Dr. Patrick: Since you mentioned the artificial sweeteners, maybe we can kind of dive into that just for a moment because it's fascinating work that your lab has done on the metabolic effects of, for example, artificial sweeteners but also like food additives, emulsifiers. So you mentioned that the people had diverse responses to artificial sweeteners. What were those responses?

Dr. Elinav: Yeah. So the study that we've published mainly focused on mice, and in mice, we studied several artificial sweeteners, but we mainly focused on saccharin as the very marked example. And what we found to our very big surprise was that mice featured a counterintuitive disturbance in their glycemic responses when they were exposed to saccharin, and this was driven by their microbiome. So, for example, when you exposed mice to saccharin at different doses and took the microbiome after this exposure and transferred it into germ-free mice that never saw saccharine, they developed the same disturbances in blood sugar control as those of the donor mice. And so this was a very complex study that provided a proof of concept that some dietary compounds that we use, mainly modern dietary compounds that we regard as inert because they don't seem to directly impact our body, may impact our body in peculiar ways indirectly through their effects on the microbiome. And this I think proof of concept study was followed by many other studies. You mentioned emulsifiers, and there were studies on food colorants and other ingredients, which may bear effect in some people based on their impacts mediated on the gut microbes, and this needs to be taken into consideration when assessing the safety and the inertness of such substances.

Dr. Patrick: I think I recall reading the levels of the dietary emulsifiers were even perhaps in levels that were relevant for humans.

Dr. Elinav: Yeah. In some of the mouse studies, the levels were higher than in humans, but in many of them, the levels were, you know, very similar to the ones observed in humans. It's difficult to directly compare mice to humans. The metabolism is not exactly the same, and we need to, you know, say that out loud. The concepts in many cases are very similar and the effects are very similar, but mice are not humans. But at least they suggest that such impacts could be happening. And, you know, the burden of proof is on us. You know, before we recommend a substance, we need to make sure that at least sufficiently we understand what it does to our microbes, what it does to our human body to make sure that we do no harm. So not every mouse-based study could be directly translated into humans, but many of them provide an intelligence hypothesis that needs to be ruled in or ruled out in human studies that follow.

Dr. Patrick: Well said. Were there any preliminary human studies that were followed up with the artificial sweeteners and/or the emulsifiers?

Dr. Elinav: So with the artificial sweeteners as part of the original study, we published a very preliminary small scale study suggesting that personalized responses to saccharine in humans do occur and could be even transferred upon microbiome transfers from humans into germ-free mice. This was a very small preliminary study that we and others are trying to follow up on in larger controlled trials that I hope would teach us on potential personalized effects and how we can anticipate them or predict them in ways which would keep the use safe while, you know, letting people enjoy sweetness. But I would certainly say that there is emerging evidence that the findings that we came up with are not only reproducible in multiple animal models, you know, starting from flies and all the way to mice, rats, and piglets, but they may be relevant to humans. The jury's still out there. This is a very young field. We'll wait for more results.

Dr. Patrick: Oh, if I can give you a suggestion, I think most people nowadays don't consume saccharin like they did 30, 20 years ago. The big ones that I know a lot of people would be interested in knowing whether or not they're affecting the microbiome in a good or bad way or if they're neutral in their effects on metabolisms as well would be some of the non-nutritive sweeteners that are from natural sources like stevia or the monk fruit extract. So if you guys are interested in looking at that, I think, you know, that many people would be very, very interested in that data as well because a lot of people consume it.

Dr. Elinav: I can only say we're on it. Stay tuned.