# Gut Microbiota as an Endocrine Organ: Unveiling Its Role in Human Physiology and Health
## 4 Gut Microbiota Metabolites and Hormonal Alterations in Human Physiology
### Gut Microbiota and Resistance to Insulin  
Accumulated evidence substantiates the pivotal role of the gut microbiome in regulating insulin secretion [158]. Insulin, a critical hormone, enhances membrane permeability to glucose, reducing glucose levels by activating the insulin receptor. Insulin binding triggers the activation of insulin receptor tyrosine kinase, initiating tyrosine phosphorylation of insulin receptor and insulin receptor substrate (IRS) proteins [159]. IRS phosphorylation facilitates the binding of lipid kinase phosphatidylinositol-3-kinase (PI3-K) [160] at the plasma membrane, which, in turn, phosphorylates the Thr308 residue of AKT by synthesising PtdIns [161] P3 (PIP3). AKT activation contributes to glucose production, utilisation, and uptake and the synthesis of glycogen, lipids, and proteins. Notably, emerging evidence indicates the involvement of the gut microbiome and bacterial metabolites in the progression of insulin resistance. A recent study revealed that the serum metabolome of insulin-resistant individuals exhibits increased levels of branched-chain amino acids (BCAs), correlated with a heightened abundance of _Prevotella copri_ and _Bacteroides vulgatus_ (_B. vulgatus_). _P. copri_ induces insulin resistance, exacerbates glucose intolerance, and elevates BCAA levels [162]. Administration of _Phellinus luteus_ polysaccharide extract (PLPE) to mice induces alterations in gut microbiota composition, enhancing short-chain fatty acid (SCFA) levels [163]. It reduces lipopolysaccharide-acrylamide (LPS) content, mitigates systemic inflammation, and ameliorates insulin resistance by inhibiting JNK and NF\(\kappa\)B activation. SCFAs, the primary fermentation products of the gut microbiota (propionate, acetate, and butyrate), significantly impact host metabolic processes, particularly insulin resistance; human and animal studies propose that acetate benefits host metabolism, enhancing insulin sensitivity through the gut hormone GLP-1 secreted by colonic L cells. Acetate inhibits appetite, reduces lipolysis, and lowers systemic proinflammatory-matory cytokine levels [164]. Additionally, microbiota-generated metabolites propionate and butyrate activate intestinal gluconeogenesis through complementary mechanisms. Faecal microbiota transplantation (FMT) emerges as a method for modulating microbial composition and has been explored for treating various microbiome-associated diseases, including insulin resistance and obesity. _Collinsella_ administration reduces tight junction protein expression, increases intestinal wall permeability, and correlates with elevated serum insulin levels, highlighting the significant impact of the gut microbiota on glucose metabolic function [165]. Furthermore, insulin resistance and compensatory hyperinsulinemia induce excess androgen, contributing to reproductive diseases such as PCOS. This occurrence creates a negative feedback loop as insulin induces androgen secretion, modulating LH pulsatility, while hyperandrogenism induces inflammation, insulin resistance, and metabolic dysfunction in PCOS [166]. Transcriptional and epigenetic changes in skeletal muscle, including differentially expressed genes like COL1A1 and MAP2K6, contribute to metabolic abnormalities, notably insulin resistance, in women with PCOS. _Bacteroides_[141], a proinflammatory bacterium, plays a crucial role in insulin resistance through an inflammatory mechanism. Elevated _Bacteroides_ levels, observed in PCOS patients, negatively correlate with fasting insulin levels. Administration of IL-22 or glycodeoxycholic acid (GDCA) can alleviate insulin resistance in PCOS mice [167]. Metformin, widely used in type 2 diabetes (T2D) treatment, alters gut microbiota composition and affects metabolic pathways. Gut microbiome profiles and gut-derived metabolites intricately link to host insulin sensitivity [168]. Metformin enhances several SCFA-producing microbiotas, including increased butyrate and propionate, which are involved in glucose homeostasis, ultimately improving insulin resistance.