Research suggests SNAC exposure alters gut microbiome and inflammatory markers in animal study — Evidence Review

A new animal study suggests the absorption enhancer SNAC, used in oral semaglutide tablets, may affect gut bacteria and inflammation-related signals beyond its intended role. Most existing research on semaglutide’s safety focuses on the active drug, not SNAC, and does not report the same gut microbiome changes, highlighting a research gap identified by the Adelaide University study.

• Prior studies have established semaglutide’s general safety, primarily noting gastrointestinal side effects, but have not systematically evaluated SNAC’s independent biological effects, especially on the gut microbiome or inflammation 1 2 5.
• Literature confirms semaglutide can cause gastrointestinal disturbances, and while short-term risks are well-characterized, the long-term impact of daily SNAC exposure on gut health or systemic inflammation remains largely unexplored 1 2 5.
• Some studies have raised concerns about adverse events with GLP-1 agonists, including psychiatric and misuse risks, but none directly assess SNAC’s unique contribution to these or other biological effects 3 4.

Study Overview and Key Findings

Oral formulations of semaglutide, a GLP-1 receptor agonist for weight management and diabetes, rely on salcaprozate sodium (SNAC) to aid absorption in the digestive tract. As the use of oral semaglutide expands globally, understanding the long-term safety of all pill components becomes increasingly important. The recent Adelaide University animal study is the first to systematically examine how repeated SNAC exposure may influence gut microbes and broader biological pathways, raising questions about the safety of chronic SNAC ingestion not previously addressed in human trials or post-marketing surveillance.

Below is a summary of the core study metadata:

Property	Value
Study Year	2026
Organization	Adelaide University
Journal Name	Journal of Controlled Release
Authors	Amin Ariaee, Karim Noueihad, Alex Hunter, Anthony Wignall, Hannah R. Wardill, Maya Davies, Clive A. Prestidge, Paul Joyce
Population	Animal study
Sample Size	n=21 days
Methods	Animal Study
Outcome	Gut microbiome changes, inflammatory markers, liver weight
Results	SNAC exposure linked to gut microbiome shifts and inflammation

Key Study Findings:

• Repeated daily exposure to SNAC over 21 days in animals led to a reduction in beneficial gut bacteria involved in fiber breakdown.
• There were lower levels of short-chain fatty acids (important for gut health), higher inflammatory markers in blood, increased liver weight, a smaller cecum, and reduced levels of a brain-derived protein linked to cognitive function.
• The findings suggest SNAC may influence the gut ecosystem and inflammation, beyond its established role in drug absorption, but causation and human relevance remain unproven.

Literature Review: Related Studies

To understand the broader context and how this study fits with existing research, we searched the Consensus paper database, which contains over 200 million research papers. The following search queries were used to identify relevant studies:

1. SNAC gut microbiome inflammation
2. semaglutide ingredient safety concerns
3. Ozempic SNAC effects research

Below, we summarize the main themes emerging from related studies and how they compare to the new findings.

Topic	Key Findings
What are the established safety and side effects of semaglutide and its formulations?	- Semaglutide is associated mainly with gastrointestinal side effects, such as nausea and diarrhea, with risk decreasing over time 1 2 5. - No unexpected safety issues have emerged in large clinical trials or real-world data for semaglutide, with both oral and injectable forms showing a similar safety profile 2 5.
How do SNAC and other absorption enhancers work and what are their effects?	- SNAC enables oral absorption of peptide drugs by creating transient membrane defects, facilitating semaglutide entry into the bloodstream 6. - The biological effects of SNAC independent of its absorption-enhancing role, particularly on gut microbiota or inflammation, have not been systematically studied in humans 6.
Are there concerns about long-term or off-target effects, including microbiome impact?	- Existing studies have not specifically addressed the long-term impact of SNAC on the gut microbiome, inflammation, or systemic health outcomes 1 2 5. - Most safety data focuses on semaglutide itself; the new animal study raises novel questions about daily SNAC exposure not previously evaluated [current study].
What other adverse events or concerns have been reported with semaglutide/GLP-1 drugs?	- Psychiatric and misuse-related adverse events are rare but have been reported, though not directly linked to SNAC 3 4. - Cholelithiasis (gallstones) risk is higher with semaglutide, but cardiovascular and other serious adverse events are similar to placebo 2 5.

What are the established safety and side effects of semaglutide and its formulations?

