Nutritional modulation of microbiome proteomics in insulin resistance

The gut microbiota serves as a pivotal mediator of host energy homeostasis, influencing metabolic health by regulating systemic inflammation and secreting bioactive metabolites (Li et al., 2022). Recent multi-omics investigations have identified specific shifts in microbial carbohydrate metabolism that correlate with increased systemic monosaccharide levels and the subsequent induction of inflammatory cytokines (Semo et al., 2024;Takeuchi et al., 2023). Specifically, the modulation of microbial enzymatic pathways through targeted dietary interventions offers a therapeutic avenue to dampen endotoxemia and improve peripheral insulin sensitivity (Gopal et al., 2024;J. Zhang, 2024). Moreover, interindividual baseline variations in gut microbial functionality significantly dictate the host's metabolic response to macronutrient perturbations, underscoring the necessity of precision-based nutritional strategies (Jardon et al., 2022). Rethinking these dynamics through a meta-organism lens suggests that insulin resistance should be framed as a systemic metabolic dysregulation wherein functional pathways-rather than mere taxonomic composition-become the primary drivers of host health (Pramono et al., 2026;Takeuchi et al., 2023). Therefore, this study aims to review the nutritional modulation of microbiome proteomics in insulin resistance. It also examines the matter of proteome layer in insulin resistance, metaproteome, host-microbiome protein crosstalk and precision management of insulin resistance towards nutrition centered metaproteomic framework.Insulin resistance (IR) is a fundamental pathological mechanism at the heart of metabolic disorders such as type 2 diabetes (T2D), obesity, and gestational diabetes mellitus (GDM). The proteome layer, which characterizes proteins as the primary functional units of the cell, is essential for deciphering these mechanisms since proteins directly regulate and catalyze the majority of cellular processes (Deshmukh, 2016). While transcriptomic studies provide valuable insights into gene expression, the frequently low correlation between transcript and protein levels necessitates proteomic analysis to achieve true biological accuracy (Kurgan et al., 2024). Proteomics enables the direct measurement of protein abundance, post-translational modifications (PTMs), and the secretome, all of which directly determine protein function and biological action (Deshmukh, 2016). Skeletal muscle, responsible for approximately 80% of insulin-stimulated glucose disposal, is the primary site of peripheral insulin resistance (Deshmukh, 2016). Proteomic research in this tissue indicates that IR conditions often involve a reduced abundance of mitochondrial oxidation proteins and altered phosphorylation of critical complexes, such as the ATP synthase beta-subunit (Kruse et al., 2020). These disruptions in the mitochondrial proteome significantly impair energy metabolism at the tissue level and weaken insulin signaling pathways (Kruse et al., 2020).Furthermore, systematic reviews of obesity reveal that the proteome layer reflects an increase in proteins associated with inflammation and oxidative stress, such as complement C3 and catalase (Rodriguez-Muñoz et al., 2024). In the context of GDM, proteomic meta-analyses have identified 262 candidate biomarkers, most strongly linked to pathways in the complement and coagulation cascades (Sriboonvorakul et al., 2022). Ultimately, proteomic data provide the essential foundation for the vision of Precision Diabetes Medicine (PDM) (Kurgan et al., 2024). By providing precise protein panels, this layer enables personalized diagnostic and therapeutic strategies that account for individuals' unique genetic and environmental differences (Kurgan et al., 2024).Metaproteomics serves as a powerful "functional readout" tool by identifying the actual proteins expressed by the gut microbiota and the host, providing insights into active biochemical processes that traditional taxonomic sequencing cannot capture (Calabrese et al., 2021). In metabolic disorders such as insulin resistance (IR) and type 2 diabetes, the functional shifts in the microbial proteome often reflect the disease state more accurately than changes in microbial composition alone (Calabrese et al., 2021). While 16S rRNA sequencing captures the potential of a microbial community, metaproteomics captures its dynamic plasticity and its response to environmental stressors such as diet, inflammation, or medication (Abbondio et al., 2023;Calabrese et al., 2021).In the context of insulin-resistant dysbiosis, the metaproteome reveals significant shifts in carbohydrate and energy metabolism (Calabrese et al., 2021). Obese and insulin-resistant individuals frequently exhibit an upregulation of microbial proteins involved in starch and pectin metabolism, such as β-glucosidase and pectate lyase (Calabrese et al., 2021). This enrichment suggests an enhanced microbial capacity to ferment unabsorbed carbohydrates into bioavailable short-chain fatty acids (SCFAs), which may provide the host with an additional energy source and exacerbate metabolic dysfunction (Calabrese et al., 2021;Jiao et al., 2018). Furthermore, specific enzymes, such as butyryl-CoA dehydrogenase, are often differentially expressed in IR states, directly impacting signaling pathways, such as PI3K/Akt, that regulate systemic insulin sensitivity (Abbondio et al., 2023;Bastos & Rangel, 2022).Childhood obesity and IR studies further illustrate the utility of this approach, showing that reductions in beneficial species, such as Akkermansia muciniphila, correlate with decreased levels of host serum proteins involved in metabolism and immunity, such as IGFBP1 and GP6 (Liu et al., 2025). The metaproteome also documents the disruption of the intestinal barrier by tracking changes in host structural proteins, such as mucin-2 and various immunoglobulin polypeptides, which serve as biomarkers for low-grade inflammation and increased gut permeabi