Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article HYPOTHESIS FORMATION Comparison with ancestral diets suggests dense acellular carbohydrates promote an inflammatory microbiota, and may be the primary dietary cause of leptin resistance and obesity Ian Spreadbury Abstract: A novel hypothesis of obesity is suggested by consideration of diet-related inflammation and evolutionary medicine. The obese homeostatically guard their elevated Gastrointestinal Diseases Research Unit, Queen’s University, Kingston, weight. In rodent models of high-fat diet-induced obesity, leptin resistance is seen initially at Ontario, Canada vagal afferents, blunting the actions of satiety mediators, then centrally, with gastrointestinal bacterial-triggered SOCS3 signaling implicated. In humans, dietary fat and fructose elevate systemic lipopolysaccharide, while dietary glucose also strongly activates SOCS3 signaling. Crucially however, in humans, low-carbohydrate diets spontaneously decrease weight in a way that low-fat diets do not. Furthermore, nutrition transition patterns and the health of those still eating diverse ancestral diets with abundant food suggest that neither glycemic index, altered fat, nor carbohydrate intake can be intrinsic causes of obesity, and that human energy homeostasis functions well without Westernized foods containing flours, sugar, and refined fats. Due to being made up of cells, virtually all “ancestral foods” have markedly lower carbohydrate densities than flour- and sugar-containing foods, a property quite independent of glycemic index. Thus the “forgotten organ” of the gastrointestinal microbiota is a prime candidate to be influenced by evolutionarily unprecedented postprandial luminal carbohydrate concentrations. The present hypothesis suggests that in parallel with the bacterial effects of sugars on dental and periodontal health, acellular flours, sugars, and processed foods produce an inflammatory microbiota via the upper gastrointestinal tract, with fat able to effect a “double hit” by increasing systemic absorption of lipopolysaccharide. This model is consistent with a broad spectrum of reported dietary phenomena. A diet of grain-free whole foods with carbohydrate from cellular tubers, leaves, and fruits may produce a gastrointestinal microbiota consistent with our evolutionary condition, potentially explaining the exceptional macronutrient-independent metabolic health of non-Westernized populations, and the apparent efficacy of the modern “Paleolithic” diet on satiety and metabolism. Keywords: carbohydrate density, metabolic syndrome, nutrition transition, Paleolithic diet Introduction Due to the complexity of a phenomenon like obesity, it is inevitable that most study assumes a “bottom-up” approach, working to elucidate detailed knowledge of the Correspondence: Ian Spreadbury systems believed to be involved. During the assembly of such detailed knowledge into GIDRU Wing, Kingston General Hospital, a working whole, a measure of conformity to prevailing views is natural, as researchers 76 Stuart Street, Kingston, Ontario K7L 2V7, Canada work in detail on their part of the puzzle and seek to integrate that work into the network Tel +1 613 549 6666 ext 6520 of existing knowledge. Bottom-up approaches do not lend themselves to rapid paradigm Fax +1 613 548 2426 Email [email protected] shifts in understanding, as each novel contribution is an incremental advancement. submit your manuscript | www.dovepress.com Diabetes, Metabolic Syndrome and Obesity: T argets and Therapy 2012:5 175–189 175 Dovepress © 2012 Spreadbury, publisher and licensee Dove Medical Press Ltd. This is an Open Access article http://dx.doi.org/10.2147/DMSO.S33473 which permits unrestricted noncommercial use, provided the original work is properly cited. Spreadbury Dovepress This is especially true in research into the dietary causes of high, in the order of 60%–70% of energy intake, much of it obesity and Western diseases, where implicating the wrong root tubers or fruit with a moderately high glycemic index,5 cause and advocating widespread dietary changes on the while their saturated fat intake is also high (17% – largely basis of that could lead to a significant worsening of the from coconut). Despite food abundance and a clear overlap epidemiological situation. of macronutrients and glycemic index with Western diets, With obesity and diabetes incidence and severity now at Kitavans are reported to possess leptin levels, fasting insulin, truly disconcerting rates, it is time to consider the possibility and blood glucose levels dramatically lower than those in that implicating dietary fat as the primary cause and advocat- Western populations deemed healthy,6,7 and appear to have a ing that it be minimized has been a fundamental error, despite virtual absence of overweight, diabetes, and atherosclerotic the large body of evidence supporting mechanisms by which disease.3,4,8,9 Environmental or genetic explanations for this high-fat diets might produce obesity. metabolic health appear unlikely, since islanders who leave The present paper attempts a “top-down” approach to for the mainland and eat Western foods become overweight.7 obesity and provides a hypothesis that is not only consistent People of this region may in fact be more susceptible to the with available detailed mechanisms but also with some of effects of Western diet than Europeans, which may include the most confusing widely observed dietary phenomena. By increased susceptibility to effects subsequent to leptin comparing “ancestral diets,” which appear to promote uni- resistance.10,11 Similar leanness and low leptin concentrations versally effective homeostatic energy balance, with Western have also been recorded in the Ache hunter-gatherers of diets, a sharp delineation is found in the proportional mass Paraguay, and in Shuar people of the Amazon who retain of carbohydrate found in Western foods versus the locked-in a traditional lifestyle.12–14 Those Shuar who have