Schellekens_BLongum_Obesity_Stress_EBIOM_103176 (003)


H. Schellekens et al. / EBioMedicine xxx (xxxx) 103176

ciated with a persistent intestinal microbiome signature after successful dieting in obese mice [18]. Nonetheless, the exact mechanisms of how diet-induced changes in gut microbiota affect gut-brain signalling, including host metabolism, appetite regulation and brain health, are currently still lacking [19,20]. Interestingly, the obese-associated microbiota has been shown to have an increased capability to harvest energy from food and contributes to host insulin resistance, gut permeability, low-grade inflammation, and fat deposition [21,22]. Intestinal microbiota-derived metabolites have also been shown to impact the central regulation of appetite [9,23,24]. For example, certain bacterial strains modify gut peptides secretion, such as glucagon-like peptide (GLP) − 1, thus contributing to hypothal- amic appetite and satiety signalling via afferent nerve fibres of the va- gus nerve as well as by direct secretion into the circulatory system [24,25]. Furthermore, germ-free mice display marked decreases in ex- pression of intestinal satiety peptides, including cholecystokinin (CCK), peptide tyrosine-tyrosine (PYY) and GLP-1 and also lower circulating levels of leptin and ghrelin [26]. In addition, serum ghrelin levels are negatively correlated with the abundance of certain bacterial taxa, in- cluding Bifidobacterium and Lactobacillus species [27]. Moreover, intake of the prebiotic oligofructose, which promotes the growth of Bifidobac- terium and Lactobacillus , decreases the secretion of ghrelin in obese hu- mans [28]. Taken together, modulation of the gut microbiota is emerg- ing as a promising strategy for the management of obesity and obe- sity-related disorders such as type-2 diabetes and cardiovascular disease [4,7-9,29]. Several probiotic strains with different anti-obesity effects in humans have been identified [4,30-36]. The bacterial strain B. longum APC1472 has recently been shown to modulate ghrelinergic signalling in vitro [37], highlighting the therapeutic potential for host metabolism, ap- petite and obesity modulation. The ghrelin receptor (GHS-R1a) is ac- tivated by the endogenous hormone ghrelin, the first and only known peripheral orexigenic peptide, which regulates peripheral metabolism and energy expenditure as well as centrally regulated homeostatic ap- petite and food-motivated reward signalling, governing eating behav- iour and food intake [38-42]. Interestingly, obese individuals have at- tenuated postprandial suppression of ghrelin and a blunted nocturnal plasma ghrelin increase, reinforcing aberrant ghrelinergic signalling in obesity [43,44]. While the precise site of action of ghrelin is some- what controversial [45-47], the high prevalence of the ghrelin receptor throughout the small and large intestine, make it a likely target for in- teraction with the gut microbiota and thus may hold potential as a local therapeutic target [48]. As such, we investigated B. longum APC1472 for its ability to ame- liorate high-fat diet (HFD)-induced obesity in mice and observed signif- icant beneficial beneficial effects on adiposity and metabolism. Based on these promising effects of B. longum in the preclinical model, we subsequently investigated whether it could improve obesity symptoma- tology in healthy overweight/obese adults. The primary objective of the human intervention study was to determine whether a 12-week daily supplementation of B. longum APC1472 decreases body-mass index (BMI), while the secondary objective was to investigate the effects on waist-to-hip ration (W/H ratio), and biomarkers associated with obesity, such as glucose, insulin, HbA1c and ghrelin levels. The exploratory ob- jectives were to investigate the impact of B. longum APC1472 on the gut microbiota composition and diversity, peripheral inflammatory profile, stress hormone profile, self-reported perceived stress, anxiety and sati- ety. 2.Methods – animal study 2.1. Animals, diets and ethical approval Five-week-old male C57BL/6 mice (Harlan Laboratories, UK) (40 mice, n =8 – 10 per group) were housed in groups of 2 mice per cage in

Evidence before this study • Evidence has shown that the gut microbiota is an important component in the regulation of the host's physiology and metab- olism, modulating energy harvest, storage and expenditure and, therefore, represents a promising target in the treatment of obesity and obesity-related disorders. • Different probiotic strains have been shown to have differ- ent beneficial anti-obesity effects such as reduced body weight gain, improvements in insulin sensitivity and glucose uptake, and reduced fat depots accumulation in rodents. • The Bifidobacterium longum APC1472 strain was recently identified in our laboratory to modulate ghrelinergic signalling in vitro , which is an important signalling pathway modulating central appetite regulation and metabolism.

Added value of this study

• Research in context B. longum APC1472 demonstrated several significant beneficial effects in HFD-induced obese mice. • B. longum APC1472 reduced fasting glucose, cortisol awakening responses and increased active ghrelin in healthy obese adults. • Effectsof B. longum APC1472 partially translated from a preclin- ical mouse model to a human intervention study where this pro- biotic positively impacted markers of obesity.

Implications of available evidence

• B. longum APC1472 has promising potential to be developed as a valuable supplement in reducing specific markers of obe- sity and is poised to have significant relevance in conditions of heightened blood glucose, such as type 2 diabetes.

1. Introduction Obesity is one of the most pervasive, chronic diseases globally, in both developed and developing countries, contributing to at least 2.8 million deaths annually and significantly impacting the healthcare sys- tem [1]. The growing obesity epidemic is associated with increases in several comorbidities, such as cardiovascular disease, stroke, metabolic syndrome, type 2 diabetes and cancer [2,3]. Current available anti-obe- sity therapeutics are limited and associated with poor efficacy and ad- verse side effects [4,5]. Diet and exercise have been demonstrated to be the most potent in reducing obesity symptomatology [6]. In addition, natural compounds and their derivatives have been proposed as safer anti-obesity alternatives, either as functional foods or nutraceuticals [4]. The gut microbiota has emerged as a key component in the devel- opment of obesity and modulates the host's physiology and metabo- lism, including energy harvest, storage and expenditure [4,7-13]. Pre- clinical and clinical evidence demonstrating the critical role of the gas- trointestinal microbiota on host metabolism is steadily increasing. For example, germ-free mice are protected against obesity and are signifi- cantly leaner than normal control mice despite consuming more calories [14]. In addition, faecal transplantation from obese donors was shown to replicate the obese phenotype in lean germ-free mice independent of diet [15-17]. Moreover, accelerated post-dieting weight regain is asso

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