“Facts are stubborn things; and whatever may be our wishes, our inclinations, or the dictates of our passions, they cannot alter the state of facts and evidence.”
– John Adams
Let me connect John Adams to this series on nutrition, gut, cancer.
Opinion is a view or judgment formed about something, not necessarily based on fact or knowledge. Evidence is the available body of facts or information indicating whether a belief, proposition, or opinion is valid. Scientific evidence is the evidence that serves to either support or counters a scientific theory or hypothesis.
More than the definition of opinion, evidence, and scientific evidence are their open discussion in the public square. Discussion is great. Healthy discourse in an open and free forum is necessary for science to impart reasoning, thought, and proof of ideas. Science is the open debate of ideas, and medicine is a science. Without the open debate of ideas, science becomes more of a religion than an arena for debate and discovery. It becomes more group think, and not critical think. Without a solid understanding of the difference between science and faux science, bias, ignorance, and confusion will cloud the difference between opinion, evidence, and scientific evidence. The result is the degradation of science to opinion-based tabloid facts, political narratives, or worse—propaganda.
Is there scientific evidence for a nutrition, gut, cancer connection? In the previous blog post, I introduced this concept and a little of the evidence for this connection. In scientific medical terms, this nutrition, gut, disease connection is called metabolic endotoxemia.
What is metabolic endotoxemia?
According to a 2016 article published in the journal Biochimie, metabolic endotoxemia is “low-grade elevation in plasma LPS…that is associated with a heightened pro-inflammatory and oxidant environment often observed in obesity” [1]. In short, metabolic endotoxemia is the disruption of normal systemic metabolic function through low-grade systemic inflammation from systemic endogenous toxins (endotoxins) primarily from the gut.
How does this process occur, and what are the implications, first, in chronic diseases of aging, and then in cancer?
The primary endotoxin in question here is lipopolysaccharide (LPS). However, there are many other gut sources for endotoxins. In metabolic endotoxemia, the primary source of LPS, currently studied, is gram-negative bacteria from the gastrointestinal tract—the gut. These are not exogenous toxins but endogenously produced toxins.
But from where? How?
It is primarily our lifestyle that drives the production and systemic dissemination of these endogenous LPS toxins.
You may have heard of the concept of “leaky gut.” Though leaky gut is not an ICD10 recognized diagnosis, it is an actual process. A leaky gut allows the movement of LPS from the gastrointestinal tract, through the gut lining (called tight junctions), into the systemic circulation to cause systemic inflammatory signaling through interaction with Toll-like 4 receptors (TLR4). The TLR4 is a transmembrane protein member of the broader toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. Pattern Recognition Receptors induce the innate immune response by recognizing Pathological Antimicrobial Peptides, or Pathogen Associated Molecular Patterns (PAMPs), leading to the activation of downstream signaling pathways and the expression of a wide multitude of pro-inflammatory host defenses against invading pathogens. In addition to the PAMPs, there are also Damaged Associated Molecular Patterns (DAMPs) that originate from tumor cells, host cells, dead and dying cells. Damaged Associated Molecular Patterns can result from myocardial infarction, cancer, autoimmune disease, and trauma and require no infectious source. In contrast, PAMPs in the cause of LPS induced metabolic endotoxemia require endogenous bacterial or pathological infectious sourcing. The LPS—TLR4 interaction stimulates NF-κB transcription signaling and the end result is chronic, systemic, low-grade inflammation. It is this exact set up that is characteristic for many of the chronic diseases associated with aging.
Inflammation is not necessarily a bad thing. Just look at a paper cut, for example. The cardinal signs of inflammation: redness, swelling, pain, heat is present and, in this context, good. In this example of the paper cut, the controlled and short-term inflammation prevents secondary infection and initiates the healing process. When healing has taken place, the inflammation is no longer necessary, and it is turned off. It is when inflammation does not turn off that we have the problem. The inflammation that does not turn off is associated with metabolic endotoxemia, any chronic disease of aging, and more relevant to An Oasis of Healing—cancer.
