Letter to the Editor: Microbial metabolites and immune regulation in inflammatory bowel disease and metabolic dysfunction-associated steatotic liver disease

Abstract

This letter aims to engage in a constructive discussion of the review written by Sokal-Dembowska et al, published in the recent issue of the World Journal of Gastroenterology. The review systematically expounds the role of the gut microbiota in linking inflammatory bowel disease with metabolic dysfunction-associated steatotic liver disease. We commend the authors for integrating evidence on gut dysbiosis, barrier dysfunction, oxidative stress, and the gut-liver axis. Based on this, we further focus on two key aspects: first, the functional impact of metabolites derived from gut microbiota; second, the complex heterogeneity reflected in the balance between T helper cell 17 and regulatory T cells. Additionally, we explore the potential and challenges of targeting the interleukin (IL)-17/IL-23 axis for treatment. To more intuitively illustrate the complex interactions mentioned above, we provide a schematic diagram of immune-metabolic crosstalk. Finally, this article further discusses the clinical significance of these understandings for the development of precise treatment strategies.

Key Words: Gut-liver axis; Metabolic dysfunction-associated steatotic liver disease; Inflammatory bowel disease; Gut microbiota; Th17-regulatory T cell balance

Core Tip: This letter builds on the important review by Sokal-Dembowska et al and further emphasizes the necessity to delve into the functional consequences of alterations in the microbial metabolome, as well as the complexity of Th17/Treg immune regulation in the gut-liver axis between inflammatory bowel disease and metabolic dysfunction-associated steatotic liver disease. Specifically, this article focuses on elaborating how metabolites from specific gut microbiota and pathogenic Th17 cell subsets promote liver damage, and further discusses the translational medical significance of novel interleukin-23 targeted therapeutic strategies and sphingosine-1-phosphate receptor modulators.

TO THE EDITOR

We read with great interest the review by Sokal-Dembowska et al[1], published in the recent issue of the World Journal of Gastroenterology, which provides a thorough and timely overview of the mechanisms linking inflammatory bowel disease (IBD) and metabolic dysfunction-associated steatotic liver disease (MASLD). The authors comprehensively summarize shared the common pathogenetic pathways of the two diseases, including intestinal flora imbalance, impaired intestinal barrier function, oxidative stress, chronic inflammation, and the central role of the gut-liver axis. At the same time, the authors systematically discussed the effects of lifestyle factors such as western diet[2], physical inactivity, sleep disorders and psychological stress on gut microbiota composition of intestinal microbiota and intestinal permeability, all of which contribute to the co-occurrence of MASLD and IBD. By integrating evidence from microbiology, metabolism, and immunology, the manuscript offers a cohesive and insightful synthesis of the complex interplay. We commend the authors for their comprehensive contribution. Here, we offer additional perspectives, unresolved questions, and potential research directions that may further extend the mechanistic and translational implications of this work.

The metabolites produced by gut microbiota can regulate the immune system and metabolic balance

The review clearly elaborated on the changes in the composition of gut microbiota, including the reduction of short-chain fatty acid (SCFA)-producing bacteria (e.g., Faecalibacterium prausnitzii, Roseburia) and the expansion of Proteobacteria. The article also discusses the role of secondary bile acids and their receptors, farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5), in maintaining immune and metabolic homeostasis. Emerging evidence, however, suggests that the functional consequences of altered microbial metabolism may be equally critical in driving disease pathogenesis.

For example, as illustrated in Figure 1, inflammation-related downregulation of SCFA receptors [G protein-coupled receptor (GPR) 41, GPR43, and GPR109A] may result in functional SCFA impairment, thereby limiting epithelial repair and regulatory immune responses even when SCFA availability is not markedly reduced[3]. This functional defect may further aggravate intestinal barrier dysfunction and systemic inflammatory response, promoting MASLD progression. In addition, emerging evidence underscores the pathogenic influence of gut-derived metabolites such as trimethylamine-N-oxide and endogenous ethanol produced by certain pathobionts (e.g., Klebsiella, Escherichia coli), both of which contribute to hepatic lipid dysregulation, oxidative stress, and activation of the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 inflammasome[4,5].

