Sucralose, Hazardous or Innocent? Part II: Appetite, Gut Health & Food Reward | Sucralose, Gluttony & Adiposity?

Plain mineral water is still the best thing to quench your thirst.

Today we are going to continue our thorough, educated reading of the recently published overview over the biological issues with sucrolase, a "popular" artificial sweetener most of you will probably know by its brand name Splenda. The focus of part I of this series was on the potential pro-diabetic effects of this agent that belongs to a class of molecules that has originally been hailed as a solution to the diabetes problem (it goes without saying that I am talking about artificial sweeteners here, right?). In a way we are thus only continuing the discussion, when we are trying to verify Schiffman's & Rother's argument that the consumption of sucralose is associated with an increase in obesity risk... or, put more simply that using sucralose is going to make you fat, not lean.

The good old "energy in" vs. "energy out" argument

As SuppVersity readers you are well aware that the oversimplified concept of an "energy balance" is fundamentally flawed. My recent post "Anorexia study suggests: Your body can easily reduce its resting metabolic rate by 10%" in the SuppVersity Facebook News is only one out of thousands of scientific papers you could quote to point out that replacing 420kcal of energy from pure sugar, i.e. three cans of regular coke, with its diet variety is not going to produce a net weight, let alone fat loss of 420g per week (suggested read: "Busting the 3,500kcal = 1lbs Weight Loss Myth!" | learn more).
Thus being "in the know", you can only shake your head, when you read how Schiffman and Rother (ab-)use a recent study by Ruyter et al. (2012) to support the non-significant, not sufficiently differentiated data from epidemiological studies which inform us that obese people are more likely to consume artificial sweetened products than lean ones, to subliminally imply that artificial sweeteners would not help, in some cases even hinder weight loss.

"In an 18-mo trial with children, participants were randomly assigned to receive an 8-oz can per day of either a noncalorically sweetened or a sugarsweetened beverage that provided 104 kcal (de Ruyter et al., 2012). [...] The calorie consumption from these beverages was 46,627 kcal greater for children in the sugar-sweetened group than in the sucralose-sweetened group (5.8 × 77.3 × 104). In spite of this highly significant difference in calories consumed from the beverages, the total weight gain over this 18-mo study was only 1 kg greater for children in the sugar-sweetened group compared to sucralose group. No explanation was provided to account for the small difference in weight gain given the large difference in caloric consumption from the beverages." (Schiffman. 2013)

Despite the fact that Schiffman & Rother acknowledge that the scientists would not have been able to detect, if the children who consumed the sugar-sweetened beverages compensated by reducing their food intake, the reviewers fail to point out that neither this, nor the second "evidence" they cite, a 2-year study by Ebbeling et al. (2012), where Schiffman & Rother simply ignore the fact that the mere provision of diet sodas to the families of the adolescent subjects did reduce the weight gain in the active intervention period (1st year, see Figure 1, below), would confirm a negative real-world effect on body weight.

Figure 1: Change in body fat percentage (vs. basleline) of adolescents during the intervention & follow up period in the Ebbeling study (2012), of which the reviewers only cite the results of the follow up.

Let's be honest: If you actually take a look at the results from the Ebbeling study (Figure 1), you will have to concede that this study refutes the claim that artificial sweeteners make you fat. During the active treatment period, in the course of which the adolescent participants were...

• "What Really Happens, When Nutrition Science Meets Real Life" | more

  ... supplied with noncaloric beverages (e.g., bottled water and “diet” beverages for the whole family) every 2 weeks, getting monthly motivational telephone calls with parents (30 minutes per call), 
• ... having three check-in visits with participants (20 minutes per visit), and 
• ... receiving written intervention messages with instructions to drink the delivered beverages and not to buy or drink sugar-sweetened beverages, were mailed to participants

...they do exactly what we originally expected them to do: They ameliorate the body fat gain in the adolescent subjects. In other words: As long as respective products are available, and dietary adherence is encourages, replacing regular sugar sweetened with artificial sweetened or unsweetened beverages can have a significant ameliorative effect on the body fat gains of adolescents - irrespective of the fact that they were obviously free to compensate with chocolate, cookies, etc..