Metabolic endotoxemia is not some opinion or loose theory; it is backed up by strong scientific evidence. The connection between metabolic endotoxemia and metabolic dysfunction and dis-aise is not just one of association but one of causation. This chronic inflammatory process has been shown to contribute too and even cause:
- Insulin resistance [2] [3] [4]
- Obesity [5] [6]
- Metabolic Syndrome [7]
- Diabetes [8] [9]
- Cardiovascular disease [10] [11]
- Autoimmune diseases [12]
- Psychiatric diseases [13] [14]
- Neurodegenerative diseases [15]
- Cancer [16]
- Mortality??
The obvious ultimate effect of any disease listed above is morbidity and mortality, but specifically mortality. If not, what is the point? In fact, the connection between poor diet, gut microbiome alteration, systemic inflammation, metabolic endotoxemia, and disease points to metabolic endotoxemia as the #1 cause of mortality worldwide. Look at the list above. Every item and category listed is associated with an increase in mortality.
How about a little current events to help prove the point? A 2021 study of patients with SARS-CoV-2 and heart involvement found that in patients with active SARS-CoV-2 infection, there was an increase in the cardiac biomarkers Troponin and NT-pro-BNP. These cardiac biomarkers are linked to increased cardiovascular events, which is associated with an increase in mortality in patients with increased LPS and LPB [17].
It is easy to point fingers at the problem(s). It is easy to be a critic. But, it takes quite a bit more effort to move from criticism to provide solutions?
The foods we eat are the most significant contributor to metabolic endotoxemia-induced systemic inflammation and the most effective solution for metabolic endotoxemia-induced systemic inflammation.
What does the published research say about how diet can affect the gut to reduce metabolic endotoxemia in treating disease? Quite a lot, actually.
I will present some of the data here, but in just a little different format:
General diet
Influence of a high-fat diet on gut microbiota, intestinal permeability and metabolic endotoxaemia [18]
I really like this literature review article because it provides a direct, sequential connection between diet, gut microbiome alteration, leaky gut, and metabolic endotoxemia (systemic inflammation). It gives a clear cause-effect discussion. Though this review article does not provide direct evidence of dietary intervention to reduce metabolic endotoxemia, it does link diet to metabolic endotoxemia to insulin resistance, obesity, diabetes, cardiovascular disease, non-alcoholic steatohepatitis, and cancer. This article connects the dots between the diet (particularly a high-fat diet), gut, metabolic endotoxemia, and disease. As a result, it provides the pathway forward in the treatment of metabolic endotoxemia by eliminating a systemic inflammatory producing diet—particularly a diet high in fats.
It should not shock anyone that the typical western diet is associated with a massively high fat intake—especially saturated and trans fats. But, as it relates to the effects of fat intake and systemic LPS, all fats are not created equally. For example, milk fat, palm oil, rapeseed oil, or sunflower oil result in the highest systemic LPS levels [19]. These fats alone can increase systemic inflammation beyond its effects on LPS through the same TLR4 receptor as LPS—a double whammy.
How does a high-fat diet induce metabolic endotoxemic inflammation? First, it damages the gut lining-specifically what are called tight junctions. Tight junctions are the “tight” connections between gut mucosal cells to limit permeability to the gut contents. Damage to these tight junctions of the gut lining causes an increase in permeability to gut contents; in this case, LPS from gram-negative bacteria. Second, and more to the topic of this post, a high-fat diet will also alter the gut microbiome. The majority of the gut microbiome is in the large intestine, an estimated 1011 compared to an estimated 108 in the small intestine. Still, this discussion is also applicable to the small intestine in what is called small intestine bowel overgrowth (SIBO). Beyond a dietary impact of calories in/out, macronutrients, diet alters gut bacteria. A high-fat diet reduces beneficial bacterial species in the gut, including Bifidobacterium, Lactobacillus, Bacteroides, and Provetella [20]. The Bifidobacterium species, specifically, heals the gut lining, reduces systemic LPS, and reduces systemic inflammation. The elimination of a high-fat diet will increase the Bifidobacterium species in the gut and promote improved gut integrity, decrease in “leaky gut”, and decrease in LPS. A plant-based vegan diet is lower in the fats and will counter this process. Beyond diet, prebiotics will increase the Bifidobacterium species in the gut also. Still more proof, antibiotics can prevent diet induced gut microbiome changes to prevent systemic LPS—metabolic endotoxemic inflammation [21].
