“Be a free thinker and don’t accept everything you hear as truth. Be critical and evaluate what you believe in.”
—Aristotle
Metabolic endotoxemia is not some opinion or loose theory, and it has strong support in scientific evidence. The connection between metabolic endotoxemia, metabolic dysfunction, and dis-aise is not just one of association but causation. As I have discussed previously, chronic inflammation, triggered in metabolic endotoxemia, has been shown to contribute to an outright cause:
- Obesity
- Insulin resistance
- Diabetes
- Cardiovascular disease
- Autoimmune diseases
- Psychiatric diseases
- Neurodegenerative diseases
- Cancer
It would be hard to find any individual or family that is untouched by this list today. Poor health and disease are rampant today. Despite the billions of dollars and investments in new technology spent over the last many decades, the number of people affected by poor health and disease only continues to grow. Why could this be? How could this be? Maybe it is because the medical community is more reactive instead of proactive. Maybe, it is because the medical community focuses on waiting for disease instead of acting to prevent disease. Maybe, the medical community is distracted and simply lost its focus.
Suppose you don’t take anything from this series on the diet, gut, metabolic endotoxemia, and disease connection. In that case, I hope that I have shown that poor health begins through diet and in the gut and moves systemically through the body in what is called metabolic endotoxemia. In direct contrast, the beginning of a return to healing and wellness begins in the same diet, gut connection.
The list above can seem categorically disconnected to individual experience. You may not be struggling with obesity or any other listed disease. You may be twenty-four years of age, in the best health of your young life, and see no relevance to discuss any such disease; because, of course, you will live forever. Disease is not a concern until it is, and the value of wellness is only known when it is lost. You may struggle with or have personal experience with one of the named diseases on this list, but why concern yourself with all of them. Not for fear, but for personal empowerment, let me make the connection extremely relevant and applicable to all people via current events. Of course, the emphasis and focus will be on those with cancer or at risk of cancer, which according to the Prospective Urban and Rural Epidemiology study published in 2019, is most adults in high-income countries.
Unless you have been living on another planet in the last year and a half, you may be aware of a particular virus that the entire world has been dealing with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus has been implicated in the harm and death of many people worldwide. The people at most risks from the SARS-CoV-2 virus are those that have coexisting comorbidities. These comorbidities include advancing age, obesity, male > female, cardiovascular disease, and diabetes. See any similarities to that of metabolic endotoxemia?
Metabolic endotoxemia and SARS-CoV-2
So, what is the connection to metabolic endotoxemia?
A December 2020 article in the Journal of Molecular Cell Biology, “SARS-CoV-2 spike protein binds to bacterial lipopolysaccharide and boosts proinflammatory activity” [i], helps to provide the connection between SARS-CoV-2 and metabolic endotoxemia? I have spent several blog posts highlighting the clear link between systemic LPS, metabolic endotoxemia, and insulin resistance, inflammation, metabolic syndrome, obesity, diabetes, cardiovascular disease, autoimmune disease, and cancer. All are comorbidities associated with SARS-CoV-2, and as a result, there is an increased risk of severe illness with SARS-CoV-2. They are different yet connected. The direct point here is that gut dysbiosis is the origin of the LPS induced systemic inflammatory (metabolic endotoxemia) response that sets the stage for severe illness and disease–comorbidities. Worse, in a global pandemic from a new coronavirus, LPS induced metabolic endotoxemia causes the comorbidities that set the stage for worse outcomes from SARS-CoV2 infection. Without metabolic endotoxemia and the other comorbidities, where is the risk from this new novel coronavirus? Your health is important in preventing the known and the still yet unknown, like a novel virus.
Oh, but it gets much more profound. This connection is not theory but is according to the available published research. Not only does LPS set the start for the comorbidities that increase the risk associated with SARS-CoV-2 infection, Gianna Petruk and colleagues show that LPS works synergistically with the spike protein from the SARS-CoV-2 virus to further increase inflammation through an increase in nuclear factor-κB (NF-κB) transcription, activation, and pro-longed signaling [ii]. Each alone, SARS-CoV-2 infection or LPS metabolic endotoxemia, can create problems, but collectively, cause significantly more systemic havoc, 50% more to be exact, through pro-longed nuclear factor-κB (NF-κB) transcription.
