Updated: Feb 21
Over the last 10 years there has been an explosion of research into the gut microbiota and its impact on weight. It has been demonstrated that alterations in the gut microbiota are associated with metabolic disorders such as obesity and insulin resistance, both of which are known to be caused by inflammation in the body. The gut microbiota is responsible for regulating immune function as well as influencing several key processes involved in energy balance and weight management (1-4).
The gut microbiota is made of two main bacterial families (Firmicutes and Bacteroidetes) as well as several smaller families. In a healthy gut, these families are maintained within specific proportions relative to each other and far out-number bacteria that are potentially harmful to the body.
Genes, diet and environment play a part in weight management, with diet and environment being modifiable factors that have the ability to significantly alter the composition of our gut microbiota, either to our benefit or detriment. Stress, medications and a diet high in refined sugar and processed food can lead to dysbiosis, a state of altered gut bacteria which has been associated with a range of metabolic disorders, including obesity (1, 5, 6).
The mechanisms by which dysbiosis can lead to weight gain are:
1. Increased extraction of calories from food
Certain gut bacteria are able to extract more calories from food. Some studies have shown that obese individuals tend to have a higher number of Firmicutes species compared to Bacteroidetes species. Firmicutes is able to extract up to 15% more calories from food than Bacteroidetes. Therefore, two people given the same diet with the same number of calories may have different outcomes when it comes to weight loss simply due to differences in their gut bacteria (1, 4).
2. Inflammation and altered appetite regulation.
Inflammation plays a large role in the development of obesity, and the gut microbiota is a key regulator of immune tolerance.
In dysbiosis there is an increase in pathogenic bacteria and with this comes an increase in a specific microbial component called lipopolysaccharide (LPS). This is a highly pro-inflammatory molecule that has repeatedly been associated with inflammation in the body. LPS activates an inflammatory cascade that ultimately leads to the accumulation of inflammatory mediators (immune cells and cytokines) in fat cells and brain matter. This inflammation then alters the function of fat cells and neurons.
Fat cells, or adipocytes, play a role in appetite regulation and energy balance through the release of a hormone called Leptin. Leptin is secreted from fat cells proportionally to the size of the cell. It sends signals of fullness to the brain, which in turn results in a reduction in food intake. The effect of LPS on leptin is two-fold. Firstly, LPS-driven inflammation in adipocytes has been shown to disrupt leptin release, therefore reducing signals of fullness to the brain. Secondly, LPS-driven inflammation in the brain has been shown to reduce sensitivity to leptin, therefore signals of fullness are no longer detected by neurons. These two mechanisms can lead to over-eating and weight gain.
3. Mitochondrial dysfunction and metabolism.
The gut microbiota communicates with our mitochondria, the powerhouse of our cells. This occurs mainly through the action of butyrate, a short-chain fatty acid (SCFA) which is produced by certain species of gut bacteria.
Mitochondria convert glucose, amino acids and fats into energy that supplies our cells and butyrate can help regulate certain steps in this process. The energy produced is then used by the cell to perform its function. In adipocytes, for example, this function includes the release of stored fat.
Butyrate also helps regenerate new mitochondria and clear out by-products that are released during energy production. These by-products, commonly termed free radicals, have the potential to damage mitochondria and therefore reduce cellular energy.
Another mechanism by which gut microbiota modify mitochondrial function is by regulating the availability of nutrients such as B-group vitamins, magnesium and zinc. These nutrients are essential for all mitochondrial reactions.
In dysbiosis, the production of SCFAs is altered and this has been associated with impaired mitochondrial function. When glucose and fats are not utilised effectively, they accumulate in the liver, muscle and adipocytes, usually as fat. With impaired mitochondrial function there is an increase in free radicals within the cell, this results in inflammation that also alters the function of the cell. In adipocytes, inflammation has been associated with reduced leptin signalling and insulin resistance, both of which can lead to an increase in appetite and weight gain.
4. Impaired detoxification
Detoxification is the process by which the liver converts toxins into safe molecules that are easily eliminated from the body via the gut, kidney, lungs or skin. Each toxin proceeds through two stages of detoxification in the liver. The first stage produces a more toxic molecule - a super-toxin - as well as by-products known as free radicals, or oxidants. The second stage converts the super-toxins into a neutral molecule that can be safely eliminated from the body. Free radicals are neutralised by certain nutrients, antioxidants and intracellular enzymes that help mop up these molecules and therefore prevent damage to the cell (2).
If detoxification is impaired, free radicals and super-toxins accumulate within cells causing inflammation and mitochondrial dysfunction. In addition, toxins are fat-soluble, which means they can easily be stored in fatty tissue where they perpetuate inflammation and prevent the release of stored fat.