What is great, the scientific evidence points to diet as a means to resolve a “leaky gut”. The thought that permeates the internet is that once a leaky gut, always a leaky gut. That statement is simply not true. The gut can move back and forth between an increase in permeability and a decrease in permeability; or leaky gut versus no leaky gut. A 2001 study entitled “Whole wheat and triticale flours with differing viscosities stimulate cecal fermentations and lower plasma and hepatic lipids in rats” found that dietary changes in obese mice alter the gut microbiome, specifically an increase in Bifidobacteria and a decrease in Lactobacillus species. The result was healing in the gut lining, a decrease in permeability, or decrease in “leakiness” or “leaky gut”, and a decrease in systemic inflammation [22]. Again, not just a focus on causation, but solutions through diet and an alteration of the gut microbiome.
Role of Metabolic Endotoxemia in Systemic Inflammation and Potential Interventions [23]
This article reviewed the entire LPS—TLR4–MyD88–NF-κB mediated process of the systemic inflammation of metabolic endotoxemia. In many ways, NF-κB transcription is Pandora’s box for chronic disease. This article is a thorough review of metabolic endotoxemia, including the contribution of a “leaky gut”, so I encourage you to check it out. The primary focus of this study was one of pharmacologic intervention, but some effort was given to the review of dietary interventions supported in the science. In this review, diets high in alcohol intake and saturated fats (dairy, processed meats, fatty meats, i.e., beef, pork) contributed to metabolic endotoxemia. In contrast, a diet deficient in vitamin A, zinc, iron, or folic acid disrupts the gut microbiome and contributes to metabolic endotoxemia.
Dietary intervention to the rescue. A plant-based diet is high in vitamin A, zinc, iron, and folic acid. Interestingly, on the specific topic of cancer here, vitamin A deficiency has the most contribution. Cancer is a state of many things, and deficiency is one of them, with vitamin A deficiency right up near the top.
Plant based diet
Impact of vegan diets on gut microbiota: An update on the clinical implications [24]
This study reviewed the scientific literature at large to assess the impact of vegan diets on the gut microbiome and disease. The review looked at four chronic diseases of aging: metabolic syndrome, cardiovascular disease, Rheumatoid arthritis, and Parkinson’s disease. In metabolic syndrome, a vegan diet reduces the Firmicutes/Bacteroidetes ratio, reduces bacteria that can promote disease (pathobionts), reduces systemic inflammation, and improves glucose and lipid metabolism. That is a direct connection to improved metabolic syndrome via a plant-based, vegan diet to reduce systemic inflammation, all through gut microbiome alteration.
Similar effects occur with cardiovascular disease, Rheumatoid arthritis, and Parkinson’s disease. In cardiovascular disease, a vegan diet reduced red meat-induced increase in trimethylamine-N-oxide (TMAO), which is associated with an increase in atherosclerosis. A vegan diet provided a decrease in TMAO, thus a decrease in atherosclerosis—cardiovascular disease.
In Rheumatoid arthritis (RA), the connection was direct: a vegan diet altered the gut microbiome balance to reduce symptoms of Rheumatoid arthritis. That is a direct, sequential connection between a vegan diet and reduction in RA through alteration of the gut microbiome.