taken the low carbohydrate density of cellular plant foods. Since initial steps toward agriculture have significant increases in this characteristic does not correlate with glycemic index, leptin levels.15 Although leptin levels have not been recorded the primary “organ” likely to be directly affected by such for other people eating traditional diets, it has been widely luminal concentration changes, and one already implicated reported that unless grains or refined foods had arrived, in leptin resistance and obesity, is the gastrointestinal (GI) all bore remarkably low incidences of “Western diseases,” microbiota. including obesity (Table 1).3,4,6–9,16–29 Also notable is the appar- ent macronutrient-independence of the health associated with Background to the hypothesis ancestral diets. The Kitavan case appears to argue against a Energy homeostasis in the absence primary causal role for carbohydrates or glycemic index in of Western foods the genesis of obesity, at least when carbohydrates are in Obesity and non-insulin dependent diabetes are growing the form of root vegetables or fruit. Their diet is higher in global phenomena, extending into the developing world carbohydrates than the estimated intake for our East African following the spread of Westernized dietary patterns.1 The ancestors30 or modern hunter-gatherers,31,32 who tend to have tendency toward overeating in the modern world is so com- carbohydrates provide around 35% of energy, ranging from mon that it has led to the widely held belief that human energy 3% to 50% of energy intake, the proportion falling with homeostasis is maladapted to food excess and a sedentary northern latitude. Similarly, other analyses of modern hunter- lifestyle,2 and that constant voluntary caloric restriction is gatherers33 have suggested that intake of unprocessed meat important to maintain healthy weight. Most epidemiological does not produce poor metabolic or cardiovascular health, overviews of obesity examine Western populations, and it in agreement with the reported historical diets and health of is often overlooked that even nominally healthy Westerners the Masai, Kavirondo, and Turkhana (Table 1). have leptin levels many times higher than those eating a non– Those populations that transitioned to a Westernized diet Westernized diet, even in the presence of food abundance. For invariably developed Western metabolic diseases,1,34 while example, the Kitavan Islanders of Melanesia live as horticul- sustaining high levels of physical activity appears to offer turists with levels of activity comparable to manual workers only a degree of protection against obesity,35,36 as would who take moderate exercise; their dietary staples are root be expected if a perturbation of homeostatic set point were vegetables and fruit, with some consumption of meat and fish, responsible. It is unlikely that environmental factors could but with little availability of Western foods. Hence as a popu- effect an absence of overweight in non-Westernized popula- lation they consume virtually no grains or refined foods such tions by means of effectively enforcing caloric-restriction as flour, sugar, or refined oils.3,4 Their carbohydrate intake is even in good times, and such an improbable constant 176 submit your manuscript | www.dovepress.com Diabetes, Metabolic Syndrome and Obesity: T argets and Therapy 2012:5 Dovepress Dovepress Leptin resistance and acellular carbohydrates e c n e 9 Refer 3,4,6– 22 16 20 29 26 24,25 17,19 27 27,28 Other health markers No stroke, diabetes or heart disease. No increase in weight or blood pressure in middle age Healthy teeth and gums, good general health, except for parasites and infections Atherosclerosis rare at autopsy Aortic atheroma at autopsy rarer than in Westerners. No increase in blood pressure through middle age No increase in blood pressure through middle age No hypertension or cardiovascular disease. Islands with Western influence showed increased blood pressure No increase in weight in middle age No hypertension, no rise in blood pressure with age 7% diabetes incidence 30% diabetes Overweight or obesity 0% overweight None reported Lean Lean Lean Lean (Western-influenced islands were heavier) Lean (5th percentile of Western weight)  5% BMI 26 Males: 7% obese Females: 20% obese Males: 64% obese Females: 75% obese mponent of diet’ ().++++ o c or s maj Acellular foods or grain - - - - - /-+ + ++ +++ ++++ m ‘absent’ (), to ‘- o d fr e k n Western foods” Macronutrient summary ~65% carbohydrate, high fibre, 17% saturated fat High carbohydrate, high fibre 66% fat, similar cholesterol intake to US High protein, high fat Mongongo nuts: ~60% fat, 25% protein Varied High protein, high fat High carbohydrate, high fibre, fat 12%, animal sources 6%, refined sugar 1% 62% carbohydrate, 25% fat, high fibre 49% carbohydrate, 15% protein, 34% fat, 10% saturated fat ular foods or grains to diet, ra n transition overview: obesity and “ Diet Starchy root vegetables, fruit, some fish and meat, coconuts. Food abundance Mostly root vegetables, fruit and nuts, very small amount of meat and fish. Food abundance Cow’s milk and blood, meat Mostly meat ~70% plant matter (mongongo nuts, fruits, roots, bulbs, leaves), some meat Root vegetables, fruit, fish, limited meat, tinned fish Mostly milk, blood, meat, but by 1983 also some traded sorghum, maize, millet, and sugar 90% from pinto beans and maize tortilla. Remainder from squash and other vegetables Beans, wheat-flour tortillas, corn tortillas, and potatoes Refined Western diet, including fried breakfasts, processed meats, hamburgers, pork chops, beans, white bread, flour tortillas, fried or baked dough, cereals, canned foods, fruit juices and : Approximate contribution of acell+++++ NutritioTable 1 People Kitava 1990s Machiguenga 1982 Masai 1971 Kavirondo Kenyans 1929 !Kung 1972 Solomon Islanders 1974 Turkana 1980–83 Tarahumara 1978–79 Mexican Pima 2006 Arizona Pima 1996–2006 , /, ,, --++++++Note: Diabetes, Metabolic Syndrome and Obesity: T argets and Therapy 2012:5 submit your manuscript | www.dovepress.com 177 Dovepress Spreadbury Dovepress food-shortage or increased physical exertion would not be reductions in weight and waist circumference in an ad libitum sufficient explanation for the dramatically different leptin Paleolithic-style diet compared with the consensus “Mediter- levels seen in hunter-gatherers and non-cereal horticulturists, ranean” or “Diabetes” diets41,42 and significant improvements which in the case of the Ache of Paraguay are significantly over the Mediterranean diet in blood glucose control, inde- lower than Western distance runners despite the lower adi- pendently of the superior waist-circumference reduction.42 posity of the latter.13 All three diets emphasize whole foods, but the restriction Moreover, even small amounts of Western influence of grains in the Paleolithic diet is a principal difference, in diet are associated with significant adverse alterations which correlated well with the reduced waist measurement42 in metabolic and physiological markers, often before any and the 20%–30% increased satiety per calorie seen in the substantial lifestyle changes.15,26 The relationship between Paleolithic-diet groups. Importantly this increased satiety health and ancestral or Western diets is reviewed in detail did not correlate with energy density, fiber, or macronutrient by Lindeberg.37 The effects of Western diet and lifestyle content,43 and significant spontaneous decreases in energy do appear to be reversible, at least in part. The metabolic intake have been reported in all the ad libitum studies to health of diabetic Australian Aborigines has been shown to date.41,42,44 However, the benefits of this dietary pattern be markedly improved by even a 7-week return to a hunter- do not appear dependent on this altered satiety or weight gatherer lifestyle and diet.38 In addition, Westerners have also change; consumed in a calorie-matched manner to prevent been shown to benefit from similar dietary changes. weight loss, a Paleolithic-style diet produced significantly greater improvements in blood pressure, glucose tolerance, Grain-free whole-food diet: early results insulin sensitivity, and lipid profiles in a small group of in Westerners healthy volunteers, with each individual participant showing Whole grains are mooted to be healthier than refined grains,39 improvements, indicating that these metabolic improvements yet comparisons between grain consumption habits in indus- occur independently of reduced caloric intake.45 Both the trialized societies indicate the effects of replacing refined spontaneous 20%–30% decrease in caloric intake and the grains with whole grains yield only modest improvements other metabolic improvements produced by a Paleolithic to health.40 These studies inevitably compare differing pat- style of eating would be consistent with an increase in leptin terns of grain consumption against a background of almost sensitivity. Leptin levels dropped by 31% after 12 weeks of universal flour, sugar, refined starches, and oils in the modern ad libitum Paleolithic diet, and were found to correlate best diet. Health patterns during nutrition transitions indicate that with consumption of cereals excluding rice.43 It is not known obesity, diabetes, and cardiovascular disease have charac- whether continued adherence to the regimen would produce teristic incubation periods, but were virtually absent prior leptin levels comparable to those reported in hunter-gatherers to the arrival of Western foods.18,21,37 The interindividual and noncereal horticulturists. variability in “Western disease” incidence in a population On the balance of evidence from the dietary patterns eating Western foods is affected by genetic and other factors, of non–Western populations and the initial findings of the but it is mostly these secondary factors that the epidemiology modern Paleolithic diet, grains and refined foods therefore of industrialized populations would be studying if the root stand implicated as potential dietary causes of the Western causes of metabolic disorders were now present throughout obesity problem. It has been hypothesized that insulin the population. receptor, epidermal growth factor receptor, or interleukin-2 Removal of grains and all refined foods is one of the receptor activities of cereal-grain lectins may be responsible hallmarks of the “Paleolithic” diet, a modern way of eating for producing leptin resistance;46 the present paper proposes that attempts to approximate the characteristics of ancestral an alternative or additional mechanism with broad applicabil- diets. Although the literature of clinical studies of this dietary ity to almost all Western foods. pattern in Westerners is currently small, it is also unanimous. Each published experimental comparison of a diet contain- Food-related inflammation and obesity ing grains with one excluding grains has found significant It is increasingly recognized that obesity is a disorder favorable metabolic effects in the grain-restricted groups, characterized by systemic low-level inflammation,47 with with beneficial effects large enough to render the studies multiple elements of the metabolic syndrome strongly cor- adequately powered despite their small test groups. The relating with circulating bacterial lipopolysaccharide (LPS) randomized clinical trials have shown significantly greater concentrations.48 LPS levels are also significantly higher in 178 submit your manuscript | www.dovepress.com Diabetes, Metabolic Syndrome and Obesity: T argets and Therapy 2012:5 Dovepress Dovepress Leptin resistance and acellular carbohydrates nonalcoholic fatty-liver patients than controls, in conjunc- mice are compared with germ-free mice over 12 weeks, a tion with elevated GI permeability,49,50 while in metabolic saturated fat-free diet of ordinary rodent chow interacts with syndrome, elevated downstream expression and activation the microbiota of conventional mice to produce elevated