Current evidence indicates obesity and other metabolic disorders such as type 2 diabetes and insulin resistance are influenced by host genetics and lifestyle. This cascade of ever growing diseases is also associated with low-grade inflammation, as indicated by an overabundance of biomarkers in serum. What initiates or triggers the inflammation associated with these metabolic disorders?
Multiple studies in humans and mice have demonstrated that a high fat diet can trigger inflammation (see references below). But a high fat diet alone is not the whole story. If it were, a lot of Paleo dieters would be in trouble. It seems what might be missing from that high fat diet and the gut bugs deep in the gut hold the answer to what triggers the inflammation.
Every person on earth has two genomes. Our human genome, which is a mash up and shuffled deck of DNA from mom and dad, is the one we are familiar with and, for better or worse, stuck with. Our second genome is more dynamic and made up of trillions of bacteria we initially receive during birth from mom and continuously throughout life from the people we hang with, to the foods we eat, and the places we live. Numbering in the thousands of species, our microbial friends (and foe) outnumber our human cells 10 to 1. In other words, humans are 90% microbe and only 10% human. Humbling.
Spawned by the success and technical achievements of the Human Genome Project, an explosion in our understanding of the role of the microbiome (all the genes of our gut microbiota) in human health has literally flipped modern medicine and the understanding of what makes us sick on its head. Importantly, even though dynamic interactions with our microbiome is conditioned by influences as varied as birthing method (vaginal vs c-section), life time exposure to antibiotics, and general lifestyle choices, diet appears to be driving the species diversity of our microbiota and the much-needed functions they encode.
Given the dynamic relationship that is emerging between diet and the composition of our microbiome, researchers have observed that adult germ-free mice had 40% less body fat their germ-bearing (conventionalized) littermates consuming the same diet. Astonishingly, when germ-free mice are colonized with the gut microbiota from genetically obese mice (ob/ob), the otherwise lean mice dramatically increase body weight. In short, gut bugs salvage energy from otherwise non-digestible polysaccharides – think dietary fiber – through special enzymes they encode and our genome does not, which in turn increases circulating glucose and insulin levels and thus weight. These and countless other experiments in mouse and human models have firmly established the role of the microbiome in energy homeostasis.
However, the most interesting finding to come of this ongoing research is the fact that germ-free mice do not gain weight when fed either a high fat or regular chow of the same caloric content. This is counter to experiments that reveal that a high fat diet promotes obesity in mice possessing a full suite of gut bacteria. Said differently, a high fat (lipids) diet alone cannot explain obesity in mice and that obesity and associated inflammation only occur in the presence of gut bacteria.
So what is it about the presence or absence of bacteria that promotes weight gain in a high fat meal/diet?
Multiple studies have shown that a high fat diet produces low-grade inflammation, which in turn promotes metabolic disease such as diabetes. Interestingly, the low-grade inflammation correlates with circulating levels of a plasma endotoxin known as lipopolysaccharide (LPS). LPS is the primary structural component of the outer membrane of Gram-negative bacteria. Importantly, LPS only originate in the gut.
Researchers also note that under conditions of a moderate or high fat meal/diet, serum levels of LPS go up, but levels of the bacteria Bifidobacterium species in the gut go down. The sum of these studies, and there are a number of them (see references below), reveal that meals of 33%, 38% and 100% fat are sufficient to raise levels of LPS and create the conditions for what is now referred to as metabolic endotoxemia – leading to metabolic syndrome.
So lets review. A high fat diet results in elevated levels of serum LPS, a condition referred to as endotoxemia. The presence of elevated levels of LPS in the blood triggers several inflammatory markers that are a precursor to the progression towards metabolic syndrome (e.g., obesity, diabetes). As circulating LPS goes up, levels of Bifidobacterium go down and germ-free mice eating either a high fat or normal chow diet weigh more or less the same (and do not have circulating LPS as the absence of bacteria – remember they are germ-free – means no LPS).
But how do the LPS translocate, or leak, from the gut into serum? And why during a high fat diet and not high caloric diets as revealed by other studies? Seems the key to the gut permeability is tied to the abundance of the Bifidobacterium mentioned above.
In a series of fascinating studies, researchers in Brussels fed a high fat diet to mice (and subsequently humans) to induce elevated levels of LPS. Elevated levels of serum LPS resulted in significant inflammation, weight gain, insulin resistance, and ultimately type-2 diabetes in the mice experiments. To test the hypothesis that serum levels of LPS are linked to levels of Bifidobacterium in the gut, a prebiotic oligofructose (from chicory roots) that is known to stimulate the growth of Bifidobacterium was added to a high fat diet fed to one group of mice, but not to the same high fat diet fed to another group.
In the high fat only group, endotoxemia was significantly increased, but in the high fat diet that also included the prebiotic, Bifidobacterium levels predictably went up and the LPS levels were normalized. This also correlated with improved glucose tolerance and a normalized inflammatory “tone.”
These set of experiments, which were also confirmed by other researchers, suggest that gut microbiota regulate endotoxemia and inflammation and mediate complications associated with metabolic syndrome. In other words, a moderate to high fat diet that does not include nutrients that will stimulate the growth of members of the genus Bifidobacterium concurrently will result in inflammation and complications associated with metabolic syndrome as LPS leaks into the blood.
