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Sweet taste without the calories sounds like a perfect example of no pain, all gain but unfortunately cumulative data suggests otherwise. A poster child for unintended consequences, diet soda (Diet drink) typically contains a type of non-caloric artificial sweetener, Sugar substitute called Aspartame, e.g., NutraSweet or Equal (sweetener). Unintended consequences in the form of not just weight gain but also increased risk of Cardiovascular disease, Diabetes mellitus type 2, Hypertension, Metabolic syndrome, all vigorously disputed of course (see some examples in references 1, 2), which brings us to the glaring caveat we need to keep front and center when considering the science about artificial sweeteners. Historically the food and beverage industry has funded nutrition research so substantially, the ensuing entrenched conflict of interest renders the phrase 'nutrition science' an oxymoron (3).North America currently leads in sales and consumption of diet beverages (see below from 4).Artificial sweetener consumption patterns tend to change rapidly in response to widespread perception of harm attendant to one type of artificial sweetener or another. US artificial sweetener consumption for example moved from cyclamate in the 1960s to Saccharin, e.g., Sweet'n Low, to aspartame which reigned supreme for several decades until being upstaged in the 2010s by Sucralose, e.g., Splenda, mainly because it's highly stable in food (5) while Acesulfame potassium (Ace-K), e.g., Sunett, Sweet & Safe, Sweet One, is also increasing in use. Pepsi embodies such rapid change. In 2015 it changed its US Diet Pepsi formulation replacing aspartame with sucralose and Ace-K (6) but for reasons best known to itself announced in 2016 it was bringing aspartame back while also retaining the reformulated products (7). Meantime so-called natural sweeteners like Stevia aka Truvia are also rapidly increasing in prevalence (4).'If you can avoid taking in more food, does diet soda still somehow make you gain weight?'Weight gain without increased food intake is in fact a strikingly consistent observation in many animal model studies on artificial sweeteners (8, 9, 10). How does this happen? Problem with understanding how these artificial sweeteners affect human metabolism and health long-term is each artificial sweetener is different in chemistry, biology and pharmacokinetics (11, 12, 13, 14, see below from 4, 15). Obviously each will induce different metabolic and health effects.For long, uncertainty dogged epidemiological studies on artificial sweeteners. Do they cause cancer or not? Do they increase risk of diabetes and/or obesity or not? Do they play a role in metabolic syndrome or not? And so on. Given the big bucks riding on ensuring people continued to guzzle at least diet soda even as the tide turned against sodas in general (16), unsurprising really that much of this data is conflicting, mostly due to avoidable study design flaws such as assessing artificial sweetener consumption in conditions far removed from how they're consumed in real life, which is as part of a typical unhealthy 'Western' diet replete in highly processed food and as part of a highly sedentary lifestyle. Few studies included children or elderly or minorities or low income, few examined long-term/chronic/habitual artificial sweetener consumption.In other words, vast chasm between such studies and real life artificial sweetener consumption patterns. Most importantly, since different artificial sweeteners are used in different processed foods and drinks and since studies rarely address a single artificial sweetener specifically, we essentially don't understand how each artificial sweetener influences metabolism and health long-term (17).The few studies such as the San Antonio Heart (18) and Longitudinal Study of Aging (19) that examined elderly and minorities long-term (7 to 9 years follow-up) found substantial weight and waist circumference gain with artificial sweetener consumption (in soda, coffee or tea), even without increased food intake, which echoes animal model studies. Increased abdominal fat is of course now a well-known risk factor for cardiovascular disease and type II diabetes.How to make at least minimal sense of the tower of Babel that is artificial sweetener-related data? Same way as other prickly scientific issues, by looking at conclusions of systematic reviews and Meta-analysis. However, given the entrenched