of TLR4 and TLR2 on circulating monocytes is seen.51 After LPS, increased white adipose tissue mass, increased levels successful Roux-en-Y gastric bypass surgery, the reductions of leptin, blood glucose and insulin, and increased infiltra- in weight and insulin resistance are associated with reduc- tion of white adipose tissue by macrophages.59 In the same tions in circulating LPS and inflammation.52 The source study, germ-free mice were monocolonized with either of the LPS is thought to be the GI tract, with ingestion of a wild-type Escherichia coli or a mutant form with less high-fat and high-carbohydrate Western-style meals found to immunogenic penta-acylated LPS. The less immunogenic produce postprandial “metabolic endotoxemia”: an increase bacterium produced lower LPS levels in the portal vein, in circulating LPS levels and other inflammatory changes.53 and was associated with lower macrophage infiltration and LPS and other gastrointestinally derived pathogen-associated inflammation of white adipose tissue, indicating a role for molecular patterns (PAMPs) have also been suggested to play LPS in this effect. However, leptin and insulin levels were a role in the etiology of many “Western diseases,” including even higher in mice monocolonized with the mutant E. coli, obesity. The small intestine has been implicated as a primary suggesting non-LPS PAMPs play a considerable role in leptin source for their systemic absorption, with possible PAMP and insulin resistance. sources including swallowed oral bacteria, small intestinal Differing profiles of inflammation and PAMP transloca- commensals, or PAMPs harbored inside foodstuffs. The far tion appear to be produced by different monosaccharides. In larger populations of Gram-negative bacteria in the large mice whose chow diet was supplemented with 30% glucose intestine are suggested to be less likely to act as a source for solution, larger weight gain and visceral adiposity were systemic PAMPs, due to the relatively small surface area seen, but with no significant changes in hepatic portal LPS of the bowel compared to the small intestine, the presumed concentration. Conversely, fructose produced smaller changes evolutionary adaptations of the bowel to high concentrations in adiposity but markedly worse markers of hepatic inflamma- of bacteria, and the fact that colonic translocatory PAMPs tion, and significantly elevated hepatic portal LPS.60 Fructose would undergo clearance by the liver, rather than bypassing is thought to have direct toxic effects on the liver,61,62 and hepatic detoxification via the lymphatic system, as small its ability to generate circulatory LPS may be an important intestinal PAMPs would (reviewed by Erridge).54 The pre- contributor to non-alcoholic fatty liver disease. cise GI location of the alterations in microbiota underlying Inflammation of the gut itself plays a potential role, with metabolic endotoxemia and inflammation in diet-induced early GI inflammation preceding and predicting obesity in obesity is not fully understood. The present hypothesis makes diet-induced obesity models.63 This inflammation is associ- suggestions regarding the dietary triggers of these changes, ated with increased gastrointestinal permeability and changes wherever they are ultimately found to be located. in microbiota.64 Leptin resistance of the vagal afferent neu- Dietary fat also appears able to facilitate transloca- rons innervating the upper GI tract is seen in diet-induced tion of PAMPs from the gut lumen into the circulation obese mice, apparently via SOCS3 signaling to inhibit by promoting a microbiota that reduces the expression of STAT3 activation by leptin, with LPS shown to be able to tight-junction proteins.55 In humans, test drinks of cream increase SOCS3 in isolated nodose neurons (the cell bodies (70% fat) produce a postmeal spike in circulating LPS, while of the vagal afferents) in vitro.65,66 The onset of increased a glucose drink does not. However, suppressor of cytokine food intake in diet-induced obese animals coincides with signalling-3 (SOCS3) protein signaling and nuclear factor this onset of leptin resistance, and substantially reduces kappa B (NFκB) activation in circulating mononuclear cells the role of leptin in maintaining vagal afferent sensitivity were markedly elevated by both cream and glucose drinks, to satiety mediators including cholecystokinin and peptide and were still elevated at 5 hours.56 The finding that glucose YY, by reducing the functional expression of their recep- consumption elevates NFκB and inflammatory pathways57 tors, and increasing the expression of appetite-increasing without producing changes in LPS or TLR4 levels is impor- receptors such as melanin-concentrating hormone 1 receptor tant evidence that a glucose-induced non-LPS/TLR4 inflam- and cannabinoid receptors.66 In similar diet-induced obesity matory pathway exists. SOCS3 has been implicated in leptin models, central leptin resistance occurs some time later,67 and insulin resistance, and both it and NFκB are significantly with SOCS3 signaling again implicated.68 Modulation of elevated in the obese.58 In animal studies, when conventional the gastrointestinal microbiota in diet-induced obese and Diabetes, Metabolic Syndrome and Obesity: T argets and Therapy 2012:5 submit your manuscript | www.dovepress.com 179 Dovepress Spreadbury Dovepress Ob/Ob mice with antibiotics is able to reduce the levels of microbiota, these currently seem unlikely to represent a LPS, inflammatory markers, and oxidative stress, along with useful intervention for obesity or metabolic disease. reduced glucose intolerance, visceral fat, and body-weight Dietary fat is an exacerbatory but gain.55,69 TLR4 and CD14 knockout mice are also protected from these effects, interestingly with subtly different effects not primary cause of human obesity on adipose tissue macrophage infiltration, indicating differing There is no question that fat has a role in obesity. The rodent roles for these