How does the new generation of obesity and diabetes treatments modulate the microbiome? We gathered the most up-to-date evidence to support the interpretation of your upcoming sequencing tests using 16S rRNA.

How do GLP-1 analogs influence microbiome composition?

A systematic review study indicates that drugs such as Liraglutide, Semaglutide, and Dulaglutide promote a significant restructuring of the microbiota. There is a trend toward an increase in genera associated with metabolic health, such as Akkermansia and Lactobacillus, along with a reduction in potentially inflammatory phyla.

It is important to note that, while metabolic effects are well established in humans, many detailed mappings of specific genera still largely derive from experimental (animal) models.

Does Tirzepatide present differences in intestinal modulation?

Yes. As a dual agonist (GLP-1/GIP), Tirzepatide has demonstrated a robust capacity to restore microbiota homeostasis. Recent data suggest that it increases the abundance of genera such as Clostridium_sensu_stricto_1 and Romboutsia.

These groups are associated with the production of protective metabolites, such as short-chain fatty acids (SCFAs), with benefits extending even to renal health (gut–kidney axis).

Is there a direct relationship between these bacterial changes and weight loss?

Evidence suggests yes. Microbiota modulation appears to mediate, at least in part, the metabolic effects of these drugs. Treatment tends to “mimic” the microbiota profile of lean individuals.

In experimental models, when the microbiota is suppressed with antibiotics, some metabolic effects are attenuated, suggesting that bacteria act as active mediators in the weight loss process rather than passive bystanders.

But is it the drug or the diet that changes the microbiota?

This is currently the most debated point in the literature. It is extremely difficult to isolate the direct effect of GLP-1 analogs from the indirect effect caused by changes in eating behavior.

It is important to highlight that these drugs reduce appetite and alter food preferences. A patient who begins consuming less saturated fat and more fiber, for example, will improve their microbiota simply due to changes in available substrates.

Conclusion

The improvements observed in gut microbiota tests should be interpreted as the result of the drug + diet interaction.

Medication creates a favorable environment, but it is nutritional support (fiber and polyphenols) that provides the substrate for consolidating a truly resilient microbiota.

What should be evaluated in a 16S rRNA report for a patient under treatment?

When analyzing results, professionals should pay attention to:

Increase in Diversity:
Although Semaglutide may cause initial fluctuations, the long-term goal is the recovery of species richness (Shannon index).

Abundance of SCFA Producers:
Check whether genera such as Faecalibacterium and Bifidobacterium are increasing, as they enhance the anti-inflammatory effects of the drug through butyrate and acetate production.

Reduction of Proteobacteria:
A decrease in this phylum is a strong indicator that systemic inflammatory load (LPS) is declining, signaling restoration of intestinal permeability.

Sources

Ma J, Tao M, Zhang W, Zhou L, Zhang H, Li F, Zhang H, Yao D, Lu W and Wang M (2025). Tirzepatide modulates gut microbiota homeostasis to protect against diabetic kidney disease. Front. Mol. Biosci., 12:1715024. doi: 10.3389/fmolb.2025.1715024

Gofron, K.K.; Wasilewski, A.; Małgorzewicz, S. Effects of GLP-1 Analogues and Agonists on the Gut Microbiota: A Systematic Review. Nutrients. 2025, 17:1303. https://doi.org/10.3390/nu17081303