Plant-based materials are an important source of bioactive compounds (BC) with interesting industrial applications. Therefore, adequate experimental strategies for maximizing their recovery yield are required. Among all procedures for extracting BC (maceration, Soxhlet, hydro-distillation, pulsed-electric field, enzyme, microwave, high hydrostatic pressure, and supercritical fluids), the ultrasound-assisted extraction (UAE) highlighted as an advanced, cost-efficient, eco-friendly, and sustainable alternative for recovering BC (polyphenols, flavonoids, anthocyanins, and carotenoids) from plant sources with higher yields. However, the UAE efficiency is influenced by several factors, including operational variables and extraction process (frequency, amplitude, ultrasonic power, pulse cycle, type of solvent, extraction time, solvent-to-solid ratio, pH, particle size, and temperature) that exert an impact on the molecular structures of targeted molecules, leading to variations in their biological properties. In this context, a diverse design of experiments (DOEs), including full or fractional factorial, Plackett–Burman, Box-Behnken, Central composite, Taguchi, Mixture, D-optimal, and Doehlert have been investigated alone and in combination to optimize the UAE of BC from plant-based materials, using the response surface methodology and mathematical models in a simple or multi-factorial/multi-response approach. The present review summarizes the advantages and limitations of the most common DOEs investigated to optimize the UAE of bioactive compounds from plant-based materials.

• High protein diet is linked to various disorders such as cancer, obesity, diabetes or dysbiosis. • Undigested protein catabolism by microbiota results in metabolites considered as risk factors related to several gastrointestinal diseases. • Ammonia, amines, polyamines, hydrogen sulfide, indole and phenol are the main gut metabolites from undigested protein fermentation. • Indole and its derivatives have been positively associated with glycemic control and inflammation suppression. • Protein microbial metabolites are potential biomarkers to be used for several diseases’ diagnosis.