Low carbohydrate (carb) diets are advocated for all kinds of health conditions (incl. ME/CFS), by Atkins/weight-loss/Paleo movements and some alternative MDs. These movements demonise carbs and oversimplify their role in health and disease. So here is a reappraisal of the humble carb.
Carbohydrates store energy and carbon
Carbohydrates (carbon hydrates) are molecules composed of carbon, hydrogen and oxygen, which are present in nature as various different simple sugars (monosaccharides) and chains of sugars (oligo- and polysaccharides). Carbohydrates are principally synthesised by photosynthetic organisms, which on land are plants. Photosynthesis essentially converts light energy into chemical energy, which can then be stored in sugars/carbohydrates. Initially light photons are used to power an electron transport chain which uses H2O and generates NADPH and ATP, these are then used in the Calvin cycle (with CO2-derived carbon fixation) to synthesise glucose (C6H12O6) and other sugars. Simple sugars are combined into polysaccharides for energy storage (starch) and cell structure (e.g. cellulose), as well as contributing to protein and fat synthesis. If we zoom out, then on a macro scale plants play a fundamental role in the carbon cycle on earth by fixing atmospheric carbon (from CO2) into carbohydrates and related molecules, which then pass through the entire animal kingdom – plants are eaten by herbivores, which are eaten by carnivores.
Glucose fuels energy, redox and biosynthesis
In animals all dietary carbohydrates must first be broken down into their respective simple sugar components before being absorbed. By far the most important sugar to human nutrition is glucose. Glucose enters cells via GLUT transporters and is rapidly converted to glucose-6-phosphate before fuelling several metabolic pathways.
Oxidation of glucose via glycolysis yields high energy molecules (NADH and ATP) and pyruvate, which can be fully oxidised in mitochondria for more ATP (note cellular respiration releases CO2 back into the environment). By weight glucose oxidation generates less ATP than lipid oxidation (fats contain more hydrogen), however despite this there is an organ, cell and activity-specific preference in the body. Glucose is a primary fuel for brain, liver, active muscle, activated immune cells, red blood cells and developing foetus 1–3. Whereas other tissues mainly use fats such as heart, kidney, resting muscle and quiescent immune cells. Why this difference? Perhaps because glucose uptake and cytosolic metabolism is quick; by contrast lipid β-oxidation occurs in mitochondria (and peroxisomes for long chain fats), demands more oxygen and generates more reactive oxygen species (ROS) 1,4. Cells benefiting from these types of differences may favour glucose as fuel.
In parallel to glycolysis, glucose feeds the pentose phosphate pathway (PPP). The first part of this pathway oxidises glucose to provide electrons for NADPH, which maintains cellular redox/glutathione homeostasis and reductive/lipid biosynthesis. The second and non-oxidative part of the PPP generates pentose/ribose and erythrose sugars for nucleotide (and therefore ATP, FAD, NAD, RNA, DNA) and aromatic amino acid synthesis respectively. Glucose flux through glycolysis vs. PPP is regulated by cellular redox. Oxidative stress inhibits glycolysis, while triggering an Nrf2-dependent expression of PPP enzymes to restore redox homeostasis 5,6. Notably in most animals glucose is also the substrate for ascorbic acid (vitamin C, C6H8O6) synthesis, although humans can no longer catalyse the last step due to a non-functional gulonolactone oxidase gene. This may not be such a bad thing since production of ascorbic acid consumes glucose and generates ROS.
Less often appreciated is that sugars and glycosylation (sugar addition) are required for the synthesis of many basic glycan-containing molecules, such as glycoproteins (e.g. mucins, immunoglobulins, etc.), glycophospholipids and glycosaminoglycans (e.g. chondroitin, hyaluronan, etc.). In fact glycans are the most abundant molecules in the body; 1-2% of the human genome encodes proteins involved in glycan formation! Of central importance is glucose metabolism through the hexosamine biosynthetic pathway, which generates sugar-amines (N-acetylgalactosamine and N-acetylglucosamine) used to build glycoconjugates 7. Finally glycosylation is analogous to phosphorylation in that it is a dynamic post-translational modification which regulates the activity of many cellular, nuclear and mitochondrial proteins.
Blood glucose is maintained within a tight range (e.g. 4.4-6.1 mmol/L) to ensure consistent supply to tissues. Postprandial (after meal) elevations in blood glucose stimulates insulin release which increases uptake into muscle and adipose tissue (via GLUT4), and also inhibits liver glucose production. Surplus glucose is combined in glycogenesis to form the polysaccharide glycogen (animal starch) which serves as a short-term glucose store (mainly in liver and muscle). Dietary fructose also contributes to liver stores via metabolism by fructolysis to glucose and glycogen. Glucose can further be converted to fat by lipogenesis for longer term storage or metabolism.
