GLP-1 Drugs May Boost Mood via the Microbiome
GLP-1 therapy reduced depression-like behaviors in mice by altering the gut microbiome.
Could antidepressant effects be among the unanticipated benefits of glucagon-like peptide (GLP-1) therapies?
In a recent study, researchers at Southeast University and Huazhong University of Science and Technology found that GLP-1 therapy alleviates depression-like behaviors by altering the gut microbiome. The findings were recently published in Cell Host & Microbe.
The unclear relationship between GLP-1s and mood
Following a meal, gut cells naturally produce GLP-1. The hormone mediates satiety by slowing gastric emptying and signaling to the brain, and it also plays a role in blood glucose control.
GLP-1 receptor agonists were developed based on this knowledge, aiming to mimic the hormone's natural function to treat conditions such as diabetes and chronic obesity.
Since the approval of semaglutide for weight loss in 2021, widespread use of GLP-1 receptor agonists has skyrocketed.
This has revealed both hidden risks and rewards.
As well as turning down the dial on “food noise”, some users have reported positive effects on mood, while others feel emotionally flat.
Studies have provided conflicting evidence on the neuropsychiatric effects of GLP-1s, reflecting broader uncertainty about the class and its long-term effects.
“Some studies reported antidepressant effects of GLP-1 agonists, while others suggested increased risk of depression or anxiety,” commented Dr. Yong Gui Yuan, head of psychosomatics and psychiatry at Southeast University.
Given that obese individuals face a bidirectional relationship with mental health conditions, as well as potential for GLP-1 misuse among individuals with eating disorders, it is important to characterize their impact on mental health to both maximize benefit and mitigate harm.
Uncovering a GLP-1 receptor-independent pathway
The researchers set out to understand the relationship between GLP-1 therapies and depression, specifically whether they affect the gut microbiome to modulate mood.
Changes in gut microbiota composition have been observed across multiple mental health conditions, and several studies have demonstrated its significance in depression.
The team began by analyzing blood samples from 70 participants, obtained under fasting conditions. They found that individuals with major depressive disorders (MDD) had lower levels of GLP-1 hormone in their blood compared to healthy controls, and that increasingly lower GLP-1 levels were associated with worsening depression and anxiety scores.
In mouse models of chronic unpredictable stress (CUS) the same correlation was observed.
This prompted the team to investigate whether GLP-1 activity “supplementation” with liraglutide could be used to treat depression.
Interestingly, treated CUS mice did not benefit from reduced appetite or weight loss, the hallmarks of GLP-1 use, but did exhibit improvements in traits of depression. These findings suggested that any antidepressant-like effects are independent of the drugs' metabolic actions.
Researchers then pharmacologically blocked GLP-1 receptor signaling to home in on the potential mechanism. Liraglutide continued to alleviate depression-like behaviors, pointing to a GLP-1 receptor-independent pathway. When antidepressant effects persisted after administering the therapy to global GLP-1 receptor knockout mice, their suspicions were confirmed.
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GLP-1s, the gut microbiome, and mood
Seeking to determine exactly how the drug induced these effects, the researchers used fluorescently tagged liraglutide to track its distribution.
“We observed that when we systemically administered liraglutide to the mice, it accumulated predominantly in the intestine rather than the brain,” noted Dr. Bing Han, senior research fellow.
This led the team to hypothesize that the antidepressant effects of liraglutide could be microbiome-mediated. This theory was supported when the liraglutide's suspected benefit disappeared in both gut microbiome-depleted and germ-free mice.
The researchers then delved deeper, using fecal sample analysis, to investigate specific microbiome changes. Liraglutide was found to restore levels of Lactobacillus delbrueckii, a gut microbe reduced in CUS models. Increasing Lactobacillus levels has previously been shown to improve MDD symptoms in patients.
Microbiome-depleted CUS mice were then given fecal microbiota transplants from untreated and liraglutide-treated CUS donors. In treated donors, L. delbrueckii levels increased, and depression-like behaviors improved.
Fecal and plasma metabolomics were later used to map the underlying sequence of events. The analysis suggested that liraglutide alters the metabolic activity of L. delbrueckii, indirectly promoting the production of 2-arachidonoylglycerol (2-AG), a chemical messenger involved in mood and emotional regulation.
Finally, they had connected the dots between liraglutide, the microbiome, and mood.
GLP-1s show promise for metabolic and mental health
In questioning how GLP-1 therapies may alter mood, this study not only provided preclinical causal evidence but also a potential therapeutic target.
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The pathways described could also serve as the foundations for microbiome-mediated antidepressant therapies.
Having been conducted in male mice, the results would need to be replicated through human gut microbiota research, given both species and sex differences in gastrointestinal anatomy and physiology, microbiome diversity, and neurobiology.
Although semaglutide administration demonstrated a pattern similar to liraglutide in this study, future research would benefit from investigating other GLP-1s to confirm any class-wide mechanisms.
The study provides early evidence behind the mental health benefits, not just metabolic benefits, that GLP-1 therapies may provide.
Reference: Bian L, Cai Y, Zhang Y, et al. Microbiota-driven gut-brain signaling underlies antidepressant effects of a GLP-1 analog. Cell Host Microbe. 2026;34(6):1000-1017.e5. doi: 10.1016/j.chom.2026.05.003
This article is a rework of a press release issued by Cell Press. Material has been edited for length and content.
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