receptors in mediating LPS effects.70–72 diet-induced obesity models discussed above predominantly The capacity for dysregulation of insulin, blood glu- make use of high-fat chows to produce their effects, which cose, and other metabolic markers as a result of intestinal for a proportion of dietary fat of 72% (lard and corn oil) microbiotal changes may be highly conserved, with altered produced around a 2.7-fold increase in circulating LPS, while microbiota strongly affecting metabolism and growth pat- 40% fat chows produced 1.4-fold changes in LPS.79 It has terns in the fruit fly Drosophila.73 In addition, microbiotal also been shown that diets of differing fatty acids are able to alterations appear able to influence the severity of myocardial differentially produce endotoxemia and complex patterns of infarction in a rodent model in a leptin-dependent manner.74 inflammatory processes.80 Saturated fatty acids themselves In humans, the species of bacteria that are present in fecal are also able to activate the LPS receptor TLR4; this appears microbial communities appear to be relatively varied between to require concentrations in the high micromolar range.81–83 individuals, with greater similarities between closely related These data appear consistent with the dominant body of people. However, the bacterial genes present across human dietary belief since the late 1970s that overconsumption of populations appear to be more conserved, hence we possess dietary fats is one of the primary nutritional problems of the a “core microbiome” composed more of similar bacterial industrialized world. However, despite all the mechanistic genes rather than similar bacterial species. The microbiota evidence that has been amassed condemning dietary fat, two of obese individuals showed alterations in the expression broader considerations nonetheless suggest fat is unlikely to of bacterial genes, many involved in metabolism of carbo- be the most pertinent factor in human obesity and metabolic hydrates, lipids, and amino acids.75 There is evidence that syndrome. less Westernized diets can produce microbial communities Firstly, if dietary fat were the primary determinant of lep- with marked differences from those seen in industrialized tin resistance in humans, one would expect a low-fat diet to countries. Children from rural Burkina Faso have a consider- produce meaningful spontaneous reductions in weight in the ably different microbiota to those from Europe, a difference obese. Reduced dietary fat intake would substantially reduce thought to be primarily dietarily mediated. With a lifestyle vagal and central leptin resistance, correcting the appetite and comparable to early Neolithic subsistence farmers, these energy-expenditure “set point,” increasing the effectiveness children carry a large representation of Bacteroidetes, with of satiety signals, reducing appetite, and correcting metabolic an unusual prevalence of species suggested to bear genes for markers. However, instead it is low-carbohydrate diets that hydrolysis of dietary fiber.76 are reported to produce the greatest weight loss in ad libitum It is also known that the GI microbiota is also able to make diets, while ad libitum low-fat diets perform less well and use of fiber to affect the efficiency of energy absorption from produce less improvement to metabolic markers.84–88 Low-fat the gut, which has been the subject of much study (reviewed diets work as effectively as low-carbohydrate diets only when by Backhed).77 By fermenting fiber into absorbable short- caloric restriction is enforced in both regimens.89,90 A recent chain fatty acids, colonic bacteria are able to provide energy small study of a “prudent” reduced-fat diet produced a 38% from fiber to the host that would otherwise not be available, reduction in endotoxin activity.91 However, despite having and affect signaling via GPR41 and GPR43 receptors. a similar sample size to some Paleolithic-diet studies, there Despite the trend toward reduced fiber intake in Western were no significant differences in blood glucose or insu- diets, the relevance of fermentable fiber mechanisms to lin levels between the “prudent” diet and an elevated-fat obesity is questionable. The addition of supplementary fiber diet that increased circulating endotoxin activity by 71%, to Western diets has been studied extensively, without any consistent with the modest metabolic improvements from improvements of the order of magnitude required for fiber to reducing fat.86,88 represent a significant part of the causal difference between The second consideration against dietary fat is the evi- ancestral and modern diets.78 While fermentable fiber is dence of ancestral diets where some populations historically able to effect certain changes in colonic gastrointestinal ate high levels of meat and/or fat, and some ate high levels of 180 submit your manuscript | www.dovepress.com Diabetes, Metabolic Syndrome and Obesity: T argets and Therapy 2012:5 Dovepress Dovepress Leptin resistance and acellular carbohydrates carbohydrates, but no overweight or poor metabolic health by mass, the bulk of the cellular weight being made up of markers were reported (see Table 1). Similarly, modern water. The acellular carbohydrates of flour,94 sugar and pro- hunter-gatherers do not have a gradient of metabolic health cessed plant-starch products are considerably more dense. or overweight outcomes based on either fat or carbohydrate Grains themselves are also highly dense, dry stores of starch consumption,32,33 as would be expected to be manifest if designed for rapid macroscopic enzymic mobilization during simple increased proportions of one of these macronutrients germination.95 Whereas foods with living cells will have their were the primary causes of obesity. low carbohydrate density “locked in” until their cell walls are These observations are consistent with some factor breached by digestive processes, the chyme produced after present in Westernized foods being