Contemporary evidence from RCTs suggest either no, or beneficial effects

If you follow Schiffman's and Rother's lead and discard potential differences between sucrose and other sweeteners, acknowledge the fact that the results from previous rodent experiments have repeatedly failed to translate to human beings and take into account that this data is "inconsistent and conflicting" (Schiffman. 2013), anyways, you will be hard pressed to find arguments to support the claim that artificial sweeteners could hinder weight loss.
In fact, the vast majority of RCTs clearly supports the assumption that non-nutritive sweeteners (NNS), artificial or not, promote weight loss and blunt weight (re-)gain (De la Hunty. 2006; Bellisle. 2007). The argument that these effects do satisfy the calories in vs. calories out hypothesis is pathetic, to say the least. Even a 100% controlled diet won't comply to an equation that is about as accurate as "1+2=343". We can thus register that:

1. There is ample evidence to support the beneficial effects of artificial sweeteners (including sucralose) as a tool during controlled dietary interventions.
2. There is insufficient evidence to support the claim that their regular consumption has a negative effect on body weight.

With respect to (2) we would even have to say that the limited amount of useful* evidence we have would rather suggest beneficial than detrimental effects (*a 'useful' study is not a study that tells me that obese individuals are more likely to consume artificially sweetened products than lean ones like the often cited epidemiological data). This is particularly true, for controlled interventions where sugar-sweetened beverages were replaced by their artificially sweetened counterparts.

The great unknown: Hunger, appetite and food reward

If data on the real-world effects of sucralose consumption on body weight gain is "scarce", consistent, experimentally verified hypotheses that would explain the potential underlying mechanism are quasi non-existent... or, I should clarify: They are still in their infancy. Against that background it's quite astonishing that more and more people appear to take it for granted that the consumption of artificially sweetened foods will mess with both, (a) your ability to control your energy intake and (b) the hedonistic response you derive from foods.

Table 1: Sweetness, dose to stimulate the sweet taste receptor (EC50; based on Matsuda. 2011) and correlation of sweetness and EC-50 value.

It goes without saying that there is no sucralose-specifc data out there, but the decrease in hypothalamic sweet taste receptor density I mentioned in the first installment of this series is something I'd expect to see in response to all artificial sweeteners that make it across the blood brain barrier (Note: Even Schiffman & Rother acknowledge that we do not know if they even do that!) - probably "sweetness" dependent,  by the way.  This would imply that sucralose would be the worst, cyclamate the least offender among the common artificial sweeteners in Table 1. With a sweetness that's 300x higher than that of sucrose, stevia would end up being the "(un?)happy medium".

Despite the fact that Schiffman & Rother don't really address this issue in their paper, I still want want to address the practical and thus relevant aspect of the various proposed theories for potential sweetener-induced increases in energy consumption.

Figure 2: Mean effective change in energy intake (%) in RCTs investigating the degree of energy compensation in response to the provision of artificial sweetened products (De la Hunty. 2006)

As the data from De La Hunty's 2006 meta-analysis of 32 study outcomes in Figure 2 clearly demonstrates, there is a statistically highly significant (p < 0.001) trend towards reduced energy consumption in the RCT [randomized controlled trial]. In that, the degree of compensation for the sudden energy reduction due to ingestion of calorically less dense, since artificially sweetened product ranged from statistically non-significant 18% to statistically highly significant 86% in trials such as Porikos et al. (1982), where 6 men lost and gained 0.8kg of body weight within 2x12 days in a metabolic ward on artificially sweetened and sucrose sweetened ad-libitum diets, respectively.
Just like the previously discussed (relatively short term) effects on insulin, GLP-1 and co, the #2 on the list of most frequently heard objections against the use of artificial sweeteners, i.e. dietary overcompensation, does thus appear to have little basis in fact. What we do not know, though, is whether the results will be identical for all types of sweeteners, or whether sucralose may be the toxic (this aspect will be covered in the next installment) or gut microbiome disrupting exception to the rule.

Sucralose induces changes in the gut microbiome

The last issue I want to address in this second installment of the "Sucralose, Hazardous or Innocent Trilogy" will thus revolve around the question, whether a modulatory effect of sucralose on the microbial composition of your gut could induce potential negative long-term effects that would not show up in the hitherto discussed RCTs.

Under the headline "Effect of Sucralose on the Number and Relative Proportions of Different Intestinal Bacterial Types", Schiffman & Rother argue that it has long been known that bacteria from the oral cavity and soil cannot use sucralose as a growth substrate. If the same was true for the bacteria in our guts the replacement of regular sugar with sucralose would thus starve our (beneficial) subtenants.

Table 2: Differences (%) in bacterial counts in feces of rodents on diets containing what in human terms would be ~14mg, 43mg, 71mg and 156mg of sucralose per day after 12 weeks treatment and 12 weeks into "recovery" (Abou-Donia. 2008)

Based on the fecal bacterial count of rodents on diets that would be equivalent to 14mg, 43mg, 71mg and 156mg of sucralose per day in human beings (see Table 2), Schiffman & Rother argue that chronic (12-week) ingestion of relatively low amounts of sucralose (a single can of Diet Crush Cream Soda, for example, has 42mg of sucralose) lead to highly significant reductions in the numbers of total anaerobes, bifidobacteria, lactobacilli, Bacteroides, clostridia, and total aerobic bacteria.