Various stimuli can trigger glucose release back into blood. During periods of stress the glucocorticoid cortisol promotes glycogenolysis and gluconeogenesis to increase blood glucose levels. Similarly under conditions of dietary carbohydrate deprivation, glycogen depletion and low blood glucose/insulin levels, compensatory pathways are activated such as gluconeogenesis and ketogenesis. Hepatic gluconeogenesis is required to supply new glucose to maintain blood levels, while ketogenesis converts acetyl-CoA (from lipid oxidation) to ketone bodies which provide an additional fuel for several tissues (esp. brain), thereby sparing blood glucose (which must not drop too low). Note ketones also act as signaling molecules to achieve metabolic adaptation, which involves suppression of sympathetic activity to lower resting energy usage 8,9.
Use of sugars as fuel is conserved throughout life and as such carbohydrates feed the gut microbiota. Gut microbes typically have a glycolytic metabolism, with some being capable of various forms of aerobic or anaerobic respiration; however the near anoxic conditions of the gut mean a fermentative anaerobic metabolism dominates. Fermentation does not completely oxidise sugars and therefore generates waste products such as ethanol, lactate and short chain fatty acids (SCFAs), which can be salvaged by the body for energy via cellular respiration.
Carbohydrates available to the gut microbiota come from both host and diet. The gut lining (and other internal surfaces) are made up of epithelial cell barriers coated in mucus secreted by goblet cells. Mucus is made from mucin, a heavily glycosylated (sugar-coated) protein composed of 80% carbohydrate 10 (e.g. N-acetylgalactosamine, N-acetylglucosamine, fucose, galactose, sialic acid, etc.). Mucin carbohydrate synthesis occurs in the goblet cell golgi complex and requires glucose 11 (hexosamine pathway above). Mucus acts to shield the epithelium 10 and maintain immune tolerance to antigen 12. In addition the outer mucus layer provides adherence and food for many beneficial microbes (e.g. Akkermansia, butyrate-producing bacteria, Lactobacilli and Bifidobacteria) 13–15. Furthermore recently it was reported that systemic immune activation induces rapid fucosylation of small intestinal cells, which presents fucose directly to the gut microbiota and maintains microbiota-host homeostasis 16.
Diet provides carbohydrates to the gut microbiota in the form of simple sugars and complex polysaccharides; note sugar-related molecules such as ascorbate (vitamin C) can also be readily fermented 17,18. Indigestible carbohydrate polysaccharides (resistant starch and fibre) pass into the colon where bacterial fermentation generates lactate and SCFAs. These molecules have a myriad of beneficial effects including: acidify colon, inhibit pathogens (e.g. Enterobacteriaceae and Candida), enhance mineral absorption, feed colonocytes, provide energy to the host, and favourably regulate systemic metabolism, immunity and neurobiology. In particular carbohydrate fermentation regulates systemic energy metabolism via multiple mechanisms including: increased satiety, fat metabolism (adipose tissues) and improved insulin sensitivity and glucose tolerance, all of which counter the metabolic syndrome phenotype 9,19,20. Ultimately we seem well adapted to a carbohydrate-based (saccharolytic) colonic fermentation; note this is not the case for high fat or protein diets 21–23!
Diet and evolution
Carbohydrates have probably played a fundamental role in human evolution 2. Humans have evolved from a mainly herbivorous anthropoid lineage, with our closest living relative, chimps (also Hominidae family), being omnivorous frugivores (prefer fruit). One of several key genes which separates us from them encodes amylase 24,25, an enzyme enabling us to digest starches, suggesting a broadening of our diet to include starchy plant foods. Another key evolutionary change is our relatively large brain and small gut and teeth. This is thought to be the result of an increase in food quality, due to greater consumption of meat, food processing and cooking 26, which makes both animal and plant foods far easier to digest and extract energy from 27,28.
In particular the brains preference for using glucose, suggests at some point humans must have started consuming more carbohydrates to meet this increased metabolic demand (at rest the brain consumes 20% of blood oxygen and 25% of blood glucose). The major dietary source of glucose is likely to have been the starch in plant tubers 2, which is rendered highly digestible after cooking 27,28.Therefore a convergence in cooking practices, starch consumption and amylase may have been pivotal in allowing the enlargement of our brains 2. Also crucial would have been increased consumption of marine life rich in the omega-3 fatty acid DHA 29, which is the major structural fatty acid in the brain, cannot be efficiently synthesised endogenously, and is positively coupled to glucose transport and metabolism 30,31.
However, on the flip side, there is the older view that Palaeolithic humans ate mostly meat. This stems from old ethnographic data 32 and archaeological studies which are unfortunately limited by methodological issues and biases favouring markers of meat consumption (see). Even the idea that Neanderthals only ever ate meat has now been overturned by modern research on dental calculus and old poop (refs in 35). However people living in extreme cold environments such as the Arctic, where there are few plants, certainly eat an almost entirely animal-based diet. Although even here they may consume 15-20% of calories as carbohydrate (they are not in ketosis), mainly in the form of glycogen which is persevered in animal muscle at low temperatures 2. Moreover Inuit peoples have enlarged livers 2 and recently genetic adaptations have been identified in circum-Arctic populations which enable a greater rate of lipid oxidation (as well as having other deleterious effects) 36.
For more on all this check out these interesting talks by hunter-gatherer/paleo researchers: Christina Warinner, Alyssa Crittenden Richard Wrangham and Nathaniel Dominy. And also the ‘Evolution of diet’ page at National Geographic.