practice of the food and beverage industry funding a massive amount of nutrition research, not meta-analyses by just anyone but rather by those not funded by them. Since Publication bias, i.e., overweening dominance of studies with statistically significant results, is widespread, such reviews and analyses will naturally also be hobbled by the same drawback. However, since they use a set of objective criteria to assess a wide variety of individual studies ranging from cross-sectional to interventional to observational to prospective to randomized, placebo-controlled trials, they're still far more robust and objective than individual studies claiming to find in favor of one or other hypothesis.One such review (20) was conducted by federally funded Purdue University researcher Susan E. Swithers. It assessed differences between diet soda non-consumers and consumers among >450000 participants across 14 independent Prospective cohort study, including the San Antonio Heart Study (18), with an average 16-year followup. It concluded that regardless of baseline weight in the two groups, regardless naturally or artificially sweetened, soda consumption increased risk of not just weight gain but also cardiovascular disease, hypertension, metabolic syndrome and type II diabetes (20). Typically, bad news about artificially sweetened stuff is discredited by arguing overweight people tend to choose it in the first place trying to lose weight, i.e., by arguing reverse causality (21). In other words, arguing drinking artificially sweetened stuff doesn't cause weight gain, rather overweight people drink it to try to lose weight. This review (20) found that not to be the case.Swithers concluded (20),‘recent data from humans and rodent models have provided little support for ASB(everages) [artificially sweetened beverages] in promoting weight loss or preventing negative health outcomes such as T2D [type II diabetes], metabolic syndrome and cardiovascular event'‘current findings suggest that caution about the overall sweetening of the diet is warranted, regardless of whether the sweetener provides energy directly or not’No surprise these conclusions were vigorously disputed on the grounds that (22)'Robust scientific evidence demonstrates benefits of artificial sweeteners’In her authoritative rebuttal (23), Swithers points out the American Heart Association (AHA) and American Diabetes Association (ADA) themselves stated in 2012 lack of robust scientific data about artificial sweeteners (24, emphasis mine),‘paucity of data from well-designed human trials exploring the potential role of (non-nutritive sweeteners) in achieving and maintaining a healthy body weight and minimizing cardiometabolic risk factors.’In other words, these products have been unleashed indiscriminately on society, making their way into thousands upon thousands of food and drinks that billions consume and yet we apparently don't know enough to conclude if they're beneficial or not. Sounds like a recipe for a slow motion disaster, which the modern-day global obesity epidemic indeed is, with both sugars and artificial sweeteners obviously playing leading roles.Another systematic review of 18 studies by US NIH researchers found association between consumption of artificial sweetened beverages and weight gain in children and teens (25).Future artificial sweetener research will likely coalesce around at least 3 aspects:1) How artificial sweeteners influence Gut flora composition and metabolism.2) How they drive behavioral & metabolic compensation.3) Biomarkers to identify those at highest risk of sugar/replacer-induced weight gain and/or metabolic disruption.1) Artificial sweetener effect on Gut flora composition and metabolism.Since most artificial sweetener studies focus on their effect on body weight, important aspects about their metabolism remain under-studied. This is because they were for long considered inert, passing through the GI tract, untouched, unused, little perturbed and little perturbing. Turns out that's not the case at all (26).In a mouse model study (27), maximal daily accepted doses of saccharin, sucralose and aspartame in their drinking water for five weeks induced mouse gut microbiota changes and Impaired glucose tolerance. How this happens is still not clear, especially since aspartame is fully digested to its constituent amino acids in the small intestine unlike saccharin and sucralose. Study found similar results in human volunteers as well. Since