Editor’s Note: The immune system is a viciously complex topic; this review essentially scratches the surface of some of these effects, that GLP-1 meds have on the immune system. Special thanks to my friend in immunology who edited & helped make this post happen.
GLP-1.
Just say that out loud now and instantly the whole room knows what you’re talking about. Despite being originally developed for diabetes, they’ve become synonymous with weight loss at this point. But in 2026 it feels like we’re approaching an inflection point as millions of people have used a GLP-1 medication and are reporting all sorts of benefits beyond just weight loss and control of their diabetes. Anecdotes are all over social media, but more importantly pharmaceutical companies are taking note of these anecdotes and starting to run trials for a plethora of indications. Recently, Eli Lilly reported that tirzepatide combined with a monoclonal antibody (Taltz) can have additive effects for control and reduction of symptoms of plaque psoriasis and psoriatic arthritis, two notoriously difficult to treat autoimmune diseases.
But it is more than that, I’ve discussed the cardiovascular and renal benefits of tirzepatide when the SURPASS-CVOT data was published (GIP: SURPASSing all expectations) But now we have trials for asthma, depression, bipolar, schizophrenia, substance use disorders, peripheral arterial disease, back pain, osteoarthritis and even more autoimmune diseases! In fact, the inspiration for this article comes from both seeing remarkable anecdotal accounts from people on these drugs, but also the recent trials of Tirzepatide and Taltz showing actual benefit!
How could a hormone produced in our gut that regulates appetite, satiety and glucose levels be so deeply intertwined to our biology have such multi-factorial effects?
In this article I hope to articulate how this is the case. We’ll focus on the gut, our immune system and the brain, or more simply what’s called the Gut-Immune-Brain axis.
While GLP-1 drugs were originally designed for diabetes and obesity, clinical data show they significantly reduce markers of inflammation (like C-reactive protein, or CRP) remarkably quickly, usually long before any significant weight loss occurs.
This is important because weight loss itself can reduce inflammation. Adipose tissue is inherently pro-inflammatory, so losing weight naturally lowers inflammatory markers. However, the speed at which these changes occur with GLP-1 therapies suggests that at least part of the effect may be independent of weight loss or glucose control.
It highlights that GLP-1 is no longer viewed just as a "gut hormone" but as a systemic regulator of immune and inflammatory responses. This has implications for everything from infections to heart attacks and even cancer. I will try and keep the science in plain terms, but as I noted, the immune system is very complex.
Let’s start with the place where GLP-1 is produced, in the intestines we have what are called enteroendocrine cells, specifically called L-cells. These cells have a myriad of functions including sensing of the various nutrients we ingest (carbs, fats, amino acids) along with detection of pathogens and inflammatory signals. Sensing of these various things then leads to varying downstream reactions as shown in this
For our purposes we want to focus on the anti-inflammatory aspect. One specific receptor exists on L-cells called TLR-4, Toll-like receptor 4 is one way L-cells can detect pathogens. It seems in pre-clinical models that when these L-cells are exposed to perceived toxins, such as lipopolysaccharides from certain bacteria that this triggers a surge in endogenous GLP-1 which is perhaps the body’s way of using GLP-1 as an anti-inflammatory hormone or perhaps as a brake pedal on the inflammatory response in general.
When we’re sick with an illness our body plays a delicate orchestra to balance producing enough of an immune and inflammatory response to deal with the illness, while also producing enough of an anti-inflammatory effect to not allow our immune system to damage our body. We have a term for this when the body’s immune response goes into overdrive, cytokine storm, which is an uncontrolled inflammatory response from the immune system that overwhelms our body’s ability to compensate, and it contributes to why some people can rapidly die from certain infections or illnesses.
What’s even more interesting is that GLP-1 levels correlate to sepsis mortality outcomes in the hospital. Those with higher GLP-1 levels tend to do worse and die more often suggesting the body is desperately trying to clamp down on inflammation. Remember, oftentimes it’s not the infection itself that kills, it’s the body’s own systemic response to the infection itself.
What can GLP-1 and GLP-1RA meds do to help?
We have cells along the lining of our gut called Intestinal intraepithelial lymphocytes or IELs. These specialized immune cells express GLP-1 receptors and when GLP-1(whether from native production or GLP-1 agonists) activates these IELs via GLP-1R it helps to suppress localized T-cell induced inflammation. And it appears endogenous GLP-1 does just that, it helps locally and temporarily to help suppress T-cell inflammation, the problem is that the half-life of endogenous GLP-1 is just a few minutes, so any systemic effects are somewhat muted. But what happens when you add a GLP-1RA? Now the signaling is prolonged for days on end, acting almost like an immunological brake check on inflammation.