responsible for obesity, consumption of acellular flour and sugar-based foods is thus with the macronutrient ratios of unprocessed foods having suggested to have a higher carbohydrate concentration than no obesogenic effects. almost anything the microbiota of the upper GI tract from mouth to small bowel would have encountered during our Background summary coevolution. This may stimulate differing bacterial species Elevating dietary fat in a Western diet can cause obesity. to prosper or be outcompeted, or increase some microbial However, the effects of low-carbohydrate diets and the metabolic pathways and waste products in preference to failure of low-fat diets to match their ad libitum weight loss others. It is proposed that the effects of these enhanced car- and metabolic effects indicate that carbohydrates somehow bohydrate concentrations will include a more inflammatory play a central role as initiators of leptin resistance in humans. GI microbiota, initially causing leptin resistance, hence the However, the Kitavan Islanders, one of the metabolically greatly elevated leptin levels seen in Western populations healthiest populations yet studied, eat a high-glycemic- when compared to those eating a wholly cellular diet.7,12–15 index, high-carbohydrate diet with staples of starchy tubers Figure 1B shows that the nutrient densities of ancestral and fruits. A unified theory of obesity should (somehow) be foods have a good degree of overlap with those of modern consistent with all these observations. food, with nuts, meats, and eggs having higher nutrient densi- ties, but still retaining low carbohydrate density. Figure 1C The hypothesis shows a similar overlap of glycemic index between ancestral Carbohydrate density and diet-related and modern foods for which data were available,5 with little inflammation correlation between carbohydrate density and glycemic To find the cause of the modern obesity epidemic, the prop- index. Hence ancestral diets are strongly distinct from erties of modern foods that perturb the homeostatic energy modern diets with regard to carbohydrate density, but not set point should be sought. The universality of the negative by either nutrient density or glycemic index. effects of Western foods on indigenous populations indi- Once an inflammatory microbiota is in place, consump- cates that these properties must be similarly widespread in tion of refined dietary fats and oils may effect a double modern foods. hit by increasing the absorption of inflammatory PAMPs Among the most common elements of Westernized foods including LPS into the circulation (Figure 2), or stabilizing are the nonperishable products flour and sugar. A fundamen- and preserving the inflammatory microbiota itself. This tal distinction between modern foods containing these and would make a diet rich in both acellular carbohydrates and ancestral foods is carbohydrate density. Figure 1A shows fat highly obesogenic, promoting a self-sustaining cycle the carbohydrate density of a broad selection of foods, with of hyperphagia in an environment where such foods are modern foods in grey (USDA data). Foods that would be abundant. Upon withdrawal of all acellular carbohydrates, permitted on a Paleolithic or “primal” diet – the “ancestral the GI microbiota is proposed to return to a less inflammatory foods” – are those in the categories of root tubers, leafy veg- form consistent with our evolutionary experience, and one etables, fruit, nuts, meats, eggs, and fish, and are shown in much more resistant to the exacerbatory effects of dietary white. Tubers, fruits, or functional plant parts such as leaves fats, consistent with the interplay between fructose and fats and stems store their carbohydrates in organelles as part of seen in rats.96 From the sensitivity of ancestral peoples’ fiber-walled living cells. These are thought to remain largely health markers to even small influences of Western foods,15,26 intact during cooking, which instead mostly breaks cell-to- there may be a nonlinear relationship between the degree cell adhesion.92,93 This cellular storage appears to mandate a of diet-related inflammation and the amount of acellular maximum density of around 23% non-fibrous carbohydrate carbohydrate in diet, with even small amounts of sugar or Diabetes, Metabolic Syndrome and Obesity: T argets and Therapy 2012:5 submit your manuscript | www.dovepress.com 181 Dovepress Spreadbury Dovepress A B Rice cakes Pretzels Rye crispbread Wholewheat cereal 8 Modern Cookies Fruitcake Ancestral Granola bar Sodabread g) 6 OaPWtBmohrteaaiPtanteMool c Bbbpucerrcahfeerfogeiiaapnreadndssll Caloricsity (kcal/ 4 PAupmplpee srntriucdkeell den 2 Cassava French fries Multigrain bread 0 Nachos Vegetarian pizza 0 20 40 60 80 100 Rye bread Carbohydrate density (g/100 g) White rice Meat pizza Milkshake Cheeseburger C Banana Potato Pistachios Ginger 100 Sweet potato PaPresanrips dex Leek n KiwAi pfrpuleit c i Orange mi 50 Watermelon COanriroont yce Modern MacadaTmuiarn nipust Gl Ancestral Kale Cheese Modern 0 Eggs Mackerel Ancestral 0 20 40 60 80 100 Pork Carbohydrate density (g/100 g) Lamb Beef Chicken 0 20 40 60 80 100 Carbohydrate density (g/100 g) Figure 1 The carbohydrate densities of ancestral foods are distinctly lower than those of the Westernized diet. (A) The carbohydrate density (excluding fiber) of a broad selection of foods, in descending order of carbohydrate density (data from USDA).112 Modern foods (gray bars) are those that have undergone refinement or desiccation, or are derived from grains. “Ancestral” foods (white bars) are unprocessed whole-foods from the categories of meats, eggs, fish, nuts, fruits, tubers, and leafy vegetables. (B) Carbohydrate density and caloric density of modern and ancestral foods. Some ancestral foods have caloric densities as high as modern foods, notably meats and nuts. (C) Carbohydrate density and glycemic index of modern and ancestral foods. Once again, there is no distinction between the two categories of food, and no