most of its experiments involved saccharin, this study's major caveat is limited relevance for diet sodas, which mostly contain aspartame. Obviously similar, larger study needs to examine aspartame effect separately.In a rat model study (28), aspartame exposure led to gut microbiota changes and elevated fasting glucose and reduced insulin-stimulated glucose consumption.Caveat common to all fecal microbiota studies, not just this one: Fecal samples mostly represent distal colon microbiota. Different parts of the GI tract obviously harbor different microbial populations (29). This is especially pertinent for diet vis-a-vis weight gain since most nutrient digestion and absorption is in the small intestine, whose microbial composition is still rather a black box.Implications of artificial sweetener-induced gut microbiota change:Are such changed microbiota better at nutrient harvesting? Better at driving adipose tissue energy storage?These would help explain weight gain even without increased food intake.Are they more harmful to gut's long-term health, making it more leaky, Intestinal permeability, triggering systemic inflammation?This would help explain the long-term harmful consequences such as metabolic syndrome and attendant increased risk of cardiovascular disease and type II diabetes.2) Hypothesis: artificial sweeteners drive behavioral & metabolic compensationSince the 1990s, Purdue University researcher Susan E. Swithers has pioneered animal model studies to explore how artificial sweeteners could uncouple sweet tastes from their metabolic consequences and thus distort ability to predict the latter. In other words, artificial sweeteners may alter how the brain processes reward for sweet taste. Her reviews refer to several such experimental studies (30, 31) by hers and other groups.3) Biomarkers to identify those at highest risk of sugar/replacer-induced weight gain and/or metabolic disruptionBiomarker are measurable, often quantifiable biological indicators of some condition.As with anything diet-related, some seem to gain weight no matter what or how much they eat, some don't while most of the rest fall somewhere in between. How to proactively identify those at highest risk of weight gain and/or metabolic disruption from artificial sweeteners? The US Scientific Report of the 2015 Dietary Guidelines Advisory Committee advises (32),'future experimental studies should examine the relationship between ASSD [artificially sweetened soft drinks] and biomarkers of insulin resistance and other diabetes biomarkers'Only when we have data from such studies will we be able to delve into genetic markers, specific gut microbiota composition, etc., that differentiate those most at risk from the harmful effects of artificial sweeteners, something we have no clue of at present.Bibliography1. Stevens, Haley Curtis. "Diabetes and diet beverage study has serious limitations." The American journal of clinical nutrition 98.1 (2013): 248-249. Diabetes and diet beverage study has serious limitations2. La Vecchia, Carlo. "Artificially and sugar-sweetened beverages and incident type 2 diabetes." The American journal of clinical nutrition 98.1 (2013): 249-250. Artificially and sugar-sweetened beverages and incident type 2 diabetes3. Vox, Julia Belluz, August 16, 2016. Why (almost) everything you know about food is wrong4. Popkin, Barry M., and Corinna Hawkes. "Sweetening of the global diet, particularly beverages: patterns, trends, and policy responses." The Lancet Diabetes & Endocrinology 4.2 (2016): 174-186.5. Sylvetsky, Allison C., and Kristina I. Rother. "Trends in the consumption of low-calorie sweeteners." Physiology & behavior (2016).6. The Guardian, Suzi Gage, 28 April, 2015. Diet Pepsi has dropped aspartame in the US, so why not anywhere else?7. Fortune, John Kell, June 27, 2016. Diet Pepsi with aspartame is making a comeback8. Abou-Donia, Mohamed B., et al. "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 (2008): 1415-1429. https://www.researchgate.net/profile/Benyagoub_Mohamed/publication/23263644_Splenda_alters_gut_microflora_and_increases_intestinal_p-glycoprotein_and_cytochrome_p-450_in_male_rats/links/02bfe50db40f9a9ef1000000.pdf9. Polyák, Éva, et al. "Effects of artificial sweeteners on body weight, food and drink intake." Acta Physiologica Hungarica 97.4 (2010): 401-407. https://www.researchgate.net/profile/Eva_Polyak/publication/49665151_Effects_of_artificial_sweeteners_on_body_weight_food_and_drink_intake/links/5710b31d08ae68dc7909a592.pdf10. de