In rat models of systemic inflammation, a GLP-1 RA, exendin, significantly lowered pro-inflammatory cytokine levels, including IL-1β, IL-6, TNF-α, and interferon-gamma (IFN-γ) (41). These effects are primarily mediated by the inhibition of NF-κB and mitogen-activated protein kinase (MAPK) pathways, both of which are associated with stress, inflammation, and apoptosis responses (10, 42). Interestingly, in the context of several in vitro studies, GLP-1 RAs have demonstrated the capacity of promoting an anti-inflammatory state by influencing immune cell differentiation. For instance, exenatide, the first GLP-1-analogue developed, demonstrated to promote human monocyte differentiation into alternatively activated M2 macrophages, leading to an increase in anti-inflammatory cytokines such as IL-10 while significantly reducing pro-inflammatory cytokines, including IL-6, TNF-α and IL-1β (43). Shiraishi et al. demonstrated that GLP-1/GLP-1R signalling plays a crucial role in activating signal transducer and activator of transcription 3 (STAT3), which directly promotes human M2 macrophage polarization while inhibiting classically activated M1 macrophages, known for their pro-inflammatory and tissue-destructive properties (44). In animal models, GLP-1/GLP-1R signalling has demonstrated to be involved in key macrophage functions such as phagocytosis and migration, though further research is needed to confirm these effects in humans (45). Additionally, both eosinophils and neutrophils express GLP-1R on their surface. Notably, eosinophils of asthmatic patients exhibit lower GLP-1Rs’ expression compared to healthy controls (46). The interaction between GLP-1 and its receptor on eosinophils has been shown to reduce the production of pro-inflammatory cytokines, including IL-4, IL-8 and IL-13 (47). Although the limited research on the role of GLP-1 in neutrophils, preliminary findings have shown that it may mitigate their activation, potentially reducing myocardial ischemic injury rodent models (48). In conclusion, the GLP-1/GLP-1R signalling plays a significant role in the balance of innate immunity, particularly in the polarisation of macrophages.

Furthermore, GLP-1 has been hypothesised to act as a mediator between innate and adaptive immune responses. In mice single-cell RNA sequencing identified a subpopulation of GLP-1R-positive memory T-cells that was mainly composed of exhausted CD8+ T cells: functionally, stimulation of the GLP-1R on these cells was found to mediate apoptosis and anergic signals, thereby suppressing effector T-cell function and the inflammatory response (49, 50). In humans, the GLP-1 pathways act as a modulator of a specific subset of T-cells, known as invariant natural killer T (iNKT) cells, and this activity might be responsible for the improvements of some immune-mediated disorders (such as psoriasis and suppurative hidradenitis) observed in obese patients treated with GLP-1 RAs (51–54). In mice, GLP-1 RA treatment also showed to inhibit the differentiation of T helper (Th) cells into Th1 and Th17 subsets and reduce the release of related proinflammatory cytokines, including IFN-y, TNF-α, and IL-17. Instead, GLP-1 promotes the polarization of Th2 and regulatory T (Treg) cells, increasing anti-inflammatory cytokines such as IL-10 and IL-5 (55, 56).

IELs are a heterogeneous population of T cells located among intestinal epithelial cells (IECs), where they contribute to maintaining mucosal barrier integrity (57). A particular subset of IELs (Tαβ and Tγδ) has been found to be enriched with GLP-1Rs (37, 58). Their proximity to enteroendocrine L-cells suggests a potential contribution of lymphoid tissue in GLP-1/GLP-1R signalling, as mediator of L-cell proliferation (59, 60). Genetically modified Glp1r ^−/− mice displayed greater levels of epithelial damage in comparison to wild-type (WT) mice following inflammatory stimulation. Conversely, WT mice exhibited higher expression of antimicrobial and anti-inflammatory genes (37). Similarly, Wong et al. described that IEL-expressing GLP-1Rs play a crucial role in controlling gut inflammation of mice, by reducing IFN-γ production in IELs and promoting IEC survival and intestinal barrier integrity (38). Additionally, GLP-1 showed to directly stimulate murine Brunner’s glands to produce and release mucin, thereby strengthening the mucosal barrier (61). Furthermore, GLP-1Rs on IELs have been found to regulate the metabolic effects of GLP-1 in animal models by entrapping it, thereby reducing its systemic availability and lowering its plasma concentrations (62). Moreover, GLP-1 could be involved in mechanisms of growth and expansion of IECs, as the loss of GLP-1Rs on IELs has been associated with shorter and smaller intestines in mice (59, 63, 64).