And we have some trial evidence to back this up based on the trials of tirzepatide in patients with psoriatic arthritis and some hypothetical/pre-clinical data that it’ll do the same for Crohn’s disease and ulcerative colitis as well.
Eli Lilly has been at the forefront of this anti-inflammatory mechanism of GLP-1 meds. Recently they published and presented data on the combination of Taltz which is a monoclonal antibody that targets interleukin 17A(IL-17a) and tirzepatide for patients with psoriatic arthritis. Remarkably there was a clear separation in what is called ACR50 in just the first 4 weeks of treatment in the patients taking tirzepatide plus Taltz together.
Red arrow indicates significant difference seen in first four weeks, while patients had only lost 2.7% of their body weight, suggesting effect is independent of weight loss.
This effect persisted until the end of the trial at 36 weeks, as the combination consistently improved symptoms better than Taltz alone. This particular measure represents at least a 50% improvement in rheumatoid arthritis (RA) or psoriatic arthritis symptoms, based on the American College of Rheumatology criteria. It measures a 50% reduction in tender and swollen joint counts, plus 50% improvement in 3 of 5 related criteria. Further reinforcing this early and rapid inflammation reduction is that a lab measure called hsCRP, or high sensitivity C-reactive protein, was significantly reduced at 4 weeks as well, when patients had only lost 2.7% of their body weight. This marker is sort of a broad marker of systemic inflammation. Overall, after 36 weeks hsCRP was reduced on average by -1.79mg/L with the combination vs -0.44mg/L with just Taltz alone (Treatment difference (95% CI) −1.35 (−2.10 to −0.61) p<0.001) All of this points to an early and then sustained reduction in inflammation.
Going back to the IEL cells for a moment, in Crohn’s disease and ulcerative colitis (UC) these cells can start to attack the gut lining itself, this further creates a cytotoxic environment, which can further exacerbate IELs to produce pro-inflammatory proteins, this can lead to a compromised intestinal lining, along with alterations in the gut microbiome. In very simple terms this leads to the symptoms most often seen with Crohn’s and UC. So how would a GLP-1RA drug help? This goes back to what I originally said, these IELs are specialized types of T-cells and contain the GLP-1 receptor. By activating this receptor, it downregulates production of inflammatory biomarkers, upregulates production of a substance called mucin which helps form the protective barrier in our intestinal lining. GLP-1RA drugs also help alter the gut microbiome towards bacteria that are less inflammatory to our intestinal lining.
There appear to be multiple pathways that GLP-1 agonists directly and indirectly target that cause a multitude of downstream effects in terms of immune, inflammatory and cellular health as I’ve just highlighted.
The first and most relevant to the discussion of inflammatory immune responses is Nuclear Factor kappa-light-chain-enhancer of activated B cells, or NF-kB for simplicity. It is one of the master switches for immune responses. GLP-1R activation inhibits NF-kB through a series of complicated actions inside the cell, but ultimately for our purposes this leads to the downregulation of multiple inflammatory cytokines, including but not limited to Tumor Necrosis Factor Alpha, (TNF-a) Interleukin 6 and 1-beta (IL6 and IL-1b) and multiple others.
Think of NF-kB sort of like a firefighter, it sits inside cells, waiting for a signal that something is wrong (like an injury, an infection, or stress) only then does it activate and tell the cell how to defend itself. In auto-immune diseases, signaling of NF-kB is stuck in the “ON” position leading to cellular destruction, increased cytokine levels and more. GLP-1 agonists are thought to flip that switch back to the “OFF” or at minimum, act as a dimmer switch to tone down the intensity of the “ON” signaling thereby reducing the production of inflammatory cytokines.