Figure 1 Schematic representation of the immunometabolic crosstalk in the gut-liver axis linking inflammatory bowel disease and metabolic dysfunction-associated steatotic liver disease. The diagram illustrates three critical mechanisms: (1) Dysbiosis: In the inflammatory bowel disease gut, dysbiosis leads to the production of pathogenic metabolites (e.g., trimethylamine N-oxide, endogenous ethanol) and a functional downregulation of short-chain fatty acid receptors (G protein-coupled receptors 41 and 43), creating a pro-inflammatory environment; (2) Pathogenic Th17: An interleukin (IL)-23-rich milieu promotes the differentiation of pathogenic Th17 cells. This axis can be therapeutically targeted by the IL-23 inhibitor Guselkumab; and (3) Sphingosine-1-phosphate modulation: Sphingosine-1-phosphate receptor modulators, such as Etrasimod, prevent lymphocyte egress from lymphoid tissues, thereby reducing immune cell infiltration into the liver. Center (gut-liver crosstalk): These metabolites and immune cells translocate via the portal vein to the liver, driving hepatic inflammation and steatosis. GPR: G protein-coupled receptors; S1P: Sphingosine-1-phosphate; TMAO: Trimethylamine N-oxide. Parts of this figure were adapted from Servier Medical Art (https://smart.servier.com/) (Supplementary material).

The interaction between bile acids and the intestinal microbiota seems to be more dynamic and complex than previously thought. Although this review discusses issues such as the reduction of secondary bile acids and the impairment of FXR/TGR5 signaling, an increasing number of research data indicate that there is a bidirectional regulatory relationship between the two. Among them, the change in FXR activity itself can also reshape the structure of the intestinal microbiota[6]. Recognizing this feedback loop may help clarify why MASLD can progress independently of classical metabolic risk factors in patients with IBD.

The imbalance of TH17/regulatory T cells and the constantly changing treatment landscape

The authors appropriately highlight the importance of Th17/regulatory T cell (Treg) dysregulation in both IBD and MASLD[7]. However, in addition to the expansion of pro-inflammatory cells, there are also Treg cells in the microenvironment with impaired function. The depletion of SCFA-producing commensals discussed in the review directly compromises intestinal Treg differentiation[8]. Furthermore, upon migrating to the hepatic microenvironment, these cells encounter oxidative stress, which may destabilize their phenotype and impair their capacity to suppress effector T cell proliferation (Figure 1)[9].

This loss of immune tolerance may further amplify the pathological effects of specific Th17 cell subsets. However, these cell subsets can show significant functional heterogeneity due to their different origins. In the inflamed IBD gut, the interleukin (IL)-23-rich inflammatory microenvironment drives the formation of pathogenic Th17 cells. These cells are more likely to release inflammatory mediators with systemic effects and further promote the process of liver fibrosis[10]. In contrast, Th17 cells, induced predominantly by transforming growth factor-beta tend to retain barrier-protective functions within the intestine without exerting deleterious effects on the liver[11]. This immunological variation helps explain why liver outcomes can vary significantly in patients with similar gut disease burdens[11,12].

Given the central role of IL-23 in driving these pathogenic cell subsets, the current therapeutic landscape is rapidly evolving toward targeting this specific pathway. While the review briefly mentions cytokine inhibitors, recent regulatory approvals have introduced novel agents specifically directed at this pathway. For example, in September 2024, the United States Food and Drug Administration approved the IL-23 inhibitor guselkumab (trade name Tremfya) for the treatment of ulcerative colitis. This approval was based largely on the phase 3 QUASAR study, which showed a significant increase in clinical remission with guselkumab compared with placebo in patients with moderate-to-severe ulcerative colitis[13]. Similarly, the sphingosine-1-phosphate receptor modulator etrasimod (trade name Velsipity) has recently been approved for use in markets such as Germany. The ELEVATE UC series showed that etrasimod was superior to placebo in inducing clinical remission and maintaining remission for up to 52 weeks[14].

In addition to immune regulation, therapeutic strategies targeting metabolic pathways, such as glucagon-like peptide-1 receptor agonists, have also shown promise for “dual benefits”. Given that this class of agents is approved for obesity management and has shown efficacy in promoting remission of metabolic dysfunction-associated steatohepatitis, there is theoretical potential for synergy with anti-inflammatory therapy. Therefore, it may bring potential benefits to patients with IBD-MASLD comorbidity[15]. However, caution is needed in clinical application. As noted in the review, careful patient screening and risk assessment are needed for the use of IBD-specific biologics in IBD patients with MASLD to avoid paradoxical compounding of liver-related problems or risk for fungal infections[16].

CONCLUSION

Overall, the review by Sokal-Dembowska et al[1] provides a comprehensive and timely synthesis of the gut-liver axis. By further clarifying the subtle differences in microbial metabolites at the functional level and the heterogeneity of immune responses (Figure 1), it may improve our understanding of the common pathogenesis of these comorbid conditions. We believe that integrating the above mechanistic understanding with the lifestyle factors discussed in the original review is of great significance for promoting the establishment of precise treatment strategies and guiding future clinical research.