correlation between the density of a carbohydrate and the nature of the blood glucose response it will elicit. flour able to produce significant leptin resistance. This is also supplement their diet with ground plant starches from roots likely influenced by the concentration and nature of dietary or gathered wild grass seeds.97–99 The pestle-and-mortar scale fats present and heritable factors. of this food preparation would likely have made the contribu- In people of European descent, relatively high resistance tion of acellular carbohydrates to diet an order of magnitude to the diabesogenic effects of Western diet is seen.1,34 This is smaller than that seen in the modern diet, where for many the proposed to be due to thousands of years of exposure to the overwhelming majority of plant foods consumed year-round acellular carbohydrates from cereal agriculture, allowing lim- are acellular processed products. Hence it is argued that any ited adaptive mechanisms to evolve. People of non-European evolutionary pressures evoked by prior hand preparations of descent hence appear more susceptible to the effects of flour, wild seeds was dwarfed by the advent of cereal agriculture, sugar, and refinement, develop worse adipokine profiles from which in turn provided only a partial evolutionary preparation Western diets,10 and show higher incidences of obesity and for the modern Western diet. diabetes. In Europeans, overt obesity or diabetes is minimal Dietary carbohydrate-density: unless consumption of bread is compounded by replacement of a link between periodontal health remaining cellular carbohydrate sources (fruit and vegetables) with sugar, flour, and refined oil-bearing processed foods. and metabolic health? Archaeological evidence from Paleolithic African and When indigenous people adopted flours and sugars into European tools indicates that some groups of people did their diets, along with the adverse metabolic effects they 182 submit your manuscript | www.dovepress.com Diabetes, Metabolic Syndrome and Obesity: T argets and Therapy 2012:5 Dovepress Dovepress Leptin resistance and acellular carbohydrates Acellular carbohydrates Periodontal disease Systemic SOCS3 activation and/or LPS elevation More inflammatory microbiota Leptin resistance (vagal, then central) PAMPs CCK, PPY, CART effects CB1, MCH effects Appetite Activity (Time) Dietary fat Obesity, metabolic syndrome Inflammatory oral microbiota and PAMPs Inflammatory microbiota/oral PAMPs Downstream microbiota changes Figure 2 Schematic of the hypothesis. Notes: The acellular dense carbohydrates of modern foods are proposed to produce an inflammatory microbiota from the mouth onwards, initially producing periodontal disease. The small bowel is exposed to lipopolysaccharide (LPS) and other pathogen-associated molecular patterns (PAMPs) from the oral microbiota, and proinflammatory modulation of its own small populations of bacteria by concentrated acellular carbohydrates. With systemic absorption enhanced by dietary fat, the inflammatory bacterial compounds induce leptin resistance and hyperphagia. The contents of the gray box represent the existing understanding of the effects of diet-induced obesity on energy homeostasis. Abbreviations: CCK, cholecystokinin; PPY, peptide YY; CART, cocaine and amphetamine related transcript; CB1, cannabinoid receptor type 1; MCH, melanin concentrating hormone. experienced a substantial downturn in their dental health.100,101 emphasizing the lack of evidence indicating a causal link It is widely accepted that consumption of refined carbo- between periodontal disease and heart disease, and suggest- hydrates can cause tooth decay and gingival inflamma- ing independent causative factors were causing both.105 If tion through bacterial means. While an inflammatory oral the high carbohydrate density of modern foods produces an microbiota may alter oral inflammation, it increasingly inflammatory microbiota in both the mouth and small bowel, appears that analogous microbial changes in the upper GI it may be this that is the root cause of both periodontal and tract appear able to produce leptin resistance in vagal affer- atherosclerotic disease, as well as obesity and other metabolic ent endings, attenuating satiety signaling.65,66 The present syndrome-linked “diseases of affluence.” hypothesis suggests that it is a diet of high-density carbo- The hypothesis and existing hydrates that produces inflammatory microbiotal changes in both areas. Periodontal disease has long been known to dietary patterns associate with obesity,102 while elevated levels of a particular The consensus “prudent” or Mediterranean dietary pat- Gram-negative oral bacterium was found to predict 98.4% terns could be expected to offer slight improvements over of obesity in one study.103 A 4-week experiment in “Stone an unrestrained Western diet, due to the inclusion of more Age” lifestyle, including removal of refined foods and con- cellular plant foods at the expense of some acellular car- sumption of reduced levels of whole cereal grains, produced bohydrate and fat, and an emphasis on some less refined significant reductions in markers of gingival inflammation and thus very slightly less carbohydrate-dense breads (see despite an absence of modern oral hygiene practices during Figure 1). However, enough breads and baked goods with the study.104 Over the last decade, interest in the associa- acellular dense carbohydrate are retained to keep an inflam- tion between periodontal disease and systemic diseases has matory microbiota and prevent substantial correction to the increased markedly, along with some reconsideration of the endemic Western leptin resistance. This is consistent with possibility of a role for dietary carbohydrate as a cause of the continued requirement for conscious caloric restriction both (reviewed by Hujoel).100 However, elsewhere this link when eating these consensus diets if a steady weight is to was misrepresented, and some were marketing dental treat- be