Dietary fiber is an important part of a healthy diet, but how it interacts with our gut microbiome and the mechanisms underlying its benefits are poorly understood in humans. A recent exploratory trial examined how two structurally distinct purified fibers affected adults with excess weight. One of the dietary fibers, arabinoxylan (AX), was fermentable by the microbiome, while the second, microcrystalline cellulose (MCC), was not fermentable. An innovative technique called biorthogonal non-canonical amino acid tagging (BONCAT) was also used to identify specific microbes involved in AX fermentation. AX supplementation increased satiety after a meal compared to non-fermentable MCC. Using machine learning models, these effects on satiety could be predicted by BONCAT identified microbes that fermented AX. AX also attenuated insulin resistance relative to MCC, but the effects were not linked to the microbiome. MCC supplementation reduced markers of both systemic and gut inflammation, TNF-α and fecal calprotectin, relative to baseline. These anti-inflammatory effects were likely independent of the gut microbiome. While more research is needed, this study shows efficacy for purified fiber supplements in humans and provides a basis for more targeted therapeutic applications of purified fibers and their personalization based on the gut microbiome.