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Microbiota mediating Vagal communication in Obesity

Periodic Reporting for period 1 - miVaO (Microbiota mediating Vagal communication in Obesity)

Reporting period: 2018-12-01 to 2020-11-30

Obesity continues to pose one of the greatest public health challenges in EU and worldwide due to its high prevalence and chronic comorbidities. To reverse this trend, a substantial progress in the identification of the complex interacting factors that regulate energy metabolism is needed.
In the last decade gut microbiota has been identified as a new factor involved obesity and metabolic health. Nevertheless, further investigations are required to identify key intestinal bacteria and their mode of action on multiple pathways regulating host metabolism.
The project miVaO aimed to deciphering the role the gut microbiota plays in the regulation of nutrient sensory transmission from the vagal innervations of the gastrointestinal tract to the brain (nutrient sensing) to ultimately control energy homeostasis after a meal. Through in vitro and in vivo studies and omic approaches, miVaO has contributed to: 1) the identification of key intestinal bacteria that modulate sensory neurons and induce anti-diabetic effects in a rodent model of diet-induced obesity and 2) the demonstration that the sensory afferent neurons are required to control energy homeostasis.
Through in vitro approaches (intracellular Ca2+ imaging and perforated whole-cell patch-clamp), we have proved that a strain of Holdemanella biformis, isolated from metabolically healthy volunteers, modulates the activity of sensory neurons (dorsal root ganglion neurons and nodose ganglion neurons). To test the hypothesis that H. biformis improves metabolic health in obesity through nutrient sensing-dependent mechanisms, we administrated this bacterial strain by gavage to diet-induce obese mice. In brief, we demonstrated that H. biformis improves glucose homeostasis independent of obesity. In addition, H. biformis directly enhanced the sensitivity of vagal afferent neurons to glucagon-like peptide 1 (GLP-1), a key intestinal hormone that counteracts the effects of obesity through diverse biological processes, including, the maintenance of glycemia after a meal. In line with the in vitro results, H. biformis enhanced the GLP-1-related vagal afferent signalling in the distal gut. In addition, H. biformis increased the colonic proglucagon transcripts and the GLP-1 plasma levels, promoted the abundance of bacteria related to a healthy metabolic phenotype in the gut microbiota and induced higher intraluminal levels of monounsaturated fatty acids (MUFAs), which may act as a GLP-1 secretagogues.

To further investigate the bidirectional relationship between gut microbiota and vagal afferents as a key component of the gut-brain axis that controls food intake and energy balance, we generated a vagal afferent deficient rodent model through genetic tools. We demonstrated that, in response to an obesogenic diet, the specific ablation of these neurons induced a partial resistance to gain weight, improved glucose tolerance, exacerbated the fasting/refeeding-induced body weight variations and impaired the long and short-term control of food intake and the intestinal immunity. Some of these effects depend on gender. The analysis of fecal samples through metabolomics and 16S rRNA amplicons is ongoing to identify vagal afferent-dependent diurnal oscillations of metabolites and/or bacterial taxa related to feeding patterns. This will help to identify intestinal bacteria and metabolites involved in vagal afferent-mediated nutrient sensing in obesity.

The main results of the action have been exposed to the scientific community by attending to conferences organized by the Spanish Society for the study of Obesity, the European Society of Neurogastroenterology and Motility, the Instituto Gulbenkian de Ciência, the Galician Society of Endocrinology, Nutrition and Metabolism and to meetings organized by the host institution (IATA-CSIC). The research has been also communicated to the general public by participating in different events including the open day event in the host institution and talks to students in the international day of Woman and Girl in Science.
The prevalence of obesity continues to increase which reflects the urgent need of identifying new strategies to effectively prevent obesity or reduce the prevalence of associated metabolic complications. Recent investigations indicate that strategies that mimic, enhance and/or modulate the gut-brain signaling pathways to ultimately control energy homeostasis are promising for the clinical management of obesity. Gut microbiome is a source of potential novel therapeutic products capable of modulating the gut-brain axis. In this regard, we have demonstrated that H. biformis, a human intestinal bacteria isolated from metabolically healthy volunteers, induces anti-diabetic effects in obese mice which is coupled with an enhanced GLP-1-mediated vagal afferent signaling, In addition, miVaO has provided a comprehensive understanding of the vagal afferent-mediated regulation of the energy homeostasis in obesity. It will also allow to identify key intestinal bacteria that regulate the gut-(vagal mediated)-brain axis which will contribute to advance in the development of microbiome-based strategies to tackle metabolic diseases.
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