Where does the gut microbiota fit in to this?
The liver is the main organ of detoxification, however the gut microbiota plays a key role in the transformation and elimination of toxins before they are absorbed into the blood stream and transported to the liver. Over 800 species of gut microbiota have been found to secrete detoxification enzymes (5, 7, 8). One study has shown that the gut microbiota has the ability to transform well over 1000 toxic compounds, including environment pollutants and pharmaceutical drugs, thereby reducing their absorption and impact on the body (9-11).
In addition, SCFAs produced by gut bacteria have been shown to stimulate the release of detoxification enzymes from gut and liver cells (12, 13). As mentioned above, SCFAs also play a role in the neutralisation of the free radicals (14-19).
Another mechanism by which the gut microbiota assist in detoxification is through modulating nutrients that act as co-factors in detoxification reactions, such as B-group vitamins, magnesium, zinc and amino acids. The gut microbiota can influence the absorption of these nutrients and many bacterial species are also able to produce various B-group vitamins (20-22).
In dysbiosis, any or all of these processes can be altered. In addition, certain pathogenic gut bacteria can secrete enzymes that convert toxins into super-toxins. These super-toxins can easily be absorbed into the bloodstream leading to an accumulation of toxins and free radicals in the liver (23, 24). This perpetuates inflammation and the vicious cycle that hinders weight loss.
5. Altered signalling to the brain
Another mechanism by which the gut microbiota can influence weight management is through their ability to communicate with the brain. This communication can take place through the bloodstream or the Vagus nerve, a nerve that originates in the central nervous system and innervates the entire gut. The Vagus nerve is able to detect changes within the gut wall and lumen and relay this information directly to the brain. This is known as the Gut-Brain connection and research shows that it has a significant impact on brain function.
The gut microbiota communicates with the brain by producing a number of signalling molecules such as SCFAs, vitamins and neurotransmitters and also influencing the release immune mediators. These molecules are mainly detected by the Vagus nerve which transmits signals to the brain. They can also enter the brain via the blood stream (25, 26).
The neurological functions influenced by gut microbiota that are important in weight management include:
Protecting the brain matter from toxins and inflammation (27).
Influencing the production of neurotransmitters which are responsible for appetite control, mood, motivation and sleep (28).
Influencing hormones that are involved in regulating appetite and improving metabolism and energy expenditure (29-32).
Assisting neurogenesis, a process that helps build new neurons and therefore helps in the development of new behaviours and habits (33-37).
In dysbiosis, the altered bacterial composition and presence of more pathogenic gut bacteria results in a reduction in beneficial signalling molecules and an increase in inflammatory signalling molecules, leading to inflammation within the brain matter. This is known as neuroinflammation. Some of the processes that are affected by neuroinflammation include appetite regulation, metabolism, mood, behaviour, stress response and sleep, all of which can result in cravings and weight gain (38-49). (More detailed information on the Gut-Brain Connection will follow in a separate blog.)
Successful weight management is much more complex than eating less and exercising more, which is why traditional diets don’t work. In order to lose weight and successfully maintain a new lower weight long-term, gut function must be restored and the above key processes must be managed.
The Biome Protocol includes supplemental nutrients that support the growth of healthy gut microbiota, as well as nutrients that are known to support the physiological processes involved in weight management. The dietary recommendations are flexible and based on foods that serve a purpose – to feed our gut microbiota and provide nutrients that assist with essential cellular functions. The protocol also provides you with information that will help you safely modify your diet according to your needs on completion of the program.
The Biome Protocol is available through a number of clinics across Australia, please contact firstname.lastname@example.org to find a clinic near you.
1. Popkin, B. M., Adair, L. S., & Ng, S. W. (2012). Global nutrition transition and the pandemic of obesity in developing countries. Nutrition reviews, 70(1), 3-21
2. Das A, Srinivasan M, Ghosh TS, Mande SS (2016) Xenobiotic Metabolism and Gut Microbiomes PLoS ONE 11(10): e0163099. doi.org:10.1371/journal.pone.0163099
3. Sales N. M. R., Pelegrini P. B., Goersch M. C. Nutrigenomics: definitions and advances of this new science. Journal of Nutrition and Metabolism. 2014;2014:6. doi: 10.1155/2014/202759.202759
4. Lim U., Song M. A. Dietary and lifestyle factors of DNA methylation. Methods in Molecular Biology. 2012;863:359–376. doi: 10.1007/978-1-61779-612-8_23.
5. Spanogiannopoulos P, Bess EN, Carmody R, et al. The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism. Nat Rev Microbiol 2016;14(5):273-287.
