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Investigating Novel Approaches to Combat Obesity

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Introduction


Obesity is a growing global concern, reaching epidemic proportions in many countries across the world1. Since obesity is a major risk factor for several life-threatening chronic diseases, including diabetes, metabolic syndrome, cardiovascular disease and cancer, it contributes to at least 2.8 million deaths annually2,3. There are thus numerous efforts underway to reverse or control the development of obesity. 
When an individual consumes more energy than they utilize, the excess is laid down as fat. When the surplus fat deposits become excessive, typically indicated by body weight increasing to ≥20% above their recommended weight, a person is deemed obese. Diet is thus a key factor in the development of obesity. 
Diet has also been shown to affect the composition of the gut microbial community, with dietary alteration being rapidly reflected in changes in the microbes present in the gut4,5,6. The relationship between bacterial colonization of the gut and obesity has been widely investigated in the hope of uncovering a novel strategy for the control of obesity. It is now clear that the human gut microbiota is a critical factor in the development of obesity. 


Gut Microbiota and Obesity


There are typically over 100 trillion microscopic living organisms residing in the gastrointestinal tract, collectively known as the gut microbiome7. The gut microbiota help with the healthy functioning of the gut, providing nutrients and energy, and combatting infection. Furthermore, the role gut microbiota plays in regulating host metabolism through their impact on energy harvesting, storage, and expenditure implicates them in developing obesity8,9. 
Preclinical studies in mice models indicate that there is indeed a relationship between the activities of the gut microbiota and obesity10. For example, transplantation of the fecal microbiomes from an obese human adult to germ-free mice caused the mice to also lay down excessive fat11. 
Similarly, germ-free mice are protected against obesity and are significantly leaner than normal control mice despite consuming more calories12. Although the exact mechanisms by which diet-induced changes in gut microbiota affect host metabolism and appetite regulation remain unconfirmed, gut microbiota offers great promise as a target for the management of obesity and obesity-related disorders13. 
Indeed, several different probiotic strains have been shown to have different beneficial anti-obesity effects, such as reduced body weight gain, improvements in insulin sensitivity, and reduced fat depots accumulation in rodents14. The bacterial strain Bifidobacterium longum APC1472, for example, has recently been shown to modulate ghrelinergic signaling, a pathway used to modulate central appetite regulation and metabolism, in vitro15.


Evaluating the Effect of Bifidobacterium Longum on Fat Metabolism


A recent study sponsored by Atlantia Clinical Trials (Cork, Ireland) investigated whether B. longum APC1472 had anti-obesity effects in mice fed a high-fat diet (HFD) to induce obesity. The study also explored whether supplementation of the human diet with B. longum APC1472 reduced body-mass index (BMI) in otherwise healthy overweight/obese individuals16. 
In the mouse study, B. longum APC1472 was added to the drinking water of C57BL/6 mice receiving a high-fat diet for 16 weeks. The HFD-fed mice administered B. longum APC1472 supplementation displayed decreased bodyweight, less fat depot accumulation and increased glucose tolerance. The only change in microbiota composition was a partial restoration of Bifidobacterium levels.
In the human intervention trial, otherwise healthy overweight/obese participants received B. longum APC1472 or placebo supplementation for 12 weeks. No change was observed in BMI or waist-to-hip ratio (W/H ratio) in the group receiving B. longum APC1472 supplementation compared with the group receiving placebo. 
In contrast, there was a reduction in fasting blood glucose levels in participants receiving B. longum APC1472 supplementation. There was, however, no change observed in insulin activity. B. longum APC1472 supplementation was also shown to be associated with cortisol awakening responses and increased active ghrelin in healthy obese adults. As seen in the preclinical study, B. longum APC1472 treatment did not have a major impact on microbiota composition.
The data obtained in this study suggests that dietary supplementation with B. longum APC1472 has the same beneficial effects on fasting blood glucose in both a preclinical mouse model of obesity and in healthy but overweight or obese human individuals. This highlights the potential for B. longum APC1472 to be developed as a valuable supplement for reducing specific markers of obesity.
Further studies are needed to investigate the mechanisms and metabolites through which B. longum APC1472 modulates host glucose homeostasis, with a particular focus on the ghrelinergic system.


References
1.    WHO. Obesity and overweight - key facts. 2018. Available from: https://www.who.int/en/news-room/fact-sheets/detail/obesity-and-overweight.
2.    Tchernof A, Despres JP. Physiol Rev 2013;93(1):359–404.
3.    Narayanaswami V, Dwoskin LP. Pharmacol Ther 2017;170:116–147.
4.    Carmody RN, et al. Cell Host Microbe 2015;17:72-84
5.    Sharma V, et al. Cell Reports 2018;24(12):3087-3098
6.    David CF, et al. Nature 2014;505:559-563
7.    Wu GD, Lewis JD. Clin Gastroenterol Hepatol. 2013;11(7):774-777.
8.    Cani PD, et al. Nat Metab 2019.
9.    Rosenbaum M, et al. Trends Endocrinol Metab 2015;26(9):493–501
10.    Everard C, et al. Proc. Natl. Acad. Sci. USA 2013;110:9066-9071
11.    Ridaura JJ, et al. Science 2013;341:12412146
12.    Backhed F, et al. PNAS 2004;101(44):15718–15723
13.    Torres-Fuentes H, et al. Lancet Gastroenterol Hepatol 2017.
14.    Hibberd AA, et al. Benef Microb 2019;10(2):121–135.
15.    Torres-Fuentes C, et al. FASEB J 2019. fj201901433R.
16.    Schellekens H. et al. EBioMedicine 2020;103176
 

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