Targeted Therapy for Gut Microbiota: Candidates for a Novel Strategy to Ameliorate Type 2 Diabetes MellitusIF:1.40

Amino acids are fermented by intestinal bacteria in the dis tal colon, with protein fermentation yielding higher amounts of BCAAs and potentially toxic substrates, such as ammo nia, than carbohydrate fermentation (Rinninella et  al.  2019).

BCAAs, including leucine, isoleucine, and valine, play critical roles in maintaining the intestinal immune system and activat

ing the intestinal mucosal immune barrier (Zhang et al. 2021).Disruption of BCAA metabolism can lead to the accumulation

of toxic metabolic intermediates and increased activation of mammalian target of rapamycin complex 1 (mTORC1), a key

regulator of cell growth. This dysregulation can impair insu lin signalling (Zhou et  al.  2019) and promote mitochondrial

dysfunction and apoptosis in pancreatic β-cells (Hamamah et al. 2024; Lynch and Adams 2014). Enhancing BCAA catabo

lism in the gut may modulate the intestinal BCAA-mammalian target of rapamycin complex 1 insulin receptor substrate

1-phosphatidylinositol 3 kinase-AKT axis, thereby mitigating  the harmful effects of BCAAs on the insulin receptor substrate

1 signalling pathway and improving T2DM (Wang et al. 2024)(Figure  5). Furthermore, disturbances in the gut microbiota

have been shown to exacerbate IR and disrupt glucose metab olism by increasing the circulating levels of BCAAs (Pedersenet al. 2016). For instance, Prevotella induces the expression of genes associated with BCAA biosynthesis, while reducing the expression of genes involved in BCAA degradation, contributing to IR in patients (Pedersen et al. 2016). Additionally, the quantity of BCAAs absorbed in the intestine correlates with the abun dance of C. difficile (Saad et al. 2016). Modifying the composi tion of the gut microbiota in diabetic mice to reduce BCAA levels can alleviate the symptoms associated with T2DM (Wu, Zuo,et al. 2021). Analysis of faecal specimens from 15 patients with diabetes and 22 healthy controls revealed that the abundance