The next couple pathways we will sorta combine together as they are both metabolism coded, the PI3K/AkT/mTOR and AMPK pathways. PI3K as a pathway is sort of like the ‘growth and survival’ pathway while the AMPK pathway acts sort of as a cellular version of a solar panel attached to a battery. When sunlight(fuel) is plentiful it stores up excess energy in the battery and when sunlight is dim it then starts using the stored energy in the battery to keep critical processes running. AMPK also triggers autophagy and mitophagy to remove and replace damaged cellular components such as mitochondria that might otherwise trigger inflammation. Autophagy is particularly important for maintaining mitochondrial health, as dysfunctional mitochondria can contribute to inflammatory signaling through pathways such as the NLRP3 inflammasome. AMPK also interacts with mTOR, which regulates cell growth. During stress, AMPK inhibits mTOR, shifting the cell away from growth and toward repair. I don’t want to dive too deep on these pathways but regardless these provide further anti-inflammatory benefits along with basically telling your cells to get rid of your garbage, so it doesn’t cause problems.
Ignore the heart, I just couldn’t find a graphic with the gut and this pathway (also note how much more I’m NOT talking about!)
GLP-1 medications have also shown other direct immune system modulation. Our macrophages, a type of immune cell, have an M1 phase which is usually seen as a pro-inflammatory and tissue destructive state, and an M2 phase which is classically an anti-inflammatory state. Various studies have now shown that GLP-1 and GLP-1RA drugs directly promote M2 phase while inhibiting M1 phase, this ties back to the reductions in TNF-a and IL-6 mentioned earlier, along with various other inflammatory cytokines.
Right hand side of this image, can see the M1/M2 changes are also tied with NF-kB
To bring this together, none of this would be possible without the brain. While peripheral actions like we have discussed dampen immune cell mediated inflammation in the gut, certain inflammatory signals require central, or brain mediated signaling to exert their anti-inflammatory effects. In this way, GLP-1 signaling may coordinate both local and systemic control of inflammation depending on the type and origin of the immune response.
Indeed, in rodent models where they lack GLP-1 receptors in the brain, the central anti-inflammatory response is essentially blocked. Furthermore, these central effects may involve recruitment of pathways that are normally involved in stress and immune regulation, including adrenergic and opioid signaling and blocking either signaling pathway in rodent models again blunts the immunosuppressive effects of GLP-1RA, but this remains an area of active research as it whether this is also the case in humans.
Decrease in lung inflammation is why GLP-1 meds work for asthma patients
In a fun twist, that is beyond the scope of this post but worth mentioning, in the rodent models lacking GLP-1R in the brain were given tirzepatide, a GLP-1 & GIP agonist, then some of the anti-inflammatory benefits returned, suggesting GIP has an anti-inflammatory role as well!
What can we take away from all of this? I think my biggest takeaway is that GLP-1 medications operate on a far deeper level than the vast majority of people think. Calling GLP-1 a hunger hormone or a blood sugar hormone is vastly underselling what it is able to do. It appears instead to be evolutionarily conserved not just for those things, but as a crucial link in our body’s defensive armamentarium against various infectious and inflammatory insults.
I think it is safe to say these are anti-inflammatory medications as well as weight loss and glucose controlling medications. In fact, these may be some of the most potent anti-inflammatory medications outside of corticosteroid medications.
Now with modern technology we can harness those anti-inflammatory effects to provide long term benefits, whether that’s a reduction in psoriasis symptoms, decreased risk of cardiovascular disease, possibly less risk of dying from infection and who knows what else. We didn’t intend for these medications to be such a panacea, but as more time passes, the more it is clear that’s exactly what we’ve created.
Stay tuned, lots of retatrutide, orforglipron, cagrisema and multiple other trial results coming in May and June! I’ll be covering all of it here!
References:
Drucker, D. J. (2025). Antiinflammatory actions of glucagon-like peptide-1–based therapies beyond metabolic benefits. The Journal of Clinical Investigation, 136(2). https://doi.org/10.1172/JCI194751
Janowitz, I., et al. (2026a). The science of safety: Adverse effects of GLP-1 receptor agonists as glucose-lowering and obesity medications. The Journal of Clinical Investigation, 136(2). https://doi.org/10.1172/JCI194740
Janowitz, I., et al. (2026b). GLP-1 physiology and pharmacology along the gut-brain axis. The Journal of Clinical Investigation, 136(2). https://doi.org/10.1172/JCI194744
Kowalski, M., et al. (2025). The multifaceted nature of GLP-1: Molecular mechanisms and signaling pathways in metabolic and neurodegenerative diseases. International Journal of Molecular Sciences, 27(4), 1886. https://doi.org/10.3390/ijms27041886
Zheng, L., et al. (2025). GLP-1 receptor agonists: Exploration of transformation from metabolic regulation to multi-organ therapy. Frontiers in Pharmacology. https://doi.org/10.3389/fphar.2025.1675552
