Commentary: Role of Gut Microbiota in Infectious and InflammatoryDiseases

Gabriela Angélica Martínez-Nava^*Alberto López-ReyesCarlos Pineda^*

• National Institute of Rehabilitation Luis Guillermo Ibarra Ibarra, Tlalpan, Mexico

The human gut microbiota plays a critical role in maintaining immune homeostasis and modulating inflammatory processes. The review article by Maciel-Fiuza et al.(2023) entitled "Role of Gut Microbiota in Infectious and Inflammatory Diseases"(1) provides a valuable overview of the current knowledge in this field, with a focus on autoimmune and infectious diseases. While the article presents a broad and detailed analysis, we noticed that gout, one of the most common forms of inflammatory arthritis, was not discussed. Given the growing body of evidence linking the gut microbiota to gout pathogenesis, we believe its inclusion could further enhance the review and provide a more complete overview on microbiotaassociated inflammatory diseases. Gout is preceded by a prolonged period of hyperuricemia, which triggers the formation and deposition of monosodium urate (MSU) crystals in joints and soft tissues. TheseMSU crystals elicit a potent acute inflammatory response that, over time, leadsleading to chronic joint damage. Gout affects millions of individuals worldwide, and is associated with a significant morbidity (12). Despite its high prevalence, it is often frequently underrepresented in discussions concerning inflammatory diseases related to the microbiome. A central component of the inflammatory cascade during gout attacks is the NLRP3 inflammasome, which senses MSU crystals through its LRR domain.NLRP3 inflammasome activation, initiatesing the production of the proinflammatory cytokine IL-1β. The ultimate result of this cascade is and ultimately promoting neutrophil recruitment and the formation of neutrophil extracellular traps (NETs). This process ; all of which results in joint damage (32,43).Beyond innate immunity, adaptive responses involving T helper 17 (Th17) and regulatory T cells (Tregs) are also implicated in the disease. Th17 cells contribute to sustained inflammation through IL-17 production. On the other hand, , whereas Tregs serve to counteract this effect and maintain immune tolerance. An imbalance between these cell types has been associated with exacerbated inflammation in gout (54). Notably, microbial-derived metabolites such as acetate short-chain fatty acids (SCFAs) modulate the immune system. Of these SCFAs, acetate have been shown to promote the differentiation of naïve T cells into Th17 cells. This effect involves suppression of histone deacetylases and modulation of the mTOR-S6K pathway (Figure 1). Al together,, thereby potentially amplifying inflammatory responses (56) (Figure 1).In addition, short-chain fatty acid (SCFA)-sensing receptors such as GPR43 (FFAR2) and GPR41 (FFAR3), presentexpressed on neutrophils and macrophages, have emerged as important modulators of the inflammatory response (76). The recognition of microbiota-derived SCFA, particularly, by GPR43 may trigger acute inflammatory arthritis by promoting IL-1β maturation and release through NLRP3 inflammasome activation in macrophage lineage cells (87). Recent research has highlightedEmerging evidence demonstrated how the gut microbiota may influence both urate metabolism but and the immunometabolic pathways involved in gout (98,910). E xtensive evidence suggests that certain bacteria have developed adaptive mechanisms for purine biosynthesis and salvage, potentially altering systemic urate levels. Additionally, microbial metabolites from the gut microbiota may reach the liver via the portal vein, promoting the synthesis of purinogenic amino acids and urate (11). Notably, fecal microbiota transplants from hyperuricemic (HUA) rats towards germ-free recipients have been shown to increase serum urate levels (12).While most early studies focused on the role of the microbiota in urate metabolism, there is now growing evidence that it also plays a crucial role in modulating the inflammatory response in gout. In a paradigm-shifting study, Vieira et al. (103) demonstrated that germ-free mice had an impaired inflammatory response to MSU crystals, which and that it was reversed by introducing acetate. This was the first study to highlight the essential role of the gut microbiota in regulating immune responses in gout. Furthermore, it pointed to acetate and it receptor GPR43 as key factors in the development and severity of gout attacks (130).Studies in in several populations have demonstrated the presence of gut dysbiosis in gout patients, supported by reduced Building on this, Martínez-Nava GA and colleagues investigated the gut microbiota composition and functionality in patients with gout. Their first study identified microbial dysbiosisα diversity measures, such as Chao1 and Abundance-base coverage estimator (ACE) indices (14,15). This dysbiosis is characterized by reduced beneficial taxa (e.g. Faecalibacterium, Ruminococcus) and increased pro-inflammatory genera in gout patients (e.g. Prevotella and Bacteroides) (910). Moreover, Iin a follow-up metatranscriptomic analysis, Martínez-Nava and colleagues they identifiedfound that at least three orthologues genes (K00161, K00162 and K01621) involved in pathways related to acetate production pathways that were differentially expressed in the gut microbiota of gout patients compared in comparison to normouricemic and asymptomatic hyperuricemic individuals (116).Together, these findings suggest that the gut microbiota not only shapes host immunity but also participates in key metabolic and inflammatory processes relevant to gout pathophysiology. This highlights its potential as a therapeutic target in the management of gout. The influence of the gut microbiota on systemic immunity has become a focal point in the understanding of chronic inflammatory diseases. While Maciel-Fiuza et al.(1) address conditions such as rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus, the omission of gout overlooks a critical intersection of metabolic and inflammatory pathology. Like rheumatoid arthritis, gout is associated with specific dysbiotic signatures and inflammasome activation.