Invited Perspective: PFOS–Pick Fiber, Oust Sulfonate

As residents of Toledo, Ohio—a city that neighbors Flint, Michigan, and lies along Lake Erie, with its frequent algal blooms—we deeply appreciate both the critical importance of clean, safe drinking water and the complexity of remediating and preventing contamination. Cooperative actions of prevention include researching the data gaps, developing safe alternatives of the toxic agent, mitigating the release of chemicals into the environment, and raising awareness to the public and policy holders. These implemented plans have been useful in reducing contamination of many toxicants, but some agents, such as perand polyfluoroalkyl substances (PFAS), have been overlooked for several reasons, including from inadequate assessment of their exposure level in the environment. Of other concern, preventing contamination events may help only so much for those who have been previously exposed to a toxic chemical. We reason this to be true when considering that many chemicals grouped under PFAS have long half-lives that range from 3 to 5 y after exposure. Other evidence to support our notion is from epidemiological studies that have uncovered environmental toxicants, such as PFAS, to cause adverse health outcomes that can vary based on their toxicokinetic properties. Altogether, we believe one of the main goals to preventing detrimental side effects of toxic exposures should be to determine a clinical intervention that can enable individuals to metabolize and excrete the agent more quickly. A recent, elegant study by Deng et al. provides a step toward this goal by identifying a potential dietary intervention to mitigate the adverse effects of perfluorooctane sulfonate (PFOS). PFOS is the most common of the PFAS and can contaminate both drinking water and food, such as fish and vegetables. For perspective, a recent 2016 report determined that drinking water supplied to 6 million U.S. residents was contaminated with PFOS at levels (>70 ng=L) exceeding the U.S. Environmental Protection Agency’s lifetime health advisory for PFOS exposure. The National Health and Nutrition Examination Survey also found that individuals ≥12 years of age who consumed even small amounts of fish had a 10%–20% increase in PFOS levels when compared with nonconsumers. Oral exposure to PFOS can result in several health consequences, including a severe imbalance and alterations in the gut microbial community, that is, microbiota dysbiosis, as demonstrated in mouse and zebrafish models. Other pathologies following PFOS exposure that could be a sequel of gut microbiota dysbiosis encompass hepatic inflammation and steatosis.12–14 There are only a few reports that nutritional agents, such as curcumin and vitamin C, protect against PFOS by alleviating hepatic inflammation; these reports are typically observed in rodent models. Of note, one study reported that a probiotic cocktail of lactic acid bacteria can revert both gut and liver damage induced by PFOS in mice. Given that gut microbiota dysbiosis is a consequence of PFOS and could be the cause of other intestinal and liver damage following PFOS exposure, interventions that target the gut microbiota would be clinically relevant. Following this concept, Deng et al. pieced together two key findings from the literature: a) ablating or reshaping the gut microbiota by antibiotic treatment or fecal microbiota transplantation, respectively, alleviated PFOS-induced hepatotoxicity in mice, and b) self-reported high intake of dietary fiber was associated with a lower serum concentration of PFOS. Dietary fibers are plant-derived complex carbohydrates with prebiotic properties that nourish the gut bacteria by their fermentation into short-chain fatty acids. Together, these studies provided a strong rationale for Deng et al. to test fermentable fibers such as inulin (polyfructosan) and pectin (polygalacturonate) as a plausible therapy to abate PFOS accumulation and the related adverse effects in mice. Indeed, the authors found dietary inulin, and to a lesser degree, pectin, corrected fecal microbiota dysbiosis detected in PFOS-exposed animals. The restoration of the fecal microbiota profile may have contributed to the observed mitigation of PFOSinduced liver pathology following dietary fiber intervention, but more studies are required to affirm this possible mechanistic link. Using an integrated multi-omics approach, Deng et al. delineated that the protective effects of dietary inulin resulted from lowering the PFOS-induced increase in hepatic ceramides and sphingolipids, molecules associatedwithmetabolic dysfunction. Previous studies have supported the notion that inulin has predominant effects in promoting health when compared with other fermentable fibers, such as pectin, but recent evidence now shows an irony of extremes. Dietary inulin can either substantially alleviate or deteriorate health conditions, and which end of the spectrum is observed depends on the context of disease. In contrast to the report by Deng et al., which highlights inulin as helpful against PFOS, our prior reports demonstrated inulin to be very harmful in mice with inflammatory bowel disease, whereas pectin rescued them from disease. We believe this disparity is probably attributed to an unevenness in fiber fermentation, as well as to the production of short-chain fatty acids and their utilization via cross-feeding among themselves by gut microbiota in different disease conditions. The disproportion in fiber fermentation would then contribute to an overwhelming and endless possibility of gut microbiota signatures for each pathology, making it impossible to label individual bacterial species as either universally good or universally bad. Accordingly, the distinct effects of dietary fiber reinforce the concept that not every intervention can be repurposed as a new treatment for another disease. In the context of PFOS, though, inulin, and to a slight degree, pectin, have some possible advantage in restoring eubiosis, or balance, in gut microbiota homeostasis and reducing liver damage caused by PFOS. Subsequent studies are warranted to verify these dietary fermentable fibers as clinically relevant interventions. Although introducing more dietary fiber into the diet could be favorable for mitigating the effects of PFOS, individuals are Address correspondence to Matam Vijay-Kumar, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo OH 43614 USA. Telephone: (419) 383-4130. Email: MatamVijay.Kumar@UToledo.edu The authors declare they have nothing to disclose. Received 17 August 2022; Revised 24 September 2022; Accepted 28 September 2022; Published 4 November 2022. Note to readers with disabilities: EHP strives to ensure that all journal content is accessible to all readers. 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