaglutide would not be effective.

The United States approved a tablet version of Wegovy late last year. Because pills are often seen as more convenient and potentially less expensive than injections, daily exposure to SNAC could rise significantly as more people choose oral options. Rates of gastrointestinal side effects — the leading cause of discontinuation — are higher with oral vs injectable semaglutide.

Obesity remains a major global health issue. Around 890 million adults and 160 million children worldwide are living with obesity, representing roughly one in eight people. Among OECD countries, the United States has the highest rate, with 43% of people age 15 and older affected. Australia ranks sixth at 31%, above the OECD average of 25%. Prescriptions for medications such as Ozempic and Wegovy have climbed rapidly in Australia in recent years, reflecting broader global trends.

Lead author Amin Ariaee, a PhD candidate at Adelaide University, said the rapid expansion of oral obesity treatments that utilize SNAC makes it important to fully understand how every ingredient in these medications affects the body over time. "Obesity is a complex, chronic disease with serious health consequences. These medicines are highly effective and are helping many people. But as oral versions become more widely used, we need to understand what repeated, long-term exposure to all ingredients in the pill means for the body — not just the active drug. While SNAC enables semaglutide to be taken as a tablet, our study found that it was also associated with shifts in potentially harmful gut bacteria, elevated inflammatory markers and depletion of proteins linked to cognitive impairment. These findings warrant further investigation."

Senior Research Fellow Dr. Paul Joyce emphasized that the findings come from animal research and should be interpreted with caution. "Importantly, our findings do not prove that SNAC causes harm in humans. However, they do show that the ingredient enabling these tablets to work may have adverse biological effects beyond drug absorption. These medicines are typically taken daily and often for long periods. As their use expands globally, it becomes increasingly important to evaluate all components of these therapies, not just the active compound."

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. 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.

The study was financially supported by The Hospital Research Foundation Group.