The main body of evidence from clinical trials and observational studies indicates that semaglutide, both oral and injectable, is generally safe and well-tolerated for diabetes and weight loss. Gastrointestinal disturbances, such as nausea, vomiting, and diarrhea, are the most common side effects and tend to decrease with continued therapy. Notably, these studies have not focused on SNAC’s independent effects.

• Large-scale clinical trials show similar safety profiles for oral and injectable semaglutide 2 5.
• Gastrointestinal adverse events are common but usually mild and transient 1 2 5.
• Serious risks, such as pancreatitis or thyroid cancer, are rare and not conclusively linked to semaglutide 2 5.
• Most studies do not distinguish between effects of the active drug and those of absorption enhancers like SNAC 1 2.

How do SNAC and other absorption enhancers work and what are their effects?

SNAC is essential for the oral delivery of semaglutide, enabling it to survive the harsh stomach environment and be absorbed into the bloodstream. Recent mechanistic research shows SNAC facilitates absorption by creating temporary, permeation-enhancer-filled membrane defects. However, its long-term biological impact, especially on the gut microbiome or inflammation, has not been assessed in humans.

• Mechanistic studies confirm SNAC increases membrane permeability for peptide drugs like semaglutide 6.
• SNAC’s absorption-enhancing effect is transient and localized, but its repeated, daily use over months or years has not been systematically studied for off-target effects 6.
• The new animal study is the first to suggest possible broader biological effects of SNAC beyond absorption [current study].
• No human data exist on SNAC’s impact on gut bacteria or inflammatory pathways 6.

Are there concerns about long-term or off-target effects, including microbiome impact?

While semaglutide’s safety has been established in short- and medium-term use, and adverse event profiles are well characterized, the specific effects of SNAC on gut microbes or systemic inflammation have not been addressed in prior research. The Adelaide University study highlights a gap, as it is the first to show potential microbiome and inflammatory changes with repeated SNAC exposure in animals.

• No clinical studies have directly assessed the long-term effects of SNAC on the gut microbiome 1 2 5.
• Existing safety data are limited to semaglutide’s known pharmacological effects 1 2 5.
• The new findings suggest a need for further research on the potential systemic impact of chronic SNAC exposure [current study].
• The translation of animal findings to human outcomes remains uncertain and requires future investigation.

What other adverse events or concerns have been reported with semaglutide/GLP-1 drugs?

Some studies and pharmacovigilance reports have identified rare but notable adverse events with semaglutide and other GLP-1 agonists, such as psychiatric symptoms and potential for misuse. However, these are not directly related to SNAC, and no evidence currently links SNAC to such outcomes.

• Psychiatric adverse events (e.g., depression, anxiety) occur in a small percentage of reports for GLP-1 agonists, but are not attributed to SNAC 3.
• Misuse or abuse potential appears higher for semaglutide compared to some other drugs, but the role of SNAC in this context is unknown 4.
• Cholelithiasis is more common with semaglutide, but cardiovascular outcomes are not adversely affected 2 5.
• There is insufficient evidence to implicate SNAC in any non-absorption-related adverse events reported to date 1 2 3 4 5.

Future Research Questions

The new study raises important questions about the long-term safety of SNAC, especially as oral semaglutide use increases. Since most safety data focus on the active drug rather than the absorption enhancer, targeted research is needed to clarify SNAC’s independent effects on the gut microbiome, inflammation, and systemic health. Addressing these gaps will help inform safe long-term use of oral GLP-1 medications.

Research Question	Relevance
What are the long-term effects of daily SNAC exposure on the human gut microbiome?	Animal studies indicate possible microbiome changes, but no data exist in humans; understanding this is crucial as SNAC use becomes more common [current study].
Does SNAC contribute to systemic inflammation in people taking oral semaglutide?	The animal study found increased inflammatory markers with SNAC, but it is unknown whether similar effects occur in humans or impact long-term health [current study, 1,2].
Are there cognitive or neurological risks associated with prolonged SNAC consumption?	Reduced brain-derived proteins were observed in animals, raising questions about potential neurological effects in humans that have not been studied [current study].
How does SNAC affect the efficacy and safety profile of oral semaglutide over years of treatment?	Most safety data focus on short-term use; the cumulative impact of SNAC, especially as more patients use oral formulations daily for extended periods, is unknown 2 5.
Do different doses of SNAC have distinct biological effects in the gut and beyond?	Dose-response relationships have not been established; understanding this could help optimize oral semaglutide formulations for safety [current study].