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The gut microbiota is a highly specialized organ containing host-specific assemblages of microbes whereby metabolic activity directly impacts human health and disease. In vitro gut fermentation models present an unmatched opportunity of performing studies frequently challenged in humans and animals owing to ethical concerns. Multidisciplinary systems biology analyses supported by ‘-omics’ platforms remain widely neglected in the field of in vitro gut fermentation modeling but are key to advancing the significance of these models. Model-driven experimentation using a combination of in vitro gut fermentation and in vitro human cell models represent an advanced approach in identifying complex host–microbe interactions and niches central to gut fermentation processes. The aim of this review is to highlight the advances and challenges exhibited by in vitro human gut fermentation modeling. [ABSTRACT FROM AUTHOR]