In Parkison’s disease, the connection is not so direct. The presence and balance of certain gut bacteria (Prevotellaceae and Enterobacteriaceae) within the gut microbiome connect symptoms to the severity of Parkinson’s disease. Diet influences the presence, absence, balance of bacteria within the gut microbiome, but no direct connection between a vegan diet, gut bacteria, and Parkinson’s disease is currently scientifically available.
Plant-Based Nutritional Supplementation Attenuates LPS-Induced Low-Grade Systemic Activation [25]
This mouse model study looked at diet as a therapy to effect change in administered LPS induced systemic inflammation, metabolic endotoxemia, immune activity, and mitochondrial activity. The specific risk assessment of this study was of neurodegenerative diseases, i.e., Parkinson’s, Alzheimer’s disease. They followed neopterin, a biomarker for immune system activation and inflammation, to assess LPS mediated systemic inflammation—LPS increases neopterin production. Specifically, the study looked at a two-month diet high in vegetables and fruit to change LPS mediated acute and chronic systemic inflammation. The study’s authors found that a two-month diet of vegetables and fruit eliminated LPS mediated increase in both acute and chronic systemic inflammation. That is a clear reversal of LPS induced metabolic endotoxemia with a plant-based diet. More, the diet restored reduced systemic inflammatory signaling, restored insulin sensitivity, glucose metabolism, and mitochondrial function. Though this blog post is about chronic diseases in general, cancer, systemic inflammation, mitochondrial dysfunction, and insulin resistance are set up for carcinogenesis.
Calorie restriction
Effect of probiotic supplementation along with calorie restriction on metabolic endotoxemia, and inflammation markers in coronary artery disease patients: a double blind placebo controlled randomized clinical trial [26]
This study was a double-blinded, randomized placebo-controlled trial of 44 individuals with coronary artery disease followed over 12 weeks. This study design, a double-blinded randomized placebo-controlled trial, is considered the best of the best in study design.
It is essential to know that no study is perfect, no evidence-based data is absolute, no peer-review is unbiased. If people are involved in a study’s design, conduction, interpretation, or review, problems can and will exist. Just an aside, absolute agreement on science is not science; it is groupthink.
The problem with this study was that it used dual interventions of probiotics and calorie restriction. However, the study did find that a very modest 500 kcal reduction and an even more modest 1.6 billion CFU Lactobacillus rhamnosus probiotic one time daily resulted in a statistically significant decrease in systemic LPS, IL-1beta, and the systemic inflammatory marker hsCRP. Additional studies have shown that calorie restriction reduces systemic LPS and thus metabolic endotoxemic inflammation [27] [28].
In conclusion, sometimes the best something, is nothing; or at least a reduction of the something. In the case of calories, the best something is a reduction in calories. Obviously, this is in direct contrast to the excess calorie intake found in the western diet.
John Adams had it right. As it relates to diet, gut, and chronic diseases of aging, facts are a very stubborn thing. If only conventional medicine could recognize these stubborn facts.
References:
[1] Boutagy NE, McMillan RP, Frisard MI, Hulver MW. Metabolic endotoxemia with obesity: Is it real and is it relevant? Biochimie. May 2016;124:11-20. doi: 10.1016/j.biochi.2015.06.020.
[2] Liang H, Hussey SE, Sanchez-Avila A, Tantiwong P, Musi N. Effect of lipopolysaccharide on inflammation and insulin action in human muscle. PLoS One. 2013 May 21;8(5):e63983. doi: 10.1371/journal.pone.0063983.
[3] Boroni Moreira AP, de Cássia Gonçalves Alfenas R. The influence of endotoxemia on the molecular mechanisms of insulin resistance. Nutr Hosp. 2012 Mar-Apr;27(2):382-90. doi: 10.1590/S0212-16112012000200007.