A high consumption of plants, carbohydrates and fibre is a key feature of healthy populations including Mediterranean 37, Okinawan 38 and Kitavan diets 39. In fact people living in areas of the world with the best health and longevity statistics (i.e. blue zones) consume semi-vegetarian diets. By contrast western industrialised diets are widely considered to contribute to chronic disease (e.g. dental/periodontal, metabolic, inflammatory, degenerative and skin diseases, amongst others). The so called ‘western diet’ is high in refined carbohydrates/sugar, fat (saturated and omega-6), meat, empty calories and additives, while being low in whole plant foods/fibre, omega-3 and micronutrients.
Similar to other nutrients, carbohydrates start to become unhealthy when they are processed and refined. Food processing removes beneficial dietary fibre and adds sugar/fructose syrup. This results in high glycaemic index (GI) foods which promote exaggerated elevations in blood glucose and challenge energy homeostasis, while the lack of fibre starves the gut microbiota and prevents its ability to promote heath. Western diets may also be relatively high in harmful advanced glycation end-products (AGEs, aka. glycotoxins). AGEs form when sugars react with free amino acids, fats and nucleic acids. In the body, AGE formation may be promoted by elevated glucose (and more so fructose) and oxidative stress. In the diet, AGEs are formed in heat-treated foods, especially those of animal origin, which greatly contribute to body pools. AGEs activate the receptor for AGE (RAGE) and generally act to promote oxidative stress, inflammation and chronic disease.
So when considering our biology, microbiome, evolution and current health epidemiology, it may be changes in carbohydrate quality rather than quantity which are most important. Note a similar quality/balance paradigm is also accepted for fats: saturated/unsaturated, omega-3/6, etc.
Many modern diseases involve problems with carbohydrate metabolism. For instance systemic insulin resistance and glucose intolerance is a characteristic of metabolic syndrome and diabetes. Brain insulin resistance and glucose hypometabolism is a hallmark of Alzheimer’s disease (aka. diabetes type-3). Impaired glucose metabolism has also recently been reported in ME/CFS blood and muscle tissue 40,41. In these conditions, low GI or even low-carb diets may be required to prevent the negative effects of poor glucose control, while other macronutrients (protein and fats/ketones) can supply alternative fuel when necessary 30. Low carb diets are also effective for weight loss (as is any calorie-restricted diet) and can improve cardiometabolic markers. However these approaches are compensatory and not necessarily going to achieve the best health. In humans, low carb diets 42 and higher animal protein intake 43 have been associated with increased disease and mortality. Furthermore, if mice are anything to go by, then they have the best cardiometabolic health, aging and longevity when fed an ad libitum low protein, high carb diet 44. This seems reminiscent of the diet of blue zone populations.
So what really causes problems with carbohydrate metabolism? Perhaps of foremost importance, most aspects of the western diet can promote insulin resistance, including increased levels of sugar (esp. industrial fructose), fat (esp. sat fat), AGEs, artificial sweeteners and emulsifiers, and low levels of fibre, polyphenols, omega-3 and micronutrients (esp. magnesium 45).
Interestingly, most things which screw up glucose tolerance, do so by inducing gut dysbiosis and inflammation 46–49. Alterations to the gut microbiota, such as small intestinal bacterial overgrowth (SIBO) or gut dysbiosis, occur in most chronic disorders. Again low-carb diets are often advocated here, since this might broadly lower microbe growth, and therefore SIBO 50 and theoretically the presence of some pathogens 51. Certainly lowering specific fermentable carbohydrates (FODMAPs) improves symptoms in irritable bowel syndrome (IBS), which is frequently associated with SIBO. However low-carb diets seem unlikely to treat the causes of SIBO and dysbiosis, such as antibiotic use, western diet, digestive insufficiency, immunodeficiency and slow intestinal motility (amongst other factors) 52,53. Moreover diets low in indigestible carbohydrates and high in protein and/or fat typically themselves induce gut dysbiosis, pathogen overgrowth, production of harmful metabolites, leaky gut and inflammation 22,54,55!
On the other hand, increasing the intake of indigestible carbohydrates, and augmenting colonic carbohydrate fermentation, has the potential to benefit many diseases; perhaps especially those featuring low levels of beneficial butyrate-producing bacteria and elevated Enterobacteriaceae (e.g. IBD, IBS, Parkinson’s, arthritic psoriasis and obesity). As discussed earlier, colonic carbohydrate fermentation positively affects most aspects of gut and systemic health (e.g. inflammation, immunity, insulin sensitivity and glucose tolerance), and can often even mitigate the negative effects of a high fat or protein diet 21,22. Even conditions with SIBO may paradoxically benefit from increased consumption of resistant starch and fibre (e.g. SIBO 56, colitis 57,58 and Crohn’s 59), perhaps in large part due to improved intestinal motility 56,57,60.
In summary, I think rather than demonising carbs, we should be asking why is carbohydrate metabolism impaired in so many disorders, and how can we improve it? Really all macronutrients are important, and their dietary balance can be manipulated to support differences in our body, lifestyle and health needs. Finally it might also be worth considering how our diet affects the wider ecosystem and entire planet.
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