Matos Feijó, Fernanda, et al. "Saccharin and aspartame, compared with sucrose, induce greater weight gain in adult Wistar rats, at similar total caloric intake levels." Appetite 60 (2013): 203-207. https://www.researchgate.net/profile/Marcello_Bertoluci2/publication/232609508_Saccharin_and_aspartame_compared_with_sucrose_induce_greater_weight_gain_in_adult_Wistar_rats_at_similar_total_caloric_intake_levels/links/09e41511db00feb3d5000000.pdf11. Byard, J. L., and L. Golberg. "The metabolism of saccharin in laboratory animals." Food and cosmetics toxicology 11.3 (1973): 391-402.12. Ranney, R. E., et al. "Comparative metabolism of aspartame in experimental animals and humans." Journal of Toxicology and Environmental Health, Part A Current Issues 2.2 (1976): 441-451.13. Arnold, D. L., D. Krewski, and I. C. Munro. "Saccharin: a toxicological and historical perspective." Toxicology 27.3 (1983): 179-256.14. Roberts, A., et al. "Sucralose metabolism and pharmacokinetics in man." Food and chemical toxicology 38 (2000): 31-41.15. Logue, C., et al. "The potential application of a biomarker approach for the investigation of low-calorie sweetener exposure." Proceedings of the Nutrition Society 75.02 (2016): 216-225.16. The New York Times, Margot Sanger-Katz, October 2, 2015. The Decline of ‘Big Soda’17. Wiebe, Natasha, et al. "A systematic review on the effect of sweeteners on glycemic response and clinically relevant outcomes." BMC medicine 9.1 (2011): 1. BMC Medicine18. Fowler, Sharon P., et al. "Fueling the obesity epidemic? Artificially sweetened beverage use and long‐term weight gain." Obesity 16.8 (2008): 1894-1900. https://www.researchgate.net/profile/Ken_Williams6/publication/5321117_Fueling_the_Obesity_Epidemic_Artificially_Sweetened_Beverage_Use_and_Long-Term_Weight_Gain./links/0a85e5389cca553bf7000000.pdf19. Fowler, Sharon PG, Ken Williams, and Helen P. Hazuda. "Diet soda intake is associated with long‐term increases in waist circumference in a biethnic cohort of older adults: The San Antonio longitudinal study of aging." Journal of the American Geriatrics Society 63.4 (2015): 708-715. http://www.nutritiondesseniors.fr/wp-content/uploads/2015/03/soda-light-et-obesite-JAGS2015-2.pdf20. Swithers, Susan E. "Artificial sweeteners produce the counterintuitive effect of inducing metabolic derangements." Trends in Endocrinology & Metabolism 24.9 (2013): 431-441. http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.689.8610&rep=rep1&type=pdf21. Drewnowski, A., and C. D. Rehm. "The use of low-calorie sweeteners is associated with self-reported prior intent to lose weight in a representative sample of US adults." Nutrition & diabetes 6.3 (2016): e202. http://www.nature.com/nutd/journal/v6/n3/pdf/nutd20169a.pdf22. Johnston, C. A., and J. P. Foreyt. "Robust scientific evidence demonstrates benefits of artificial sweeteners." Trends in endocrinology and metabolism: TEM 25.1 (2014): 1.23. Swithers, Susan E. "A paucity of data, not robust scientific evidence: a response to Johnston and Foreyt." Trends in Endocrinology & Metabolism 25.1 (2014): 2-4.24. Gardner, Christopher, et al. "Nonnutritive sweeteners: current use and health perspectives a scientific statement from the American heart association and the American diabetes association." Diabetes care 35.8 (2012): 1798-1808. http://care.diabetesjournals.org/content/diacare/35/8/1798.full.pdf25. Brown, Rebecca J., Mary Ann De Banate, and Kristina I. Rother. "Artificial sweeteners: a systematic review of metabolic effects in youth." International Journal of Pediatric Obesity 5.4 (2010): 305–312. http://seriecientifica.org/sites/default/files/art_swt_ped_brown_2010.pdf26. Nettleton, Jodi E., Raylene A. Reimer, and Jane Shearer. "Reshaping the gut microbiota: Impact of low calorie sweeteners and the link to insulin resistance?." Physiology & behavior (2016).27. Suez, Jotham, et al. "Artificial sweeteners induce glucose intolerance by altering the gut microbiota." Nature 514.7521 (2014): 181-186. https://www.researchgate.net/profile/Ilana_Kolodkin-Gal/publication/265791239_Artificial_sweeteners_induce_glucose_intolerance_by_altering_the_gut_microbiota/links/543266890cf22395f29c08b6.pdf28. Palmnäs, Marie SA, et al. "Low-dose aspartame consumption differentially affects gut microbiota-host metabolic interactions in the diet-induced obese rat." PLoS One 9.10 (2014): e109841. http://journals.plos.org/plosone/article/asset?id=10.1371%2Fjournal.pone.0109841.PDF29. Lichtman, Joshua