What exactly is NF-κB? Nuclear factor-κB is a protein complex that serves as a key transcription factor in inflammation. It is found in all nucleated cells in the body and is one of the primary regulatory signals in inflammatory signaling within the body. Together with the SARS-CoV-2 virus increases systemic inflammation, cytokine storm, complications, and mortality risk [iii].
It is essential to connect a few dots to bring cancer into this relationship. More than just the SARS-CoV-2 infection, an increase in NF-κB transcription signaling is the link between inflammation and cancer. It is the line of differentiation between normal function and abnormal function, or wellness and disease.
A publication from 2002 first suggested the link between NF-κB transcription and cancer [iv]. Broadly, an increase in NF-κB activation and signaling is associated with an increase in cancer development, progression, and metastasis. Specifically, NF-κB plays a role in:
- Carcinogenesis [v] [vi] [vii]
- Malignant transformation [viii] [ix]
- Oncogenic metabolism [x] [xi] [xii]
- Alters the Tumor Microenvironment (TME) [xiii]
- Prevents apoptosis (programmed cell death) [xiv]
- Promotes angiogenesis [xv] [xvi]
- Promotes proliferation [xvii]
- Promotes invasion [xviii]
- Promotes immune evasion and escape [xix] [xx]
- Promotes Epithelial to Mesenchymal Transition (EMT) [xxi] [xxii] [xxiii] [xxiv]
- Promotes metastasis 11 [xxv] [xxvi]
- Chemoresistance [xxvii] [xxviii]
- Radiation resistance [xxix] [xxx] [xxxi]
I will say what appears to be the obvious, nuclear factor-κB (NF-κB) transcription sits at the heart of many processes critical to cancer. Chronic inflammation is the bed in which cancer lies. In addition, cancer produces further inflammation. Inflammation begets cancer and cancer, in turn, begets inflammation. It is a vicious cycle.
If more proof is required, NF-κB is at the center of promoting cancer cell stem (CSC) activity, treatment resistance, and ultimately metastasis [xxxii] [xxxiii] [xxxiv] [xxxv]. Cancer stem cells are the cancer backups that play a pivotal role in treatment resistance and recurrence. It is the backup that nobody wants any part of. A computer backup or phone backup can be life-saving in terms of data and frustration, but cancer cell backups (CSC) literally take lives. Whether with chemotherapy or radiation, which is often the result of CSC activity, treatment resistance is vital in treatment failure, morbidity, and mortality.
The important take-home points here are that metabolic endotoxemia (LPS) alone sets the stage for obesity, metabolic syndrome, diabetes, cardiovascular disease, neurodegenerative disease, and many other chronic diseases of aging. In the new era of SARS-CoV-2, these diseases are also known as comorbidities. Whether in disease or as a comorbidity, LPS plays a critical role. SARS-CoV-2 is the new coronavirus that creates problems alone in those with the same pre-existing comorbidities. However, in conjunction with systemic LPS through metabolic endotoxemia, the combination imparts more risk and damage than either individually. The fireworks here are provided by NF-κB, augmented by LPS, and it plays a vital role in the cancer process.
[i] Petruk G, Puthia M, Petrlova J, et al. SARS-CoV-2 spike protein binds to bacterial lipopolysaccharide and boosts proinflammatory activity. J Mol Cell Biol. 2020;12(12):916-932. doi:10.1093/jmcb/mjaa067
[ii] Petruk G, Puthia M, Petrlova J, Samsudin F, Strömdahl AC, Cerps S, Uller L, Kjellström S, Bond PJ, Schmidtchen AA. SARS-CoV-2 spike protein binds to bacterial lipopolysaccharide and boosts proinflammatory activity. J Mol Cell Biol. 2020 Oct 12;12(12):916-932. doi: 10.1093/jmcb/mjaa067.
[iii] Attiq A, Yao LJ, Afzal S, Khan MA. The triumvirate of NF-κB, inflammation and cytokine storm in COVID-19 [published online ahead of print, 2021 Oct 15]. Int Immunopharmacol. 2021;101(Pt B):108255. doi:10.1016/j.intimp.2021.108255
[iv] Karin M, Cao Y, Greten FR, Li ZW. NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer. 2002;2(4):301–310.
[v] Brücher B, Lang F, Jamall LS. NF-κB signaling and crosstalk during carcinogenesis. 4open, 2 (2019) 13. doi: https://doi.org/10.1051/fopen/2019010
[vi] Nakshatri H. (2019) NF-κB Signaling Pathways in Carcinogenesis. In: Badve S., Kumar G. (eds) Predictive Biomarkers in Oncology. Springer, Cham. https://doi.org/10.1007/978-3-319-95228-4_27
[vii] Brücher BLDM, Jamall IS (2014), Cell-Cell communication in tumor microenvironment, carcinogenesis and anticancer treatment. Cell Physiol Biochem 34, 2, 213–243. https://doi.org/10.1159/000362978.
