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

A new study from Adelaide University has identified measurable biological effects associated with salcaprozate sodium (SNAC), the absorption-enhancing ingredient that enables semaglutide to work in pill form. The research, appearing in the Journal of Controlled Release, is the first in vivo study to systematically evaluate the effects of repeated SNAC exposure on gut microbiota composition, function, and metabolic outcomes.

Every Wegovy tablet contains semaglutide, the molecule that mimics a gut hormone, and SNAC, a compound doing the work of ferrying semaglutide through the stomach wall and into the bloodstream. Without SNAC, the pill would not work. Semaglutide, left to its own devices in the acidic chaos of the gut, would be destroyed before it reached circulation. When injected, semaglutide enters the bloodstream directly. In tablet form, it relies on SNAC to protect it from enzymatic degradation in the stomach and enable absorption into the bloodstream. Oral semaglutide achieves only 0.4 to 1 per cent bioavailability; the rest of the drug is lost, and the SNAC that enabled it to work passes, largely intact, into the small intestine and colon.

A team at the University of South Australia gave rats daily doses of SNAC alone, semaglutide alone, or the combination, then examined their gut microbiota, liver, faecal chemistry, and blood for markers of inflammation over 21 days. The doses were calculated to approximate human therapeutic exposures. In an animal model extending 21 days, researchers identified lower levels of beneficial gut bacteria that help break down dietary fiber, reduced short-chain fatty acids which protect the gut lining and help regulate inflammation, higher levels of blood inflammatory markers, an increase in liver weight which can reflect low-grade inflammation, a smaller cecum (the part of the intestine where gut bacteria break down fiber and produce protective compounds), and reduced levels of a brain-derived protein associated with cognitive impairment.

The microbiota results showed that SNAC did not reduce the sheer number of microbial species, the metric researchers typically use to gauge gut health. Overall diversity held steady. What shifted, significantly, was the composition. Two families of bacteria that ferment dietary fibre and produce protective short-chain fatty acids, Muribaculaceae and Bacteroidaceae, were depleted by 62 per cent and 77 per cent respectively in the SNAC-only group compared with controls. Meanwhile Desulfovibrionaceae, a family associated with inflammatory conditions, expanded roughly sevenfold. Faecal butyrate, the fatty acid that feeds the cells lining the colon and keeps the gut wall intact, fell by 77 per cent.

SNAC-treated rats showed a 12.9 per cent increase in liver weight and a 30 per cent reduction in caecum mass, the intestinal chamber where most microbial fermentation happens. Neither change was seen in rats given semaglutide alone. Plasma cytokine readings added another layer. TNF-alpha, a central marker of systemic inflammation, was elevated by 70 per cent in the SNAC group. Animals given the semaglutide-SNAC combination showed a 25 per cent rise in interleukin-6 and, more unexpectedly, an 85 per cent suppression of brain-derived neurotrophic factor, a protein involved in neuroplasticity and cognitive function.

A PhD researcher in the School of Pharmacy and Biomedical Sciences and colleagues propose that SNAC's membrane-disrupting properties, which in the stomach serve to open pathways for drug absorption, may continue to act on the densely colonised microbial communities in the lower gut. SNAC essentially has a second career downstream, one nobody designed it for.

The study's senior author is precise about the limits of what the data show. "Our findings do not prove that SNAC causes harm in humans," he says. "However, they do show that the ingredient enabling these tablets to work may have adverse biological effects beyond drug absorption." The study used healthy rats, not humans, not people with obesity or diabetes. Six animals per group is a small sample. The 21-day window is enough to capture microbiota restructuring but not to say whether the changes persist or reverse when treatment stops.

SNAC has been quietly present in oral drug formulations for years. It carries FDA approval, holds "generally regarded as safe" status, and until recently attracted little scientific scrutiny of its own. With the United States approving the Wegovy tablet late last year, and expectations that it will be cheaper and more convenient than injections, long-term daily exposure to SNAC is likely to increase substantially.

Globally, about 890 million people and 160 children live with obesity, equivalent to one in eight people worldwide. The United States has the highest obesity rate among OECD countries, with 43% of people aged 15+ living with the condition; Australia ranks sixth at 31%, above the OECD average of 25%. In Australia, prescriptions for drugs such as Ozempic and Wegovy have risen sharply in recent years.

A PhD candidate says the rapid growth in oral obesity treatments that utilize SNAC makes it critical to understand its full biological impact, in order to mitigate any longer-term adverse health effects. "Obesity is a complex, chronic disease with serious health consequences. These medicines are highly effective and are helping many people," the researcher says. "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."

A senior research fellow says that as these are early results from animal models, not humans, the findings should be interpreted carefully and highlight an important research gap. "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."