maintained. ments as a means to improve cardiovascular health. This led Low-carbohydrate diets will reduce acellular carbohy- to a recent American Heart Association scientific statement drate consumption as a by-product of markedly reducing Diabetes, Metabolic Syndrome and Obesity: T argets and Therapy 2012:5 submit your manuscript | www.dovepress.com 183 Dovepress Spreadbury Dovepress all carbohydrates. This is suggested to result in a larger reduc- (and assuming no permanent diabetes-related damage) the tion in the inflammatory nature of the GI microbiota, weight resulting restoration of insulin sensitivity should mean a diet loss without conscious caloric restriction, and improved met- with a higher level of unrefined whole fruit and starchy root abolic syndrome markers.86,88,106 However, low-carbohydrate vegetables should be compatible with maintaining optimal diets retain some carbohydrates (usually less than 20–50 g metabolic health and stable healthy weight. This is now per day), often with no regard to their density. This means being reported anecdotally by Paleolithic-diet eaters, and what little carbohydrate is eaten may still lay the basis for is consistent with the condition of the Kitavan Islanders. an inflammatory microbiota, which is proposed to receive a The proposed importance of the cellularity and low car- second hit via additional energy for bacteria and increased bohydrate density of fruit and vegetables in maintaining LPS translocation from the elevated fat content that often an evolutionarily appropriate microbiota might explain the accompanies a low-carbohydrate diet. This is suggested to failure of supplementary fiber, vitamins, or antioxidants to explain the “stall” process, where low-carbohydrate dieters replicate the health effects of a diet of fruit and vegetables can lose large amounts of weight, but then cease weight loss when taken with a Western diet.110 while still overweight or begin to slowly regain weight.84,85 Severe caloric restriction for 8 weeks with a diet of Suggestions for the future refined-liquid meal-replacement formula supplemented with The available evidence suggests that whole-food grain-free some vegetables (510 kcal Optifast with vegetables to a total diets are substantially metabolically healthier than modern of 600 kcal per day) was reported to normalize beta-cell diets. How generalizable these findings are to differing function and insulin sensitivity in a small group of type II populations and to what extent Western diseases such as diabetics (4 years from diagnosis).107 This represents an obesity, diabetes, and atherosclerosis can be reversed by intake of acellular carbohydrates of around 237 kcal per adoption of this dietary pattern should now be assessed in day (the liquid diet was 46.4% carbohydrate), which might large-scale clinical trials. Whether the means of action is represent a sufficient reduction to avoid adverse metabolic as proposed in this paper should also be tested in humans, microbial effects. It is of note that a Paleolithic-style diet also measuring levels of inflammation, SOCS3, NFκB and normalized type II diabetic glucose tolerance in a randomized leptin with titrated intake of acellular carbohydrate and fat. trial with a similar small group, but crucially these patients Whether any effects of carbohydrate density are found to were eating ad libitum.42 Both 237 kcal per day of acellular be dependent on cellularity will be a crucial determinant of carbohydrate and an ad libitum Paleolithic style of eating may whether processed foods can be made safer by reformulation. produce similarly sparse concentrations of carbohydrate in Potential interactions of the Paleolithic dietary pattern with the upper GI tract, but only the Paleolithic diet is practical or common medications should be studied carefully.23 Whether sustainable in the long term. Time of intervention may be of the advice of some variants of the diet regarding exclusion the essence due to beta-cell damage; in a later study, longer- of legumes or dairy products have demonstrable metabolic established type II diabetics (mean = 8 years postdiagnosis) or anti-inflammatory roles should also be evaluated. still showed greater improvements with Paleolithic eating The complexity of the microbiome and its interplay with than with a consensus diet, but they did not obtain fully the host is hard to overstate. Detailed 16S RNA bacterial normalized blood glucose regulation.41 profiles from multiple levels of the GI tract, of both the lumi- Hence a grain-free whole-food diet would be predicted nal contents and mucosa, may be needed to identify any bac- to restore the GI microbiota to the less inflammatory state teria or bacterial genes that vary while carbohydrate density that humans coevolved with. This is consistent with the or cellularity are altered (holding macronutrient ratios as larger falls in blood glucose response and leptin/insulin- constant as possible). Putative microbiota-related signaling resistance, and the 20%–30% spontaneous reduction in molecules and metabolic effectors such as fasting-induced caloric intake seen in the Paleolithic diet when eating to adipocyte factor and adenosine monophosphate-activated satiety,41–43 as well as the population-wide maintenance of protein kinase should also be monitored for correlations healthy weight in Kitava6,7 and in other grain-free whole with carbohydrate density and fat. It may be possible to food-eating populations.16,20,22,29,108,109 Upon initial adoption establish an index system for assessing the obesogenic of dietary change, overweight Westerners with higher insulin potential of foods, based upon the rate of proliferation resistance might initially benefit from a low-carbohydrate of relevant bacteria either in the gut or under simulated form of Paleolithic-style eating. However, over time conditions in vitro. 184 submit your manuscript | www.dovepress.com Diabetes, Metabolic Syndrome and Obesity: T argets and Therapy 2012:5 Dovepress