The anti-inflammatory role of GLP-1 in the gut is not limited to the maintenance of IELs and L-cells but it is also interconnected with gut microbiota. Thus, several microbiota-derived metabolites have been found to stimulate enteroendocrine L-cells producing GLP-1. Short-chain fatty acids (SCFAs) such as butyrate, a bacterial metabolite produced from dietary fibre, can directly trigger GLP-1 release by binding to the membrane receptor GPR43 (65). Additionally, dietary protein-derived metabolites, including tryptophan-indole, as well as LPS from Gram-negative bacteria, directly promote the production of GLP-1 (66, 67). Interestingly, bile acid metabolites have a dual effect on GLP-1 secretion: they can both stimulate and inhibit its production (66). Furthermore, the ileum of germ-free and antibiotic-treated mice showed lower Glp1r gene expression compared to controls, with higher incretin effect resistance (68).

Both preclinical and clinical studies have demonstrated that GLP-1’s modulate the gut microbiota composition by delaying gastric emptying and altering luminal glucose (12). Zhao et al. observed that the gut microbiota of diet-induced obese (DIO) mice treated with liraglutide for four weeks displayed a similar phylogenetic composition in comparison to the start of the treatment, but was characterized by a significant decrease in microbial phenotypes associated with obesity (e.g., Firmicutes Lachnospiraceae and Clostridiales), alongside an increase in Proteobacteria (e.g., Burkholderiales bacterium YL45) and Akkermansia muciniphila—a species largely associated with high-fibre diets and mucosal barrier health (11, 69–71). Notably, the administration of GLP-1 RA resulted in an elevated Firmicutes/Bacteroidetes ratio and an increase in Prevotella, species that have been linked to lower inflammation (12, 70). Similar results were reported by Wang et al., where GLP-1 RA treatment had a notable impact on the abundance of weight-related microbial phylotypes, though no significant change in the Firmicutes/Bacteroidetes ratio was observed (72).

The findings concerning human gut microbiota remain controversial. Although liraglutide treatment led to a decrease in pro-inflammatory microbial species (e.g., Escherichia–Shigella, Megamonas, and Bacillus) in DM2 patients, no statistically significant differences were observed when compared to metformin treatment. However, a significant increase in Bifidobacterium, Dialister, and Alistipes was reported (73). A recent study conducted on 41 diabetic patients demonstrated that exposure to the GLP-1 RA dulaglutide over a 48-week period was associated with a substantial decrease in non-butyrate-producing Firmicutes (e.g., Ruminococcus and Blautia), accompanied by an increase in Bacteroides, Lactobacillus, and Prevotella (74).

In conclusion, GLP-1 contributes to gut homeostasis and inflammation control through its modulatory effects on immunity, epithelial cell proliferation, and microbial composition ( Figure 1 ). Whilst emerging evidence suggests the extensive therapeutic potential of GLP-1, further studies are needed to fully elucidate its mechanisms and its clinical applications in gastrointestinal disorders.

The previously mentioned intrinsic connection between metabolism and the inflammatory response led researchers to investigate the role of GLP-1 modulation in the management of IBD. Evidence suggests that IBD pathogenesis is closely linked to gut failure in controlling inflammation, with enteroendocrine cells (EECs) playing a pivotal role in the process (91). In this regard, TNF-α has been demonstrated to trigger the NF-κB pathway in EECs, which are a target of the GLP-1/GLP-1R pathway. This, in turn, results in the production of IL-17C, a process that contributes to the propagation of inflammation in individuals suffering from IBD (92). Preclinical models found that GLP-1 RAs reduce intestinal inflammation in dextran sulfate sodium (DSS)-induced colitis, by increasing IL-22 production by colonic IELs and several beneficial bacteria, including Firmicutes, Proteobacteria and Lactobacillus reuteri (93). Furthermore, in human samples, GLP-1R was deregulated in IBD active biopsies (94), with elevated GLP-1 plasmatic levels being associated with severe active disease (95). Anecdotal evidence suggests that GLP-1 RAs may be beneficial in IBD treatment. A case report documented clinical remission in a 42-year-old UC patient following liraglutide administration for obesity treatment (96). This lends further weight to prospective investigation of the benefits and safety of GLP-1 RAs in the real world which are resumed in Table 2 .

