Scale of the Obesity Crisis

By Elizabeth Wimborne

The ongoing obesity endemic presents a huge societal burden from both a health and an economic perspective. According to the WHO, obesity has almost tripled globally since 1975; 39% of adults are overweight and 13% obese in 2016, contributing to more than 4 million related deaths in 2017 (WHO, 2020). Obesity is often associated with other conditions included in the metabolic syndrome, such as diabetes and hypertension which are risk factors for further cardiovascular diseases (NHS, 2019). Therefore, this places a huge burden on health care services. By 2050, the NHS is predicted to spend over £9.7 billion per year on obesity related ill health and the economic impacts on wider society will account for up to £49.9 billion in losses per year (Public Health England, 2017). This all stems from a condition which, to a great extent, is preventable. 

Therefore, despite current therapies existing, the problem clearly still needs addressing. Previous therapies have often been limited and associated with negative side effects, hence there is growing demand for new, novel treatment options to target this global burden (Bloom, et al., 2008). 

Influence of gut microbiota

Increasing interest in many areas of research has been seen surrounding the impacts of the gut microbiome on previously unconnected health conditions and disorders. These include, to name a few, Inflammatory Bowel Diseases, Clostridium Difficile Infections and even conditions such as autism (Allegretti, et al., 2019). This spark of interest has also been seen in obesity related research due to evidence suggesting a critical role of the gut microbiome in regulating metabolic homeostasis. Therefore, this presents a possibly ideal target for a novel obesity treatment.  

Microbiota associated with obesity and their metabolites impact many aspects of : energy uptake, expenditure, and storage as well as central appetite regulation (DiBaise, et al., 2012; Van de Wouw, et al., 2017). Germ free mice do not experience obesity and have a significantly leaner phenotype than normal mice, even on a higher calorie diet, while obese phenotypes can be recreated in lean germ-free mice just through faecal transplant of microbiota (Backhed, et al., 2004)(Ridaura, et al., 2013). The transferable nature of these opposing phenotypes just through microbiota transplants presents an exciting avenue for therapeutic options, however many of the mechanisms inducing the anti-obesity effects currently lack clarity

Bifidobacterium Longum APC1472

Various bacterial strains have previously been identified with potential anti-obesity effects in humans. The strain Bifidobacterium Longum APC1472 (Schellekens et al., 2020) set out to investigate had previously been shown to have ghrenlinergic signalling modulating capacities in vitro (Torres-Fuentes, et al., 2019). Ghrelin is a hormone that stimulates hunger among having other metabolic effects, and aberrant ghrelin signalling is typical of obesity, leading to dysregulation of the metabolism, glucose homeostasis and appetite control (Muller, et al., 2015). Hence, this strain was investigated as a potential therapeutic target as its effects are so central to metabolic regulation.

Promising results from mice model

The investigation results from preclinical mouse models presented the possibility of a highly successful anti-obesity treatment. In mice with high fat diet (HFD)-induced obesity, they demonstrated extensive positive anti-obesity related results including reductions in body weight, fat depot size, circulating leptin levels – also known as the satiety hormone – increased glucose tolerance and normalisation of hypothalamic-CART expression, a neuropeptide associated with satiety (Schellekens, et al., 2020). Therefore, this appeared to be a miracle treatment just from something as simple as the microbiota transplantation!

Partial translation to humans

However, the results were not recreated as easily in human studies. In a cohort of overweight/obese healthy adults, no significant changes in BMI or W/H ratio were seen after treatment, therefore this appeared an unlikely choice as a successful anti-obesity treatment (Schellekens, et al., 2020). However, some promising results were seen. Fasting blood glucose levels decreased, the levels of active ghrelin were normalised and the cortisol awakening response was reduced (Schellekens, et al., 2020). Both the cortisol awakening response and ghrelin feed into the hypothalamic-pituitary-adrenal (HPA) axis, often termed the “body’s stress system”, and presents as a risk factor for increased metabolic disorders (Schellekens, et al., 2020). Therefore, the changes in fasting blood glucose could be associated with HPA axis regulation which presents a viable mechanism for the microbiota-based changes. 