[viii] Monisha J, Roy NK, Bordoloi D, Kumar A, Golla R, Kotoky J, Padmavathi G, Kunnumakkara AB. Nuclear Factor Kappa B: A Potential Target to Persecute Head and Neck Cancer. Curr Drug Targets. 2017;18(2):232-253. doi: 10.2174/1389450117666160201112330
[ix] Zhao Y, Xu Y, Li Y, Xu W, Luo F, Wang B, Pang Y, Xiang Q, Zhou J, Wang X, Liu Q. NF-κB-mediated inflammation leading to EMT via miR-200c is involved in cell transformation induced by cigarette smoke extract. Toxicol Sci. 2013 Oct;135(2):265-76. doi: 10.1093/toxsci/kft150.
[x] Londhe P, Yu PY, Ijiri Y, Ladner KJ, Fenger JM, London C, Houghton PJ, Guttridge DC. Classical NF-κB Metabolically Reprograms Sarcoma Cells Through Regulation of Hexokinase 2. Front Oncol. 2018 Apr 11;8:104. doi: 10.3389/fonc.2018.00104.
[xi] Mauro C, Leow SC, Anso E, Rocha S, Thotakura AK, Tornatore L, et al. NF-kappaB controls energy homeostasis and metabolic adaptation by upregulating mitochondrial respiration. Nat Cell Biol. 2011;13:1272–9
[xii] Xia Y, Shen S, Verma IM. NF-κB, an active player in human cancers. Cancer Immunol Res. 2014;2(9):823-830. doi:10.1158/2326-6066.CIR-14-0112
[xiii] Hagemann T, Lawrence T, McNeish I, Charles KA, Kulbe H, Thompson RG, Robinson SC, Balkwill FR. “Re-educating” tumor-associated macrophages by targeting NF-kappaB. J Exp Med. 2008 Jun 9;205(6):1261-8. doi: 10.1084/jem.20080108.
[xiv] Abdin SM, Tolba MF, Zaher DM, Omar HA. Nuclear factor-κB signaling inhibitors revert multidrug-resistance in breast cancer cells. Chem Biol Interact. 2021 May 1;340:109450. doi: 10.1016/j.cbi.2021.109450.
[xv] Huang S, Pettaway CA, Uehara H, Bucana CD, Fidler IJ. Blockade of NF-kappaB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis. Oncogene. 2001;20:4188–97.
[xvi] Sokolova O, Naumann M. NF-κB Signaling in Gastric Cancer. Toxins (Basel). 2017;9(4):119.
[xvii] Prabhu L, Mundade R, Korc M, Loehrer PJ, Lu T. Critical role of NF-κB in pancreatic cancer. Oncotarget. 2014 Nov 30;5(22):10969-75. doi: 10.18632/oncotarget.2624.
[xviii] Aggarwal BB, Sung B. NF-κB in cancer: a matter of life and death. Cancer Discov. 2011 Nov;1(6):469-71. doi: 10.1158/2159-8290.CD-11-0260. PMID: 22586649
[xix] Bruce JP, To KF, Lui VWY, Chung GTY, Chan YY, Tsang CM, Yip KY, Ma BBY, Woo JKS, Hui EP, Mak MKF, Lee SD, Chow C, Velapasamy S, Or YYY, Siu PK, El Ghamrasni S, Prokopec S, Wu M, Kwan JSH, Liu Y, Chan JYK, van Hasselt CA, Young LS, Dawson CW, Paterson IC, Yap LF, Tsao SW, Liu FF, Chan ATC, Pugh TJ, Lo KW. Whole-genome profiling of nasopharyngeal carcinoma reveals viral-host co-operation in inflammatory NF-κB activation and immune escape. Nat Commun. 2021 Jul 7;12(1):4193. doi: 10.1038/s41467-021-24348-6.
[xx] Ravi R, Bedi A. NF-κB in cancer—a friend turned foe. Drug Resistance Updates. Feb 2004;7(1):53-67.
[xxi] Huber MA, Azoitei N, Baumann B, et al. NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest. 2004;114(4):569–581.