6. Lim S et al. Persistent organic pollutants, mitochondrial dysfunction, and metabolic syndrome. Ann N Y Acad Sci. 2010 Jul;1201:166-76
7. Nayak RR, Turnbaugh PJ. Mirror, mirror on the wall: which microbiomes will help heal them all? BMC Medicine 2016;14:72.
8. Lindenbaum J, Rund DG, Butler VP, Jr., Tse-Eng D, Saha JR. 1981. Inactivation of digoxin by the gut flora: reversal by antibiotic therapy. N Engl J Med 305:789–794.
9. Carmody RN, Turnbaugh PJ. Host-microbial interactions in the metabolism of therapeutic and diet-derived xenobiotics. J Clin Invest 2014;124(10):4173-4181
10. Lu K, Mahbub R, Fox JG. Xenobiotics: interaction with the intestinal microflora. ILAR J 2015;56(2):218-227.
11. Claus SP, Guillou H, Ellero-Simatos E. The gut microbiota: a major player in the toxicity of environmental pollutants. Biofilms and Microbiomes 2016;2:Article No.16003.
12. Beatrice Louise Pool-Zobel, Veeriah Selvaraju, Julia Sauer, Tanja Kautenburger, Jeannette Kiefer, Konrad Klaus Richter, Malle Soom, Stefan Wölfl; Butyrate may enhance toxicological defence in primary, adenoma and tumor human colon cells by favourably modulating expression of glutathione S -transferases genes, an approach in nutrigenomics , Carcinogenesis, Volume 26, Issue 6, 1 June 2005, Pages 1064–1076, https://doi.org/10.1093/carcin/bgi059
13. Stein, J. , SChroder, O. , Bonk, M. , Oremek, G. , Lorenz, M. and Caspary, W. F. (1996), Induction of glutathione‐S‐transferase‐pi by short‐chain fatty acids in the intestinal cell line caco‐2. European Journal of Clinical Investigation, 26: 84-87.
14. Cardozo LF, Pedruzzi LM, Stenvinkel P, et al. Nutritional strategies to modulate inlammation and oxidative stress pathways via activation of the master antioxidant switch Nrf2. Biochimie 2013;95(8):1525-1533.
15. Huang Y, Li W, Su Z, et al. The complexity of the Nrf2 pathway: Beyond the antioxidant response. J Nutr Biochem 2015;26(12):1401-1413
16. Kumar H, Kim IS, More SV, et al. Natural product-derived pharmacological modulators of Nrf2/ARE pathway for chronic diseases. Nat Prod Rep 2014; 31(1):109-139
17. Shen G, Jeong, WS, Hu R et al. Regulation of Nrf2, Nf-kB, and AP-1 signaling pathways by chemopreventive agents. Antioxid Redox Signal 2005;7(11-12):1648-1663.
18. Taha R, Blaise G. Nrf2 activation as a future target of therapy for chronic diseases. Functional Foods in Health and Diseases 2014;4(11):510-523.
19. Jones RM, Desai C, Darby TM, Luo L, wolfarth AA, Scharer CD, et al. Lactobacilli Modulate epithelial Cyto-protection through the Nrf2 Pathway. Cell reports. 2015;12(8):1217-25.
20. Gustafsson BE, Daft FS, McDaniel EG et al (1962) Effects of vitamin K-active compounds and intestinal micro-organisms in vitamin K-deficient germfree rats. J Nutr 78:461–468
21. Said HM (2013) Recent advances in transport of water-soluble vitamins in organs of the digestive system: a focus on the colon and the pancreas. Am J Physiol Gastrointest Liver Physiol 305:G601–G610
22. Macfarlane GT, Cummings JH, Allison C (1986) Protein degradation by human intestinal bacteria. Microbiology 132:1647–1656
23. Marnewick J. L., Joubert E., Swart P., van der Westhuizen F., Gelderblom W. C. Modulation of hepatic drug metabolizing enzymes and oxidative status by rooibos (Aspalathus linearis) and Honeybush (Cyclopia intermedia), green and black (Camellia sinensis) teas in rats. Journal of Agricultural and Food Chemistry. 2003;51(27):8113–8119. doi: 10.1021/jf0344643.
24. Rowland IR (Ed). Role of the gut flora in toxicity and cancer. London: Academic Press, 1988.
25. Galland L. (2014). The gut microbiome and the brain. Journal of medicinal food, 17(12), 1261-72.
26. Borovikova L.V. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405:458–462.
27. Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L, Daniels D, et al. The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J. Biol. Chem. 2003;278:11312–11319. doi: 10.1074/jbc.M211609200.