[4] Rorato R, Borges BC, Uchoa ET, Antunes-Rodrigues J, Elias CF, Elias LLK. LPS-Induced Low-Grade Inflammation Increases Hypothalamic JNK Expression and Causes Central Insulin Resistance Irrespective of Body Weight Changes. Int J Mol Sci. 2017 Jul 4;18(7):1431. doi: 10.3390/ijms18071431.
[5] Neves AL, Coelho J, Couto L, Leite-Moreira A, Roncon-Albuquerque R. Metabolic endotoxemia: a molecular link between obesity and cardiovascular risk. Journal of Molecular Endocrinology. 2013;51(2), R51-R64.
[6] Ahn SY, Sohn SH, Lee SY, Park HL, Park YW, Kim H, Nam JH. The effect of lipopolysaccharide-induced obesity and its chronic inflammation on influenza virus-related pathology. Environ Toxicol Pharmacol. 2015 Nov;40(3):924-30. doi: 10.1016/j.etap.2015.09.020.
[7] Jialal I, Rajamani U. Metabolic Syndrome and Related Disorders.Nov 2014.454-456.http://doi.org/10.1089/met.2014.1504
[8] Gomes JMG, Costa JA, Alfenas RCG. Metabolic endotoxemia and diabetes mellitus: A systematic review. Metabolism. 2017 Mar;68:133-144. doi: 10.1016/j.metabol.2016.12.009.
[9] Hawkesworth S, Moore S, Fulford A et al. Evidence for metabolic endotoxemia in obese and diabetic Gambian women. Nutr & Diabetes. 2013;3,e83. https://doi.org/10.1038/nutd.2013.24
[10] Moludi J, Maleki V, Jafari-Vayghyan H, Vaghef-Mehrabany E, Alizadeh M. Metabolic endotoxemia and cardiovascular disease: A systematic review about potential roles of prebiotics and probiotics. Clin Exp Pharmacol Physiol. 2020 Jun;47(6):927-939. doi: 10.1111/1440-1681.13250.
[11] Kallio, K.A.E., Hätönen, K.A., Lehto, M. et al. Endotoxemia, nutrition, and cardiometabolic disorders. Acta Diabetol. 2015;52:395–404. https://doi.org/10.1007/s00592-014-0662-3
[12] Kasselman LJ, Vernice NA, DeLeon J, Reiss AB. The gut microbiome and elevated cardiovascular risk in obesity and autoimmunity. Atherosclerosis. 2018 Apr;271:203-213. doi: 10.1016/j.atherosclerosis.2018.02.036.
[13] Sulakhiya K, Keshavlal GP, Bezbaruah BB, Dwivedi S, Gurjar SS, Munde N, Jangra A, Lahkar M, Gogoi R. Lipopolysaccharide induced anxiety- and depressive-like behaviour in mice are prevented by chronic pre-treatment of esculetin. Neurosci Lett. 2016 Jan 12;611:106-11. doi: 10.1016/j.neulet.2015.11.031.
[14] Lasselin J, Elsenbruch S, Lekander M, Axelsson J, Karshikoff B, Grigoleit JS, Engler H, Schedlowski M, Benson S. Mood disturbance during experimental endotoxemia: Predictors of state anxiety as a psychological component of sickness behavior. Brain Behav Immun. 2016 Oct;57:30-37. doi: 10.1016/j.bbi.2016.01.003.
[15] Brown, G.C. The endotoxin hypothesis of neurodegeneration. J Neuroinflammation. 2019;16,180. https://doi.org/10.1186/s12974-019-1564-7
[16] Massoumi RL, Teper Y, Ako S, Ye L, Wang E, Hines OJ, Eibl G. Direct Effects of Lipopolysaccharide on Human Pancreatic Cancer Cells. Pancreas. 2021 Apr 1;50(4):524-528. doi: 10.1097/MPA.0000000000001790.