S., et al. "The effect of microbial colonization on the host proteome varies by gastrointestinal location." The ISME journal (2015).30. Swithers, Susan E. "Artificial sweeteners are not the answer to childhood obesity." Appetite 93 (2015): 85-90. http://www1.appstate.edu/~kms/classes/psy5300/Documents/Swithers2015-obesity.pdf31. Swithers, Susan E. "Not-so-healthy sugar substitutes?." Current opinion in behavioral sciences 9 (2016): 106-110. Not-so-healthy sugar substitutes?32. https://health.gov/dietaryguidelines/2015-scientific-report/pdfs/scientific-report-of-the-2015-dietary-guidelines-advisory-committee.pdfThanks for the R2A, Daniel Kaplan.

Rationale for Taxing Sugar OverconsumptionChronic diseases such as obesity, diabetes and cardiovascular disease now impose enormous cost in many countries while metabolic syndrome looms large over all of them. To reverse such distressing trends requires understanding why such diet-associated diseases started increasing in the first place.In recent decades, among a wide range of factors, sugar overconsumption became increasingly noticeable as one that correlates with weight gain and type 2 diabetes. This led the WHO to recommend in 2015 that sugar should constitute <10% of total energy intake (1).Problem is sugar is overproduced, making it cheap to add to beverages and processed foods. As the food industry started adding extra sugar and engaged in carpet bombing-style marketing to peddle such products, consumers enthusiastically took to them, upshot being added sugar now finds its way into practically any comestible imaginable with sugar-sweetened beverages (SSB) leading the cavalcade. In the Americas, SSB overconsumption is the major source of excess sugar intake (2). Turns out a sweet tooth is deeply ingrained in many taste buds. No surprise a heedless soda chugging habit developed in short order the world over.Breaking entrenched dietary habits decades in the making is an uphill task to say the least. Meantime, the structural elements that underpin this ecosystem present formidable challenges to redressal tools. Consider food labels. Outcome of intense politicking, they leave out much critical information so they're a dubious information source at the best of times. They also require active decision making on the part of consumers, whose weight gain patterns anyway suggest such measures are failing to make a dent.In the midst of this turmoil, taxing sugar in the form of a 'soda tax', Sugary drink tax - Wikipedia, emerged as a public policy and behavior modification tool to combat sugar overconsumption (3),Hits consumer wallets forcing them to purchase less of such taxed food products.Raises revenue that could be used for heath care.Puts pressure on consumers to change entrenched eating and drinking habits and on food manufacturers to reformulate their products.Pros & Cons of Sugar Overconsumption TaxOpponents raise ethical concerns about such an intrusive public policy that to them reeks of wholesale meddling in how a free market should operate even as it unforgivably intrudes into individual autonomy and freedom of choice.However, such stances fail to acknowledge that food staples such as milk, salt and cereals are routinely fortified with supplements such as Vitamin D or iodine to ensure that the terrible diseases from micronutrient deficiency can be and remain scourges of the past. This now-century old public policy of Food fortification - Wikipedia also intrudes on an individual's autonomy and freedom of choice but is now so much a part of daily life that it passes unnoticed.Some proponents also liken it to alcohol taxation where public good is again multi-fold; it discourages excessive drinking, helps prevent drunk driving accidents and raises revenue to treat alcohol abuse and disease.Likewise, taxing tobacco consumption has led to steady declines in cigarette smoking, changed the norms regarding the public's acceptance of smoking in public spaces, and generates revenue for health care. It is hoped that in coming decades, declines in cigarette smoking would lead to declines in lung and pancreatic cancer diagnoses as well as reduction in chronic pulmonary diseases such as COPD (chronic obstructive pulmonary disease) and emphysema.No less a figure than Adam Smith - Wikipedia himself, the free marketeer's original hero, extolled the virtues of taxing these three commodities (sugar, alcohol, tobacco) (see below from 4).'Sugar, rum, and