Gut Microbiota Signaling Axes as Candidate Therapeutic Targets in Type 2 Diabetes Mellitus: Mechanistic Crosstalk and Translational Challenges

Abstract: Gut microbiota disturbance serves as a critical pathogenic factor for metaflammation (metabolic inflammation) and insulin resistance in type 2 diabetes mellitus (T2DM). Growing preclinical evidence demonstrates that gut microbial metabolites modulate systemic metabolic and immune homeostasis via multiple interactive signaling axes rather than independent single pathways. This narrative review systematically summarizes four core signaling axes derived from gut microbiota. These axes include the SCFAs–AMPK energy-sensing axis, the BA- FXR/TGR5 metabolic regulatory axis, the LPS–TLR4/NF-κB proinflammatory axis, and the tryptophan–AhR intestinal barrier repair axis. This work further discusses the crosstalk among these axes and their potential functional roles in T2DM progression. We propose that intestinal metabolic and immune homeostasis relies on the dynamic balance between protective metabolic pathways and proinflammatory injury pathways. Consistent with cumulative preclinical findings, the NF-κB/NLRP3 inflammasome complex acts as a potential downstream convergence node. This node integrates upstream microbial metabolic disorders, amplifies chronic low-grade inflammatory cascades, and subsequently induces intestinal barrier impairment, insulin resistance and T2DM deterioration.This review further defines two conceptual regulatory patterns of relevant signaling networks. One is the synergistic homeostatic protection dominated by energy-sensing pathways, and the other is the antagonistic pathological imbalance triggered by excessive inflammatory activation. This study also highlights major existing limitations in current research. These limitations involve insufficient investigations into multimodule crosstalk, ambiguous spatiotemporal regulatory characteristics of core inflammatory hubs, and inadequate clinical translational validation. In conclusion, the dysregulation of multiple interactive signaling axes disrupts metabolic and immune homeostasis, which constitutes a preclinically validated upstream pathogenic mechanism for T2DM and requires further comprehensive verification in human clinical cohorts. Conventional therapeutic strategies focus on single-target intervention. The transformation toward precise combinatorial strategies targeting the gut microbiota-associated multi-signal network can provide novel theoretical references and translational directions for early intervention and holistic management of T2DM. Nevertheless, clinical evidence supporting simultaneous multi-axis targeted intervention remains insufficient. Keywords: gut microbiota, type 2 diabetes mellitus, signaling crosstalk, metaflammation, intestinal barrier, therapeutic targets