[17] Hoel H, Heggelund L, Reikvam DH, Stiksrud B, Ueland T, Michelsen AE, Otterdal K, Muller KE, Lind A, Muller F, Dudman S, Aukrust P, Dyrhol-Riise AM, Holter JC, Trøseid M. Elevated markers of gut leakage and inflammasome activation in COVID-19 patients with cardiac involvement. J Intern Med. 2021 Apr;289(4):523-531. doi: 10.1111/joim.13178.
[18] Moreira A, Texeira T, Ferreira A, Do Carmo Gouveia Peluzio M, De Cássia Gonçalves Alfenas R. Influence of a high-fat diet on gut microbiota, intestinal permeability and metabolic endotoxaemia. British Journal of Nutrition. 2012;108(5):801-809. doi:10.1017/S0007114512001213
[19] Laugerette F, Furet JP, Debard C et al. Oil composition of high-fat diet affects metabolic inflammation differently in connection with endotoxin receptors in mice. Am J Physiol Endocrinol Metab. 2012;302:E374–E386.
[20] Kim K-A, Jeong J-J, Yoo S-Y, Kim D-H. Gut microbiota lipopolysaccharide accelerates inflamm-aging in mice. BMC Microbiol. 2016;16(1):9.
[21] Cani PD, Bibiloni B, Knauf C et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes. 2008; 57:1470–1481.
[22] Adam A, Levrat-Verny MA, Lopez HW, Leuillet M, Demigne C, Remesy C. Whole wheat and triticale flours with differing viscosities stimulate cecal fermentations and lower plasma and hepatic lipids in rats. J Nutr. 2001; 131(6):1770-1776.
[23] Mohammad S, Thiemermann C. Role of Metabolic Endotoxemia in Systemic Inflammation and Potential Interventions. Front Immunol. 2021;11:594150. Published 2021 Jan 11. doi:10.3389/fimmu.2020.594150
[24] Wong MW, Yi CH, Liu TT, Lei WY, Hung JS, Lin CL, L SZ, Chen CL. Impact of vegan diets on gut microbiota: An update on the clinical implications. Tzu Chi Medical Journal. 2018; 30. 10.4103/tcmj.tcmj_21_18.
[25] Yu J, Zhu H, Taheri S, Mondy W, Perry S, Kindy MS. Plant-Based Nutritional Supplementation Attenuates LPS-Induced Low-Grade Systemic Activation. Int J Mol Sci. 2021;22(2):573. Published 2021 Jan 8. doi:10.3390/ijms22020573
[26] Moludi J, Kafil HS, Qaisar SA, Gholizadeh P, Alizadeh M, Vayghyan HJ. Effect of probiotic supplementation along with calorie restriction on metabolic endotoxemia, and inflammation markers in coronary artery disease patients: a double blind placebo controlled randomized clinical trial. Nutr J. 2021;20(1):47. doi:10.1186/s12937-021-00703-7
[27] Bleau C, Karelis AD, St-Pierre DH, Lamontagne L. Crosstalk between intestinal microbiota, adipose tissue and skeletal muscle as an early event in systemic low-grade inflammation and the development of obesity and diabetes. Diabetes Metab Res Rev. 2015;31(6):545–561. doi: 10.1002/dmrr.2617.
[28] Ott B, Skurk T, Hastreiter L, Lagkouvardos I, Fischer S, Büttner J, Kellerer T, Clavel T, Rychlik M, Haller D, Hauner H. Effect of caloric restriction on gut permeability, inflammation markers, and fecal microbiota in obese women. Sci Rep. 2017;7(1):11955. doi: 10.1038/s41598-017-12109-9.
Subscribe to our YouTube channel and our Podcast for more!
An Oasis of Healing is an integrative medical and healing facility utilizing alternative cancer treatments that help patients and their families learn to re-establish health after having been diagnosed with cancer.
By incorporating alternative and conventional medical services, natural healing modalities, high-quality nutritional products, and a unique educational and training program, we inspire patients to regain their birthright – health.