It is well established that byproducts associated with the fermentation of the prebiotics by Bifidobacterium, such as short-chain fatty acids (butyrate, propionate and lactate) positively effect gut barrier (reduce leaking) and improve tight junctions between gut epithelial cells. Therefore, by stimulating the growth of species of Bifidobacterium you may lower endotoxemia and improve or avoid any metabolic disturbances. Further improvement in barrier function has recently been linked crosstalk between the gut microbiota and the endocannabinoid system (a group of neuromodulatory lipids and their receptors).
Therefore, if you are following a high fat Paleo Diet, you might do well to include additional sources of known prebiotic foods in your diet. On a daily basis, most of us consume very small amounts of prebiotics (1-4g) – mainly from foods like onion, leek, garlic, and dandelion greens (prebiotics are the non digestible oligofructose, inulin, galactooligosaccharides within these plants). If in fact the levels of Bifidobacterium in our microbiota mediate gut permeability to the extent discussed above, then our chronic low intake of prebiotic dietary fibers may be a significant player in our epidemic of metabolic syndrome.
Our ancestors without a doubt consumed prebiotic-bearing plants. Over 36,000 species of the world’s flora contain the carbohydrate fructan (prebiotics), many of which are subsurface tubers, which would have played an increasingly important role in early Homo diet.
In a paper I published in the British Journal of Nutrition, a colleague and I noted that archaeological evidence from dry cave deposits in the northern Chihuahuan Desert reveal inulin-type fructans from the desert succulents agave and stool were a primary carbohydrate for at least 10,000 years. Evidence from ancient cooking features, stable carbon isotope analysis of human skeletons, and well-preserved coprolites and macrobotanical remains reveal an average daily intake of 135 g of prebiotic inulin for an average adult male.
It is interesting to think that all of the attention that has been given to various substances that might lead to a leaky gut might be missing the 800 pound gorilla in the room – Bifidobacterium. Think I will have onion and garlic with my dinner tonight – how about you?
Backhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI (2005) Host–bacterial mutualism in the human intestine. Science 307:1915–1920
Backhed F, Manchester JK, Semenkovich CF, Gordon JI (2007) Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci USA 104:979–984
Bäckhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA 2004; 101:15718-23; PMID:15505215; http:// dx.doi.org/10.1073/pnas.0407076101.
Cani, P. D., J. Amar, et al. (2007). “Metabolic Endotoxemia Initiates Obesity and Insulin Resistance.” Diabetes 56(7): 1761-1772.
Cani, P. D., R. Bibiloni, et al. (2008). “Changes in Gut Microbiota Control Metabolic Endotoxemia-Induced Inflammation in High-Fat Diet–Induced Obesity and Diabetes in Mice.” Diabetes 57(6): 1470-1481.
Cani, P. D. (2012). “Crosstalk between the gut microbiota and the endocannabinoid system: impact on the gut barrier function and the adipose tissue.” Clinical Microbiology and Infection 18: 50-53.
Deopurkar, R., H. Ghanim, et al. (2010). “Differential Effects of Cream, Glucose, and Orange Juice on Inflammation, Endotoxin, and the Expression of Toll-Like Receptor-4 and Suppressor of Cytokine Signaling-3.” Diabetes Care 33(5): 991-997.
Eckel RH, Grundy SM, Zimmet PZ. The meta- bolic syndrome. Lancet 2005; 365:1415-28; PMID:15836891; http://dx.doi.org/10.1016/S0140- 6736(05)66378-7.
Everard A, Lazarevic V, Derrien M, Girard M, Muccioli GG, Neyrinck AM, et al. Responses of gut micro- biota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice. Diabetes 2011; 60:2775-86; PMID:21933985; http:// dx.doi.org/10.2337/db11-0227.
Ghanim, H., C. L. Sia, et al. (2010). “Orange juice neutralizes the proinflammatory effect of a high-fat, high-carbohydrate meal and prevents endotoxin increase and Toll-like receptor expression.” The American Journal of Clinical Nutrition 91(4): 940-949.
Laugerette, F., C. Vors, et al. (2011). “Complex links between dietary lipids, endogenous endotoxins and metabolic inflammation.” Biochimie 93(1): 39-45.
Laugerette, F., C. Vors, et al. (2011). “Emulsified lipids increase endotoxemia: possible role in early postprandial low-grade inflammation.” The Journal of nutritional biochemistry 22(1): 53-59.
Leach, J. D. (2007). “Prebiotics in Ancient Diets.” Food Science and Technology Bulletin 4(1): 1-8.
Leach, J.D., K. D. Sobolik (2010). High dietary intake of prebiotic inulin-type fructans in the prehistoric Chihuahuan Desert. British Journal of Nutrition, 103 , pp 1558-1561 doi:10.1017/S0007114510000966
Ley RE, Turnbaugh PJ, Klein S, Gordon JI (2006) Microbial ecology: human gut microbes associated with obesity. Nature 444:1022– 1023
Tuohy KM, Rouzaud GC, Bruck WM, Gibson GR (2005) Modulation of the human gut microflora towards improved health using prebiotics—assessment of efficacy. Curr Pharm Des 11:75– 90
Turnbaugh PJ, Ley RE, Hamady M, et al. (2007) The Human Microbiome Project. Nature 449, 804 – 810.
Van Loo J, Coussement P, De Leenheer L, et al. (2005) On the presence of inulin and oligofructose as natural ingredients in the Western diet. Crit Rev Food Sci Nutr 35, 525–552.
Vijay-Kumar M, Aitken JD, Carvalho FA, Cullender TC, Mwangi S, Srinivasan S, et al. Metabolic syn- drome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 2010; 328:228-31; PMID:20203013; http://dx.doi.org/10.1126/sci- ence.1179721.