In view of the fact that Abou-Donia et al. (2008) observed the most significant losses in bifido- and lactobacillus strains, i.e. those strains that have repeatedly been implicated as the driving forces of the beneficial health effects of probiotic supplementation, this and not the previously discussed pro-diabesity effects should be the point where people start to freak out.

Table 4: Other sweeteners are preferred food for certain bacteria and may also alter the gut microbiome (Payne. 2012).

This is particularly true if you take into account that at least part of the beneficial effects of lactobacilli may be related to their ability to keep the number of enterobacteria, a large family of Gram-negative bacteria that includes both harmless symbionts, as well as a whole host of familiar pathogens, such as Salmonella, Escherichia coli, Yersinia pestis, Klebsiella and Shigella, Proteus, Enterobacter, Serratia, and Citrobacter in check (Liévin-Le Moal. 2006) - exactly those bacteria, which produce the nasty lipo polysaccharides (LPS) that have been associated with inflammation and its downstream metabolic effects, such as obesity, diabetes, heart disease, gastrointestinal cancer etc. and, as the data in Table 2 tells you. Now, unfortunately, the these villains are all part only type of bacteria that was not significantly decimated by the sucralose challenge.

As Schiffman et al. point out these reductions are not, as Brusick et al. (2009) suggest simply a result of "normal variation". In fact, the probability to see a similar random reduction in bifidobacterial count occur "naturally"within 12 weeks would be 1/5000. It is thus more than just unlikely that the71.9%, 76%, and 77.7% reductions in bifidobacteria counts Abou-Donia et al. observed at dosages of 3.3, 5.5, and 11 mg/kg/d were coincidental.
Reference:

• Abou-Donia, M. B., El-Masry, E. M., Abdel-Rahman, A. A., McLendon, R. E., & Schiffman, S. S. (2008). Splenda alters gut microflora and increases intestinal p-glycoprotein and cytochrome p-450 in male rats. Journal of Toxicology and Environmental Health, Part A, 71(21), 1415-1429.
• Bellisle, F., & Drewnowski, A. (2007). Intense sweeteners, energy intake and the control of body weight. European Journal of Clinical Nutrition, 61(6), 691-700.
• De la Hunty, A., Gibson, S., & Ashwell, M. (2006). A review of the effectiveness of aspartame in helping with weight control. Nutrition Bulletin, 31(2), 115-128.
• de Ruyter, J. C., Olthof, M. R., Seidell, J. C., & Katan, M. B. (2012). A trial of sugar-free or sugar-sweetened beverages and body weight in children. New England Journal of Medicine, 367(15), 1397-1406.
• Ebbeling, C. B., Feldman, H. A., Chomitz, V. R., Antonelli, T. A., Gortmaker, S. L., Osganian, S. K., & Ludwig, D. S. (2012). A randomized trial of sugar-sweetened beverages and adolescent body weight. New England Journal of Medicine, 367(15), 1407-1416.
• Liévin-Le Moal, V., & Servin, A. L. (2006). The front line of enteric host defense against unwelcome intrusion of harmful microorganisms: mucins, antimicrobial peptides, and microbiota. Clinical Microbiology Reviews, 19(2), 315-337.
• Mattes, R. D. (1996). Dietary compensation by humans for supplemental energy provided as ethanol or carbohydrate in fluids. Physiology & Behavior, 59(1), 179-187.
• Mattes, R. D., & Popkin, B. M. (2009). Nonnutritive sweetener consumption in humans: effects on appetite and food intake and their putative mechanisms. The American journal of clinical nutrition, 89(1), 1-14.
• Payne, A. N., Chassard, C., & Lacroix, C. (2012). Gut microbial adaptation to dietary consumption of fructose, artificial sweeteners and sugar alcohols: implications for host–microbe interactions contributing to obesity. Obesity Reviews, 13(9), 799-809.
• Porikos, K. P., Hesser, M. F., & Van Itallie, T. B. (1982). Caloric regulation in normal-weight men maintained on a palatable diet of concentional foods. Physiology & behavior, 29(2), 293-300.
• Schiffman, S. S., & Rother, K. I. (2013). Sucralose, A Synthetic Organochlorine Sweetener: Overview Of Biological Issues. Journal of Toxicology and Environmental Health, Part B, 16(7), 399-451.