# Gut Microbiota as an Endocrine Organ: Unveiling Its Role in Human Physiology and Health
## 4 Gut Microbiota Metabolites and Hormonal Alterations in Human Physiology
Altered gut microbiota may modulate appetite by influencing central insulin signalling [127, 128]. Understanding the interplay between gut microbial metabolites and appetite regulation holds promise for personalised nutritional interventions in managing eating disorders. Adding to the previously discussed topic of short-chain fatty acids (SCFAs), they serve as signalling molecules, engaging with G-protein-coupled receptors (FFAR2 and FFAR3) to modulate appetite. Succinate, a typical product of gut microbial carbohydrate fermentation, has garnered attention for its potential role in appetite regulation. Studies in humans have shown that circulating succinate concentrations are elevated in obese individuals compared to healthy counterparts, suggesting a link between succinate production and host energy homeostasis [129]. Furthermore, researchers have found that dietary weight loss alters gut microbiota composition and decreases circulating succinate levels in obese patients. Despite these associations, the effects of succinate on appetite-related signalling remain inconsistent. While some studies suggest that succinate treatment improves glucose and insulin tolerance without affecting food intake in mice fed a high-fat/high-sucrose or high-fat diet [130], others have demonstrated that succinate supplementation reduces food intake and plasma insulin concentration in obese (ob/ob) mice. This discrepancy in findings highlights the complexity of succinate's role in appetite regulation and the need for further research, particularly in human studies, to elucidate its mechanisms and effects on appetite control. Tryptophan (Trp) metabolism, influenced by the gut microbiota, is vital in regulating metabolic homeostasis and appetite. The gut microbiota modulates the availability and metabolism of Trp, which can directly or indirectly affect appetite [131]. Trp, as a precursor to serotonin (5-HT), can influence gut hormone secretion and activate satiety circuits in the brain. Studies investigating the effects of dietary Trp supplementation or reduction on appetite control have yielded inconsistent and contradictory results. Animal studies have shown that Trp administration can stimulate food intake by enhancing signalling pathways in appetite regulation [132]. However, in humans, intragastric or intraudoudenal Trp administration has been found to inhibit appetite and promote the production of anorexia hormones such as CCK, GLP-1, and PYY, albeit with varying effects in obese individuals. Furthermore, the gut microbiota-derived metabolite indole, a derivative of Trp, has been implicated in appetite regulation by stimulating GLP-1 secretion and improving intestinal barrier function [133]. These findings highlight the intricate interaction between Trp metabolism, gut microbiota, and appetite regulation, emphasising the need for further research to understand the underlying mechanisms and potential therapeutic implications. Bile acids (BAs), influenced by the gut microbiota, modulate appetite by binding to gastrointestinal receptors and regulating appetite-associated hormones' secretion. Alterations in BA composition affect GLP-1 and PYY secretion, ultimately impacting food intake. Furthermore, BAs are crucial in lipid absorption and metabolic signalling pathways, contributing to overall energy homeostasis. Branched-chain amino acids (BCAAs), derived from the diet and gut microbiota, play a role in appetite regulation and energy metabolism [134]. Alterations in BCAA levels are associated with insulin resistance, and dietary manipulation of BCAAs can affect feed intake. BCAAs also influence gut microbiota composition and metabolic pathways, highlighting their multifaceted role in appetite control and metabolic health (Figure 2). As detailed in previous sections of this review, bacterial metabolites influence host metabolism, while specific bacterial components may also serve as factors that modulate host endocrine functions. Recent data have revealed insights into specific microbial proteins that can influence host physiology.