tobacco, are commodities which are nowhere necessaries of life, which are become objects of almost universal consumption, and which are therefore extremely proper subjects of taxation'However, a consistency of approach on what's taxed is essential. What good is it to tax soda and leave untouched all manner of fruit juices, smoothies, protein and 'hi-energy' drinks that may have as much or even more added sugar? Recent years have also seen a deluge of snack and 'energy' bars with shockingly astronomical levels of added sugar. Unless sugar tax is applied evenly across the entire gamut of foods with added sugar, chances it will backfire badly remain high.Much as water seeks its own level, absent rigorous research and vigilance specific to each culture in deciding what is taxed and how,The food industry's need for blockbuster sales will likely ensure added sugar, fat and salt find their way in all kinds of foods that escape regulatory scrutiny at any given moment.Consumers addicted to extra sugar in their diet may easily suss out and glom onto untaxed sugar-heavy food and beverage alternatives.Whether going down this path would lead to Whac-A-Mole - Wikipedia in the future is anybody's guess at this time. It's still better than doing nothing considering how much the ill-effects of sugar overconsumption are taxing societies the world over.What is taxed where could encourage cross-border shopping and smuggling of the taxed item.Economists such as Robert H. Frank - Wikipedia invoke the imperative of the common good to defend a sugar tax policy, saying (5),'Every dollar raised by taxing harmful activities is one dollar less that we must raise by taxing useful ones' .After all, a consumer with unhealthy eating habits who ends up with a chronic disease typically doesn't pay the full price of their consumption decisions. Rather, all of society pays the price in the form of publicly funded programs and services that treat chronic diseases.The well-known legal scholar, Larry Gostin - Wikipedia, sums up the case for taxing sugar overconsumption in a recent opinion piece (see below from 6, emphasis mine),‘It is staggering to observe the new normal in America: 37.9 percent of adults are obese, and 70.7 percent are either obese or overweight. One out of every five minors is obese. The real tragedy, of course, is the disability, suffering, and early death that devastates families and communities. But all of society pays, with the annual medical cost estimated at $147 billion. The causal pathways are complex— poor diets and sedentary lifestyles. But if we drill down, sugar is a deeply consequential pathway to obesity (and to dental disease), and the single greatest dietary source is sugar-sweetened beverages (SSBs) sodas, fruit drinks, energy drinks, and specialty coffees with added sugar, corn syrup, sucrose, fructose, glucose, or honey. Socioeconomic class drives SSB consumption, exacerbating unconscionable health disparities.1...Public health agencies have their hands tied by the forces of politics, constitutionalism, industry spending, and corporate personhood. America has placed the value of individualism on a pedestal, and the results mean that more people are coping with chronic diseases and dying prematurely. For the first time in history, the next generation may live shorter lives than their parents. Why not try another way, placing the common good as a high value? A good place to start is to take action against the major harms wrought by the pervasive presence of sugar in the American diet.'Finally, it's important to acknowledge that such a policy alone isn't a magic bullet that could lessen the burden of chronic diseases all by itself. It needs to go hand in glove with public education campaigns and food manufacturer disincentives. After all, what good is taxing SSBs if the food industry turns around and plugs foods heavy in salt and fat instead in order to make up for falling revenue from the sugar side?That said, the public policy of taxing SSBs is rapidly gaining ground the world over as many countries, cities and other jurisdictions have already levied them or plan to do so in the near future (see below from 7).Bibliography1. World Health Organization. Guideline: sugars intake for adults and children. World Health Organization, 2015. Sugars intake for adults and children2. Le Bodo, Yann, et al. "Is sugar the new tobacco? Insights from laboratory studies, consumer surveys and public health." Current obesity reports 4.1 (2015): 111-121.3. Le Bodo, Yann, Marie-Claude Paquette, and Philippe De Wals. "Sugar-Sweetened Beverage Taxation Logics and Ethical Concerns." Taxing Soda for Public Health. Springer, Cham, 2016. 