Ortega, E. F. | bioRxiv Science

bioRxiv2025

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. At each timepoint, diet was measured by averaging up to 3 consecutive days of 24-hour dietary records (NCI ASA24; 35 patients; 2.5{+/-}1.1 timepoints per patient), while microbiome composition was measured from stool (16S rRNA gene sequencing, metagenomics, qPCR; 40 patients; 5.6{+/-}1.4 timepoints per patient). 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 Faecalibacterium prausnitzii 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 Fusobacterium nucleatum in patients and inhibited F. nucleatum in cell assays. Together, these data suggest that changes in diet during chemotherapy 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.

microbiology↗

bioRxiv2025

Gut bacterial lactate stimulates lung epithelial mitochondria and exacerbates acute lung injury

Acute respiratory distress syndrome (ARDS) is an often fatal critical illness where lung epithelial injury leads to intrapulmonary fluid accumulation. ARDS became widespread during the COVID-19 pandemic, motivating a renewed effort to understand the complex etiology of this disease. Rigorous prior work has implicated lung endothelial and epithelial injury in response to an insult such as bacterial infection; however, the impact of microorganisms found in other organs on ARDS remains unclear. Here, we use a combination of gnotobiotic mice, cell culture experiments, and re-analyses of a large metabolomics dataset from ARDS patients to reveal that gut bacteria impact lung cellular respiration by releasing metabolites that alter mitochondrial activity in lung epithelium. Colonization of germ-free mice with a complex gut microbiota stimulated lung mitochondrial gene expression. A single human gut bacterial species, Bifidobacterium adolescentis, was sufficient to replicate this effect, leading to a significant increase in mitochondrial membrane potential in lung epithelial cells. We then used genome sequencing and mass spectrometry to confirm that B. adolescentis produces L-lactate, which was sufficient to increase mitochondrial activity in lung epithelial cells. Finally, we found that serum lactate was significantly associated with disease severity in patients with ARDS from the Early Assessment of Renal and Lung Injury (EARLI) cohort. Together, these results emphasize the importance of more broadly characterizing the microbial etiology of ARDS and other lung diseases given the ability of gut bacterial metabolites to remotely control lung cellular respiration. Our discovery of a single bacteria-metabolite pair provides a proof-of-concept for systematically testing other microbial metabolites and a mechanistic biomarker that could be pursued in future clinical studies. Furthermore, our work adds to the growing literature linking the microbiome to mitochondrial function, raising intriguing questions as to the bidirectional communication between our endo- and ecto-symbionts.

molecular biology↗