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Interactions of Environmental Pollutants with Human Gut Bacteria https://doi.org/10.17863/CAM.113796 Lindell, Anna Patil, Kiran The environmental contamination by manufactured chemicals has by some estimates exceeded the safe planetary boundary. Due to the widespread contamination of water and agricultural systems, a vast number of chemical pollutants make it into the food and hence into the human body. While pharmaceutical drugs have been shown to have a strong impact on the human gut microbiota both in vitro and in vivo, relatively little is known about the effects of other compounds, such as pesticides, processing contaminants and environmental pollutants. To systematically assess the impact of chemical pollutants on gut bacterial growth I screened a comprehensive library of 1076 compounds likely to enter food and water due to pollution, agricultural application, or industrial processing against 22 phylogenetically representative human gut bacterial strains. This screen uncovered 588 interactions involving 168 (15.5 %) of the compounds tested, the majority of which were not previously reported to display anti-commensal activity. Fungicides and industrial chemicals showed the largest impact with circa 30 % exhibiting anti-commensal activities. Sensitivity of bacteria to pollutants showed strong correlation with sensitivity to therapeutic drugs as identified by a previous study, bringing forward future opportunities to computationally predict xenobiotic-bacteria interactions. A subset of 42 chemicals was further investigated for their susceptibility to depletion by gut bacterial communities. Thirteen chemicals were found to be depleted by at least one of the tested communities. Ten compounds were further assessed to identify the responsible bacterial strains. 52 interactions between seven compounds and thirteen strains were thus identified, with 38 instances of bioaccumulation and 14 instances of biotransformation. The fluorinated organic compounds bisphenol AF, perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA) were bioaccumulated, while boscalid, propiconazole, tributyl phosphate and triphenyl phosphate showed both interaction types depending on the bacterial strain. PFOA and PFNA belong to the chemical group of per-/poly-fluoroalkyl substances (PFAS) – the so called “forever chemicals”. PFAS are a major cause of environmental and health concern due to their toxicity, long-term persistence, and lack of an efficient way for their removal from the environment or the human body. I therefore pursued the observation of PFAS enrichment by gut bacterial strains. PFNA bioaccumulation showed distinct grouping by bacterial phylum, with Bacteroidetes showing highest accumulation capacity. Bioaccumulation occurred over a wide concentration range from ng/L to mg/L exposure levels until an equilibrium was reached. The abundant gut bacterium Bacteroides uniformis showed 50-fold enrichment of PFNA in the bacterial pellet compared to the exposure level. Escherichia coli, which accumulated PFAS to a much lesser extent, showed substantially increased PFAS bioaccumulation when lacking TolC efflux pump, indicating trans-membrane transport in PFAS bioaccumulation. PFAS bioaccumulation by specific gut bacteria is further supported by morphological changes observed in transmission electron microscopy and physiological changes as identified using metabolomics and proteomics. In an in vivo context, mice colonized with human gut bacteria showed, compared to germ-free controls or those colonized with low-bioaccumulating bacteria, higher PFNA levels in excreted feces, opening possibilities for bioprotection and detoxification. In summary, my results uncover novel chemical-bacteria interactions, reveal correlation of compound sensitivity between different xenobiotic classes, and bring forward the remarkable capacity of human gut bacteria to accumulate PFAS. The results have fundamental implications for understanding microbiome dynamics and its role in the toxicokinetics of chemical pollutants. University of Cambridge 2024-06-29 Thesis Doctoral Doctor of Philosophy (PhD) eng https://www.repository.cam.ac.uk/handle/1810/376634 embargo 2025-11-25 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/12ee235a-1bb3-4558-96b8-efb2ff1b0639/download 2b622e3b63ecea8ed75d3d2bb87a6b89 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/f2bf900b-c374-47ac-b63e-fbdadf4af3d0/download 87eda9de84448d1f82354d60eee3eb5f https://creativecommons.org/licenses/by-nc-nd/4.0/ Microbiota Pollutants PFAS Gut bacteria