Coupling NaDES-Based Polyphenol Extraction and Anaerobic Fermentation in Grape Pomace Biorefineries: Experimental Evidence and Stoichiometric Assessment of Residual Solvent Effects

Grape pomace (GP) is a promising feedstock for integrated biorefineries that combine the recovery of high-value compounds with biological conversion processes. In this study, polyphenol extraction using Natural Deep Eutectic Solvents (NaDES) was coupled with anaerobic fermentation of white and Red-GP operated at two hydraulic retention times (10 and 20 days) at 37 ± 1 °C. The selected NaDES comprised glucose–citric acid– water (GCW) or glucose–lactic acid–water (GLW). Polyphenol extraction was substrate-dependent: NaDES recovered approximately 3.0–6.8 mg GAE g–1 from white GP, below MeOH/HCl (11.2 mg GAE g–1 ), whereas 3.6–4.6 mg GAE g–1 were recovered from Red-GP, comparable to MeOH/HCl (4.6 mg GAE g–1 ). Untreated substrates exhibited distinct fermentation behaviors: white GP achieved higher total biogas yields (180–250 L kgVS–1 ), whereas Red-GP produced H2-rich biogas at an HRT of 10 days (approximately 39% H2) and CH4-rich biogas at an HRT of 20 days (approximately 80% CH4). In contrast, NaDES-pretreated GP showed a drastic reduction in biogas production (3–17 L kgVS–1 ), with the biogas composed almost exclusively of CO2. A stoichiometric model revealed that NaDES carry-over accounted for a substantial solvent-derived fraction of the influent COD, corresponding to up to 0.93 g COD g–1 GP for glucose–citric acid systems and 0.34 g COD g–1 GP for glucose–lactic acid systems. This readily biodegradable carbon stream, together with substrate modification induced by extraction, reshaped microbial pathways, promoting acidogenesis and the accumulation of soluble intermediates. Volatile fatty acid (VFA) profiles were strongly influenced by NaDES composition: glucose–citric acid systems favored acetate-dominated patterns, whereas glucose–lactic acid systems enabled the formation of more reduced products and caproate (up to ∼8% w/w) at longer retention times. However, NaDES pretreatment did not enhance overall caproate production compared to untreated GP. Overall, the results demonstrate that NaDES cannot be regarded as biologically inert extraction media. Their carry-over introduces a composition-dependent carbon input that markedly alters fermentation performance, highlighting the need for solvent management strategies when integrating NaDES extraction with anaerobic bioconversion in GP biorefineries.