Microbiota-dependent in vivo biotransformation, accumulation, and excretion of arsenic from arsenobetaine-rich diet

Arsenic (As) is a naturally occurring metalloid that is ubiquitous in the environment. Various chemical forms of As, collectively referred to as "As species", find their way into the food chain, impacting the health of millions globally. Many of these As species are products of bacterial enzymatic transformations in different environments. Yet, the in vivo gut microbial transformation of As and its consequences in the host, especially for less toxic As species like arsenobetaine (AB), remain elusive. Current regulatory assessments regard AB-rich foods, including various seafoods, as safe due to low toxicity and rapid unmodified urinary excretion of the ingested AB. This notion has been challenged by reports of AB metabolism by intestinal bacteria in vitro and by more recent evidence of in vivo AB metabolism in mice. However, these studies did not definitively establish the causal role of intestinal bacteria in AB transformation in vivo. To address this, we employed gnotobiology that allowed us to compare the biotransformation of As from a naturally AB-rich rodent diet in isogenic mice that were either completely germ-free, or colonized with gut microbiota of varying microbial diversity. Additionally, we examined the body distribution, accumulation, and clearance of the ingested As in these mice. Our results confirm the in vivo metabolism of AB in the intestine under chronic dietary exposure. The transformation of ingested As was found to be dependent on the presence/absence and complexity of the gut microbiota. Notably, specific toxic As species were absent under germ-free condition. Furthermore, gut microbial colonization was linked to increased As accumulation in the intestinal lumen as well as systemically, along with delayed clearance from the body. These findings emphasize the mammalian gut microbiota as a critical factor in evaluating the safety of AB-accumulating seafoods.