Desai et al. found that both UC and CD patients with DM2 presented a reduced risk of surgery when treated with GLP-1 RAs compared to other hypoglycemic agents (97). A Danish nationwide cohort study also reported a lower risk of corticosteroid use and hospitalization in IBD patients with DM2 undergoing GLP-1 RAs rather than other antidiabetic treatments (98). Additionally, a nationwide study conducted in Israel found improved IBD outcomes, with a significant reduction of hospitalization rates; however, these benefits were limited only to obese patients (99). Furthermore, recent finding reported that GLP-1 RAs significantly reduced C-reactive protein (CRP) levels in obese IBD patients, alongside a nearly statistically significant reduction in fecal calprotectin (100). However, not all studies align with these results. Levine et al. observed no statistically significant differences in disease exacerbation, corticosteroid-free remission, or therapy escalation in the same cohort of 224 IBD patients after one year of GLP-1 RAs treatment. Despite this, CRP levels showed improvement (101). A further study conducted on IBD patients and not diagnosed with DM2 also reported no significant alterations in inflammatory markers. However, only a small number of patients were included in the study, and median levels were not elevated even before the commencement of GLP-1 RAs’ treatment (102). These discrepancies may stem from short observation periods and small sample sizes respectively (101, 102).

With regard to safety concerns, the most prevalent adverse effects associated with GLP-1 RAs are gastrointestinal, such as bloating, dyspepsia, nausea, vomiting, diarrhea and constipation (107). It is noteworthy that the majority of these gastrointestinal manifestations are of a mild nature and predominantly occur during the titration phase (108). These symptoms are often the reasons why patients stop their treatment. Registration clinical trials show that 16-37% of patients discontinue within a year (109–111). However, real-life analyses indicate a higher discontinuation rate, of approximately 70% stopping within 2 years, especially in non-diabetic patients (112, 113). Interestingly, GLP-1 RAs showed a favorable safety profile in IBD patients, exhibiting comparable tolerability to non-IBD populations. Clarke et al. found that IBD did not affect weight loss outcomes in obese patients and that anti-TNF-α therapy did not reduce the likelihood of achieving ≥5% total weight loss (TWL) (66% vs. 58%, P = 0.33). This indicates that the combination of these agents can be safely and effectively administered to patients with IBD (103). Moreover, IBD patients exhibited lower prevalence of nausea, vomiting, and diarrhea, but increased rates of constipation (11%) in comparison to the general population (103). Two retrospective studies further corroborated the safety and efficacy of GLP-1 RAs in treatment of obesity in IBD patients. They reported mild gastrointestinal symptoms and no substantial changes in disease activity scores (104, 105). Semaglutide has been observed to induce the most substantial weight loss in IBD patients, with no discrepancies in the attainment of >5% TWL when compared to the general population (104–106). Additionally, semaglutide has been shown to have a comparable risk profile to other GLP-1 RAs with respect to gastrointestinal adverse effects in the IBD population (106). Consequently, some authors consider GLP-1 RAs to be safe in the IBD population, however, they emphasise the necessity of providing educational advice to patients (e.g. small and frequent meals) and employing a gradual dose-up titration strategy (114).

Currently, two ongoing clinical trials are investigating the role of GLP-1 RAs in IBD management, that would lead to further knowledge: a French study (ID NCT05196958) evaluating the safety and efficacy of GLP-1 RAs in treatment of DM2 in overweight IBD patients (115), and an American study (ID NCT06774079) comparing the efficacy of GLP-1 RAs tirzepatide versus diet in CD patients (116).

In summary, the interplay between IBD and metabolism represents a growing area of research and therapeutic interest, with GLP-RAs emerging as a promising therapeutic option. While preclinical and clinical studies have reported anti-metabolic and anti-inflammatory benefits with a favourable safety profile, further evidence from long-term and large-scale trials is necessary to guide clinicians in real-life scenarios.