Shifts in the human gut microbiome during cancer chemotherapy are diet-dependent

Numerous studies have implicated both dietary intake and the human gut microbiome in colorectal cancer (CRC) treatment outcomes. However, little is known about how patients adjust their dietary intake during cancer chemotherapy or if these dietary changes contribute to treatment-associated alterations in the gut microbiome. We performed paired longitudinal diet and microbiome analysis during CRC treatment with oral fluoropyrimidines (NCT04054908) and validated key associations using cell culture assays. Diet quality significantly decreased during chemotherapy. Carbohydrate and refined grain intake increased, accompanied by decreased consumption of fats, nuts and seeds, and fat-soluble micronutrients. Multiple individual dietary components were strongly linked to the gut microbiome. Decreases in theobromine intake correlated with decreases in overall microbial diversity and more gastrointestinal toxicities. Diet shifts partly explained changes in bacterial abundance during chemotherapy, including more severe depletion of <i>Faecalibacterium prausnitzii</i> in patients with decreased vitamin K₁ intake. Changes in diet were correlated with multiple bacterial gene families involved in micronutrient metabolism and drug sensitivity. Increased copper intake was linked to decreased <i>Fusobacterium nucleatum</i> in patients and inhibited <i>F. nucleatum</i> in cell assays. Together, these data suggest that chemotherapy-related decreases in diet quality and micronutrient intake contribute to changes in gut bacterial diversity, taxonomic composition, and gene abundance. Our approach may generalize to other cancer therapies and emphasizes the need for collecting more robust dietary data in clinical microbiome studies.