[xxii] Wang X, Belguise K, Kersual N, et al. Oestrogen signalling inhibits invasive phenotype by repressing RelB and its target BCL2. Nat Cell Biol. 2007;9(4):470–478.
[xxiii] Gao S, Sun Y, Zhang X, Hu L, Liu Y, Chua CY, Phillips LM, Ren H, Fleming JB, Wang H, Chiao PJ, Hao J, Zhang W. IGFBP2 Activates the NF-κB Pathway to Drive Epithelial-Mesenchymal Transition and Invasive Character in Pancreatic Ductal Adenocarcinoma. Cancer Res. 2016 Nov 15;76(22):6543-6554. doi: 10.1158/0008-5472.CAN-16-0438.
[xxiv] Huber MA, Beug H, Wirth T. Epithelial-Mesenchymal Transition: NF-κB Takes Center Stage. Cell Cycle. 2004;3:12:1477-1480. doi: 10.4161/cc.3.12.1280
[xxv] Naugler WE, Karin M. NF-kappaB and cancer-identifying targets and mechanisms. Curr Opin Genet Dev. 2008;18(1):19-26. doi:10.1016/j.gde.2008.01.020
[xxvi] Park B, Zhang H, Zeng Q. et al. NF-κB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF. Nat Med 13, 62–69 (2007). https://doi.org/10.1038/nm1519
[xxvii] Li Q, Yang G, Feng M, Zheng S, Cao Z, Qiu J, You L, Zheng L, Hu Y, Zhang T, Zhao Y. NF-κB in pancreatic cancer: Its key role in chemoresistance. Cancer Lett. 2018 May 1;421:127-134. doi: 10.1016/j.canlet.2018.02.011.
[xxviii] Yang G, Xiao X, Rosen DG, et al. The biphasic role of NF-kappaB in progression and chemoresistance of ovarian cancer. Clin Cancer Res. 2011;17(8):2181-2194. doi:10.1158/1078-0432.CCR-10-3265
[xxix] Bhat KPL, Balasubramaniyan V, Vaillant B, Ezhilarasan R, Hummelink K, Hollingsworth F, Wani K, Heathcock L, James JD, Goodman LD, Conroy S, Long L, Lelic N, Wang S, Gumin J, Raj D, Kodama Y, Raghunathan A, Olar A, Joshi K, Pelloski CE, Heimberger A, Kim SH, Cahill DP, Rao G, Den Dunnen WFA, Boddeke HWGM, Phillips HS, Nakano I, Lang FF, Colman H, Sulman EP, Aldape K. Mesenchymal differentiation mediated by NF-κB promotes radiation resistance in glioblastoma. Cancer Cell. 2013 Sep 9;24(3):331-46. doi: 10.1016/j.ccr.2013.08.001.
[xxx] Galeaz C, Totis C, Bisio A. Radiation Resistance: A Matter of Transcription Factors. Front Oncol. Jun 2021. https://doi.org/10.3389/fonc.2021.662840
[xxxi] Fan M, Ahmed KM, Coleman MC, Spitz DR, Li JJ. Nuclear Factor-kappaB and Manganese Superoxide Dismutase Mediate Adaptive Radioresistance in Low-Dose Irradiated Mouse Skin Epithelial Cells. Cancer Res (2007) 67(7):3220–8. doi: 10.1158/0008-5472.CAN-06-2728
[xxxii] Alvero, A.B.; Chen, R.; Fu, H.H.; Montagna, M.; Schwartz, P.E.; Rutherford, T.; Silasi, D.A.; Steffensen, K.D.; Waldstrom, M.; Visintin, I.; et al. Molecular phenotyping of human ovarian cancer stem cells unravels the mechanisms for repair and chemoresistance. Cell Cycle 2009, 8, 158–166.
[xxxiii] Harrington BS, Annunziata CM. NF-κB Signaling in Ovarian Cancer. Cancers. 2019; 11(8):1182. https://doi.org/10.3390/cancers11081182
[xxxiv] Gupta, V.; Yull, F.; Khabele, D. Bipolar Tumor-Associated Macrophages in Ovarian Cancer as Targets for Therapy. Cancers 2018, 10.
[xxxv] Browning, L.; Patel, M.R.; Horvath, E.B.; Tawara, K.; Jorcyk, C.L. IL-6 and ovarian cancer: Inflammatory cytokines in promotion of metastasis. Cancer Manag. Res. 2018, 10, 6685–6693.
