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Developmental Biology - Gut Development

Artificial Sweeteners On Trial Again

Exposure to artificial sweeteners sucralose and acesulfame-K in the womb and via breastmilk leads to altered intestinal bacteria and liver toxicity in mouse pups...

As a sugar substitute, zero-calorie sweeteners can reduce tooth decay and blood sugar spikes. Seven are approved worldwide as safe for humans - but does this mean they're healthy?

For the first time, scientists exposed pregnant and lactating mice to sucralose and acesulfame-K - a common combination found in sodas, sports drinks and other sweetened products - to find mouse pups develop harmful metabolic and gut bacterial changes.

Published in Frontiers in Microbiology, the study reinforces an emerging consensus: artificial sweeteners may be safe when used in moderation by adults, but are not a "magic bullet" alternative to sugar.

The Problem With Sweeteners

"Non-nutritive sweeteners are generally believed to be safe when used in moderation," says John Hanover PhD, a glycobiologist at the U.S. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health — and senior author of the study. Hanover collaborated with Stephanie Olivier Van Stichelen PhD, formerly at NIDDK and now Assistant Professor at the Medical College of Wisconsin, along with Dr. Kristina Rother, Chief of the NIDDK Section on Pediatric Diabetes and Metabolism.
"Sweetness itself seems to some extent mimic the effects of sugar - triggering insulin secretion, inflammation and changes to the gut microbiome - which promotes fat storage and type 2 diabetes."

John A. Hanover PhD, Glycobiologist, U.S. National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) and senior author of the study.

As sweeteners are known to be passed on in small amounts via the mother's placenta and through breast feeding, researchers wanted to know whether similar metabolic and microbiome changes occur in offspring following a mother's sweetener intake. They fed mouse moms one of three sweetener solutions throughout pregnancy and lactation, and analyzed the effects on their pups before being weaned. The solutions fed to the mother mice contained a mixture of sucralose and acesulfame-K at (1) the 'acceptable daily intake' (ADI), (2) double the ADI, or (3) a control of just water. The ADI is the maximum consumption deemed safe in humans based on toxicology studies.

"Sweeteners are often used in combination, partly because a blend can reduce the unpleasant bitter taste that some consumers experience," explains Kristina Ingeborn Rother PhD and a senior researcher at the National Institutes of Health in Bethesda, Maryland, USA. Olivier Van-Stichelen adds, "Combining sweeteners might also amplify the metabolic and microbiome effects - so we used the typical pairing of sucralose and ace-K to maximize the applicability of our results."

Sweetener Affects Nursing Offspring

Analysis of blood, feces and urine from a total of 226 mouse pups confirmed that both sweeteners are transmitted prenatally - and affect the metabolism and gut microbiome of mice offspring.

Even though the pups' exposure was low, researchers found significant metabolic changes in both ADI and 2xADI groups versus the control group drinking only water. Specifically, these changes indicated mouse pup livers had impaired function in clearing toxins from the pups' blood, and a dramatic shift in bacterial metabolites in their guts. For example, researchers observed the loss of a major beneficial gut bacterial species, Akkermansia muciniphila.
Similar microbiome alterations in humans have been linked to type 2 diabetes and obesity.

Should Pregnant or Nursing Mothers Avoid Sweeteners?

"Our results showed dose-dependent effects of sweetener exposure," researchers found — meaning the larger the amount of artificial sweetener consumed, the larger the affect on mouse pups.
Of note, the degree of metabolic change was much greater in the 2xADI than in the ADI group. Also, changes in sweetener exposed pups included lower overall body weight. Lower fasting blood glucose only became more prevalent in the 2xADI group.

However, microbiome changes were drastic even at the "acceptable" daily intake level.

Current recommendations for artificial sweetener during pregnancy state they may be used in moderation - except for saccharin, which should be avoided entirely.

However, artificial sweeteners are now found in more products than ever, including mouthwash, toothpaste, and medicines, as well as food and drinks. As food labels do not specify the amounts of added sweeteners, it is impossible to accurately track our intake.

In accordance with their findings, Olivier-Van Stichelen adds: "This research will be continued both in my recently started lab at the Medical College of Wisconsin, as well as in Drs. Hanover's and Rother's labs at the National Institutes of Health".
"The perinatal period is a critical developmental stage for the microbiome and emerging detoxification systems in the rodent and human neonate alike, and our study defines potentially adverse consequences of early exposure to sweeteners. Therefore, based on our findings, zero-calorie sweeteners warrant further investigation in humans in this critical developmental window."

John A. Hanover PhD

Columnar structure is a basic unit of the brain, but the mechanism underlying its development remains largely unknown. The medulla, the largest ganglion of the Drosophila melanogaster visual center, provides a unique opportunity to reveal the mechanisms of three-dimensional organization of the columns. In this study, using N-cadherin (Ncad) as a marker, we reveal the donut-like columnar structures along the two-dimensional layer in the larval medulla that evolves to form three distinct layers in pupal development. Column formation is initiated by three core neurons, R8, R7, and Mi1, which establish distinct concentric domains within a column. We demonstrate that Ncad-dependent relative adhesiveness of the core columnar neurons regulates their relative location within a column along a two-dimensional layer in the larval medulla according to the differential adhesion hypothesis. We also propose the presence of mutual interactions among the three layers during formation of the three-dimensional structures of the medulla columns.

Olena Trush, Chuyan Liu, Xujun Han, Yasuhiro Nakai, Rie Takayama, Hideki Murakawa, Jose A. Carrillo, Hiroki Takechi, Satoko Hakeda-Suzuki, Takashi Suzuki and Makoto Sato.

The authors thank Hugo Bellen, Takashi Hayashi, Aljosha Nern, Takumi Suzuki and Tetsuo Yasugi for critical comments on the manuscript. We are grateful to Martin Heisenberg, Graeme Mardon, Hideji Murakoshi, Tadashi Uemura and S. Lawrence Zipursky for reagents and fly strains. We thank Bloomington Stock Center, Vienna Drosophila RNAi Center and DGRC, Kyoto for fly strains and Developmental Study Hybridoma Bank (DSHB) for antibodies. This work was supported by Grant-in-Aid for JSPS Research Fellow (to O.T.), CREST from JST, Grant-in-Aid for Scientific Research (B) from MEXT, Takeda Science Foundation and Cooperative Research of 'Network Joint Research Center for Materials and Devices' (to M.S.), and by Grant-in-Aid for Scientific Research on Innovative Areas from MEXT (To M.S. and T.S.).

Frontiers is an award-winning Open Science platform and leading open-access scholarly publisher. Our mission is to make high-quality, peer-reviewed research articles rapidly and freely available to everybody in the world, thereby accelerating scientific and technological innovation, societal progress and economic growth. Frontiers received the 2014 ALPSP Gold Award for Innovation in Publishing. For more information, visit http://www.frontiersin.org and follow @Frontiersin on Twitter.

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Jul 1 2019   Fetal Timeline   Maternal Timeline   News  

Mouse pups developed harmful metabolic and gut bacteria changes after eating food laced with sucralose and acesulfame-K, both found in soda, sports supplements and pre-sweetened foods.

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