75-82.4. Smith, Adam. An Inquiry into the Nature and Causes of the Wealth of Nations,(1776). Volume 2, page 426.5. The Darwin Economy: Liberty, Competition, and the Common Good: Robert H. Frank: 8580001257006: Amazon.com: Books6. Gostin, Lawrence O. "Tackling Obesity and Disease: The Culprit Is Sugar; the Response Is Legal Regulation." Hastings Center Report 48.1 (2018): 5-7. https://onlinelibrary.wiley.com/doi/pdf/10.1002/hast.8047. Baker, Phillip, Alexandra Jones, and Anne Marie Thow. "Accelerating the Worldwide Adoption of Sugar-Sweetened Beverage Taxes: Strengthening Commitment and Capacity: Comment on" The Untapped Power of Soda Taxes: Incentivizing Consumers, Generating Revenue, and Altering Corporate Behavior"." International journal of health policy and management 7.5 (2018): 474. Accelerating the Worldwide Adoption of Sugar-Sweetened Beverage Taxes: Strengthening Commitment and Capacity: Comment on "The Untapped Power of Soda Taxes: Incentivizing Consumers, Generating Revenue, and Altering Corporate Behavior"Thanks for the R2A, Jonathan Brill.

An answer here requires two provisos. One, inflammation being an essential feature of normal immune system function, that it per se is not the problem so much as its inappropriate start, control or stop. In other words, a healthy body is one that properly modulates inflammation. For the purpose of this question then the issue is inappropriate inflammation that entails persistent GI tract disturbance and barrier function disruption, and is implicated in Metabolic syndrome that some say is more accurately 'chronic systemic low-grade inflammation induced energy reallocation' (1).Two, effect of diet on physiology in general and on immune function in particular is much more difficult to dissect than other areas of medicine. An article in Vox recently explained why this is so (2). Summarizing from this piece,It's not practical to run randomized trials for most big nutrition questionsSo nutrition researchers have to rely on observational studies, which are rife with uncertainty.Many nutrition studies rely on (wildly imprecise) food surveys.People and food are diverse.Conflict of interest is a huge problem in nutrition research.So if a food ingredient causes inappropriate inflammation, studies ranging from lab-based to animal models as well as those in humans should show this. An example of such a food ingredient is found among dietary emulsifiers, a group of processed food ingredients that a body of data suggest play a role in sculpting gut microbiota away from commensal towards the more pathogenic kind. Gist of these studies is that such a shift tends to be accompanied by gut wall thinning, and greater likelihood of barrier function disruption and leakage of microbial antigens into systemic circulation.Dietary emulsifiers are ubiquitous food additives in modern processed food. They fall under the so-called GRAS (generally recognized as safe) loophole in the 1958 law that the US Congress passed. The loophole consists of an exemption to bypass the FDA's safety review process for ingredients GRAS. As such, companies prove on their own that GRAS are indeed GRAS. A recent Center for Public Integrity report notes that in the years since, the number of such food additives falling under GRAS 'has skyrocketed from 800 to >10000' (3).Emulsifiers (Emulsion) are molecules with both hydro- and lipophilic portions. This helps them maintain fat molecules in aqueous suspensions or water-soluble ones in a hydrophobic environment. In processed food and beverages, they're used to extend product stability and slow the phase separation rate. According to Glade et al, dietary emulsifiers 'maintain the texture, hydration, plasticity, fluidity, consistency, viscosity, volume, structural integrity, color, heat resistance, mold resistance, mouthfeel and taste of multiphase processed food and beverages, and tend to be considered harmless' (4).Carboxymethylcellulose, a commonly used dietary emulsifierOne of the most commonly used dietary emulsifiers is the artificial Carboxymethyl cellulose. Water soluble, used as a thickener, emulsion stabilizer and suspending agent, it's found in everything from dry pet foods, frozen dairy foods, diet sodas, white and sparkling wines, tortillas (4).In vitro tests showed