Diverse mechanisms by which chemical pollutant exposure alters gut microbiota metabolism and inflammation.

The human gut microbiome, the host, and the environment are inextricably linked across the life course with significant health impacts. Consisting of trillions of bacteria, fungi, viruses, and other micro-organisms, microbiota living within our gut are particularly dynamic and responsible for digestion and metabolism of diverse classes of ingested chemical pollutants. Exposure to chemical pollutants not only in early life but throughout growth and into adulthood can alter human hosts' ability to absorb and metabolize xenobiotics, nutrients, and other components critical to health and longevity. Inflammation is a common mechanism underlying multiple environmentally related chronic conditions, including cardiovascular disease, multiple cancer types, and mental health. While growing research supports complex interactions between pollutants and the gut microbiome, significant gaps exist. Few reviews provide descriptions of the complex mechanisms by which chemical pollutants interact with the host microbiome through either direct or indirect pathways to alter disease risk, with a particular focus on inflammatory pathways. This review focuses on examples of several classes of pollutants commonly ingested by humans, including (i) heavy metals, (ii) persistent organic pollutants (POPs), and (iii) nitrates. Digestive enzymes and gut microbes are the first line of absorption and metabolism of these chemicals, and gut microbes have been shown to alter compounds from a less to more toxic state influencing subsequent distribution and excretion. In addition, chemical pollutants may interact with or alter the selection of more harmful and less commensal microbiota, leading to gut dysbiosis, and changes in receptor-mediated signaling pathways that alter the integrity and function of the gut intestinal tract. Arsenic, cadmium, and lead (heavy metals), influence the microbiome directly by altering different classes of bacteria, and subsequently driving inflammation through metabolite production and different signaling pathways (LPS/TLR4 or proteoglycan/TLR2 pathways). POPs can alter gut microbial composition either directly or indirectly depending on their ability to activate key signaling pathways within the intestine (e.g., PCB-126 and AHR). Nitrates and nitrites' effect on the gut and host may depend on their ability to be transformed to secondary and tertiary metabolites by gut bacteria. Future research should continue to support foundational research both in vitro, in vivo, and longitudinal population-based research to better identify opportunities for prevention, gain additional mechanistic insights into the complex interactions between environmental pollutants and the microbiome and support additional translational science.

Unbiased approach for the identification of molecular mechanisms sensitive to chemical exposures.

Targeted methods that dominated toxicological research until recently did not allow for screening of all molecular changes involved in toxic response. Therefore, it is difficult to infer if all major mechanisms of toxicity have already been discovered, or if some of them are still overlooked. We used data on 591,084 unique chemical-gene interactions to identify genes and molecular pathways most sensitive to chemical exposures. The list of identified pathways did not change significantly when analyses were done on different subsets of data with non-overlapping lists of chemical compounds indicative that our dataset is saturated enough to provide unbiased results. One of the most important findings of this study is that almost every known molecular mechanism may be affected by chemical exposures. Predictably, xenobiotic metabolism pathways, and mechanisms of cellular response to stress and damage were among the most sensitive. Additionally, we identified highly sensitive molecular pathways, which are not widely recognized as major targets of toxicants, including lipid metabolism pathways, longevity regulation cascade, and cytokine-mediated signaling. These mechanisms are relevant to significant public health problems, such as aging, cancer, metabolic and autoimmune disease. Thus, public health field will benefit from future focus of toxicological research on identified sensitive mechanisms.