28. Cryan JF, Dinan TG: Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci2012;13:701–712
29. Holzer P, Reichmann F, Farzi A. Neuropeptide Y, peptide YY and
pancreatic polypeptide in the gut-brain axis. Neuropeptides.2012;46:261–274.
30. Dockray GJ. Gastrointestinal hormones and the dialogue between gut and brain [published online March 17, 2014]. J Physiol. doi:10.1113/jphysiol.2014.270850
31. Kimura I, et al. The SCFA receptor GPR43 and energy metabolism. Front. Endocrinol. 2014;5:85.
32. Inoue D, et al. Regulation of energy homeostasis by GPR41. Front. Endocrinol. 2014;5:81.
33. Maalouf M, Rho JM, Mattson MP. The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. Brain Res Rev. 2008;59(2):293-315.
34. Xiong GL, Doraiswamy PM. Does meditation enhance cognition and brain plasticity? Ann N Y Acad Sci. 2009 Aug;1172:63-9.
35. Beltz, B. S., Tlusty, M. F., Benton, J. L., & Sandeman, D. C. (2007). Omega-3 fatty acids upregulate adult neurogenesis. Neuroscience letters, 415(2), 154-8.
36. Mostafa Rahvar, Mohsen Nikseresht, Sayed Mohammad Shafiee, Fakhraddin Naghibalhossaini, Mozhgan Rasti, Mohammad Reza Panjehshahin, Ali Akbar Owji. Effect of oral resveratrol on the BDNF gene expression in the hippocampus of the rat brain. Neurochem Res. 2011 May; 36(5): 761–765. Published online 2011 Jan 9. doi: 10.1007/s11064-010-0396-8
37. Li Q, Zhao HF, Zhang ZF, Liu ZG, Pei XR, Wang JB, Cai MY, Li Y. Long-term administration of green tea catechins prevents age-related spatial learning and memory decline in C57BL/6 J mice by regulating hippocampal cyclic amp-response element binding protein signaling cascade. Neuroscience. 2009 Apr 10;159(4):1208-15. doi: 10.1016/j.neuroscience.2009.02.008. Epub 2009 Feb 11.
38. Morris G, Anderson G, Dean O, Berk M, Galecki P, Martin-Subero M, et al. The glutathione system: a new drug target in neuroimmune disorders. Mol Neurobiol. 2014;50:1059–84. doi: 10.1007/s12035-014-8705-x
39. Fischer MT, Sharma R, Lim JL, Haider L, Frischer JM, Drexhage J, et al. NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury. Brain. 2012;135:886–99. doi: 10.1093/brain/aws012
40. Gilgun-Sherki Y, Melamed E, Offen D. The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy. J Neurol. 2004;251:261–8. doi: 10.1007/s00415-004-0348-9.
41. Prolo C, Alvarez MN, Radi R. Peroxynitrite, a potent macrophage-derived oxidizing cytotoxin to combat invading pathogens. Biofactors. 2014;40:215–25. doi: 10.1002/biof.1150.
42. Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med. 2010;49:1603–16. doi: 10.1016/j.freeradbiomed.2010.09.006.
43. Vaziri ND. Causal link between oxidative stress, inflammation, and hypertension. Iran J Kidney Dis. 2008;2:1–10.
44. Alvarez MN, Peluffo G, Piacenza L, Radi R. Intraphagosomal peroxynitrite as a macrophage-derived cytotoxin against internalized Trypanosoma cruzi: consequences for oxidative killing and role of microbial peroxiredoxins in infectivity. J Biol Chem. 2011;286:6627–40. doi: 10.1074/jbc.M110.167247
45. JP Thaler, CX Yi, EA Schur, SJ Guyenet, BH Hwang, MO Dietrich, et al. Obesity is associated with hypothalamic injury in rodents and humans J Clin Invest, 122 (2012), pp. 153-162
46. Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D (2008) Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell 135:61–73.
47. M. Milanski, G. Degasperi, A. Coope, et al., Saturated fatty acids produce an in-
flammatory response predominantly through the activation of TLR4 signaling in
hypothalamus: implications for the pathogenesis of obesity, J. Neurosci. 29 (2009)
48. S. Carraro, Rodrigo & Souza, Gabriela & Solon, Carina & Razolli, Daniela & Chausse, Bruno & Barbizan, Roberta & Victório, Sheila & Velloso, Licio. (2017). Hypothalamic mitochondrial abnormalities occur downstream of inflammation in diet-induced obesity. Molecular and Cellular Endocrinology. 460. 10.1016/j.mce.2017.07.029.
49. CT De Souza, EP Araujo, S Bordin, R Ashimine, RL Zollner, AC Boschero, et al.
Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus Endocrinology, 146 (2005), pp. 4192-4199