that carboxymethylcellulose can penetrate GI tract mucus more readily because it hydrates more easily compared to other non-starch polysaccharides (5, 6). OTOH, it doesn't ferment or bind to cholesterol or bile acids meaning it doesn't benefit the GI tract either. So what does it do? One study showed it exacerbated the growth of Neisseria gonorrhoeae, a pathogenic bacterium (7). In other words, at least one in vitro study showed carboxymethylcellulose has the capacity to support pathogen metabolism by increasing the availability of free sugars within the GI tract mucus layer.Mouse Model Studies Of Carboxymethylcellulose Show It Can Promote/Support Inappropriate InflammationIn a mouse model study (8), mice were fed carboxymethylcellulose (2%). Such mice had extensive bacterial overgrowth in their small intestine and mucosal inflammation, suggesting its sustained intake had severely perturbed their GI tract ecology and local pH, helping alter the relative proportions of commensal and pathogenic GI tract microbes.In another study, mice fed carboxymethylcellulose dissolved in water (~1%w/v when they're found in various foods at up to 2%) were compared to those fed water alone (9). The former developed a range of colonic inflammation that ranged all the way from low-grade to symptomatic colitis. Substantial thinning of colonic mucus layer inevitable outcome of such inflammation, bacterial antigens could more easily penetrate intestine contributing to systemic inflammation. Again extensive bacterial overgrowth occurred, including species such as mucolytic Ruminococcus gnavus and inflammatory Proteobacteria, i.e., not the beneficial kind.Human Studies Of Carboxymethylcellulose Show It Can Modulate Dietary Absorption and Promote Fecal IncontinenceWhen taken as a substitute for dietary fiber, carboxymethylcellulose inhibits absorption of dietary flavonoids (10). The hypothesis is carboxymethylcellulose deprives gut microbes of the fermentable energy they need to enzymatically convert dietary flavonoids to their more absorbable counterparts. Flavonoids are common dietary components of fruits, vegetables, tea and wine and their intake is inversely linked to chronic cardiovascular diseases.In a randomized, placebo-controlled trial of 206 subjects, carboxymethylcellulose increased fecal incontinence frequency when taken at 16 grams daily (11).Thus far, in vitro and mouse model studies show a clearer propensity of carboxymethycellulose to promote inappropriate intestinal inflammation while the data from human studies, though less comprehensive, also hint at the same. As Chassaing et al point out (9), their GRAS status means that these kinds of food additives haven't been carefully tested, and even such tests as have been done were intended to detect acute toxicity or tumor-inducing propensity. Such studies don't study the effect of chronic, lower dose exposure that mimics regular dietary exposure, an important gap in food science and safety research.Bibliography1. Ruiz-Núñez, Begoña, et al. "Lifestyle and nutritional imbalances associated with Western diseases: causes and consequences of chronic systemic low-grade inflammation in an evolutionary context." The Journal of nutritional biochemistry 24.7 (2013): 1183-1201.2. I asked 8 researchers why the science of nutrition is so messy. Here's what they said. Julia Belluz, Vox, Jan 16, 2016. Why (almost) everything you know about food is wrong3. Why the FDA doesn't really know what's in your food. Erin Quinn, Chris Young, Center for Public Integrity, April 14, 2015. Why the FDA doesn't really know what's in your food4. Glade, Michael J., and Michael M. Meguid. "Dietary Emulsifiers, The Human Intestinal Mucus and Microbiome, and Dietary Fiber." Nutrition (2015).5. Adiotomre, Joseph, et al. "Dietary fiber: in vitro methods that anticipate nutrition and metabolic activity in humans." The American journal of clinical nutrition 52.1 (1990): 128-134.6. Bliss, Donna Z., et al. 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"Intestinal absorption of luteolin and luteolin 7‐O‐β‐glucoside in rats and humans." FEBS letters 438.3 (1998): 220-224. http://onlinelibrary.wiley.com/doi/10.1016/S0014-5793%2898%2901304-0/epdf11. Bliss, Donna Z., et al. "Dietary fiber supplementation for fecal incontinence: a randomized clinical trial." Research in nursing & health 37.5 (2014): 367-378. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4296893/pdf/nihms616457.pdfThanks for the A2A, Terrence Yang.