However, the lack of changes to body weight and composition do not discount it as a treatment option as there are multiple, viable explanations for the discrepancies between the mice and human studies. The mice with HFD induced obesity had a decreased glucose tolerance, whereas the human cohort was specifically selected to have non-diabetic fasting glucose levels (Schellekens, et al., 2020). As the mechanism of action appears to surround the regulation of glucose metabolism, it suggests this treatment may produce greater success in individuals suffering from diabetic conditions. The mice were also given this treatment as a preventative measure before obesity was induced, whereas the human cohort already presented with obesity and therefore gave a more severe condition to treat. 

Outlook

Overall, this emphasises how multifactorial obesity is an issue and therefore how both the studies researching it further and future treatments will need to account for this consideration. The extensive success of the anti-obesity parameters demonstrated in the mouse model suggest that B. Longum APC1472 does have potential therapeutic benefits, particularly for those suffering from conditions associated with dysregulated glucose metabolism, such as type 2 diabetes. Microbiota based therapies present a very exciting new area for treatments in the future and it will be interesting to see how this field expands further. 

References

Allegretti, J., Mullish, B., Kelly, C. & Fischer, M., 2019. The evolution of the use of faecal microbiota transplantation and emerging therapeutic indications. The Lancet, Volume 394, pp. 420-431.

Bäckhed, F., Ding, H., Wang, T., Hooper, L.V., Koh, G.Y., Nagy, A., Semenkovich, C.F. and Gordon, J.I., 2004. The gut microbiota as an environmental factor that regulates fat storage. Proceedings of the national academy of sciences, 101(44), pp.15718-15723.

Bloom, S.R., Kuhajda, F.P., Laher, I., Pi-Sunyer, X., Ronnett, G.V., Tan, T.M. and Weigle, D.S., 2008. The obesity epidemic: pharmacological challenges. Molecular Interventions, 8(2), p.82.

DiBaise, J.K., Frank, D.N. and Mathur, R., 2012. Impact of the gut microbiota on the development of obesity: current concepts. The American Journal of Gastroenterology Supplements, 1(1), p.22.

Muller, T.D., Nogueiras, R., Andermann, M.L., Andrews, Z.B., Anker, S.D., Argente, J., Batterham, R.L., Benoit, S.C., Bowers, C.Y. and Broglio, F., 2015. Ghrelin. Molecular Metabolism 4, 437–460.

NHS, 2019. Metabolic Syndrome. Available at: https://www.nhs.uk/conditions/metabolic-syndrome/ [Accessed 31 December 2020].

Public Health England, 2017. Health matters : obesity and the food environment. [Online] Available at: https://www.gov.uk/government/publications/health-matters-obesity-and-the-food-environment/health-matters-obesity-and-the-food-environment–2#:~:text=The%20overall%20cost%20of%20obesity,%C2%A349.9%20billion%20per%20year. [Accessed 31 December 2020].

Ridaura, V.K., Faith, J.J., Rey, F.E., Cheng, J., Duncan, A.E., Kau, A.L., Griffin, N.W., Lombard, V., Henrissat, B., Bain, J.R. and Muehlbauer, M.J., 2013. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science, 341(6150).

Schellekens, H., Torres-Fuentes, C., van de Wouw, M., Long-Smith, C.M., Mitchell, A., Strain, C., Berding, K., Bastiaanssen, T.F., Rea, K., Golubeva, A.V. and Arboleya, S., 2020. Bifidobacterium longum counters the effects of obesity: Partial successful translation from rodent to human. EBioMedicine, p.103176.

Torres‐Fuentes, C., Golubeva, A.V., Zhdanov, A.V., Wallace, S., Arboleya, S., Papkovsky, D.B., Aidy, S.E., Ross, P., Roy, B.L., Stanton, C. and Dinan, T.G., 2019. Short‐chain fatty acids and microbiota metabolites attenuate ghrelin receptor signaling. The FASEB Journal, 33(12), pp.13546-13559.

Van de Wouw, M., Schellekens, H., Dinan, T.G. and Cryan, J.F., 2017. Microbiota-gut-brain axis: modulator of host metabolism and appetite. The Journal of nutrition, 147(5), pp.727-745.
WHO, 2020. Obesity and overweight – key facts. [Online] Available at: https://www.who.int/en/news-room/fact-sheets/detail/obesity-and-overweight [Accessed 31 12 2020].

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