Periodic Reporting for period 1 - MicroILCs (MicroILCs: Deciphering how the gut Microbiota influences Innate Lymphoid Cells in obesity")
Período documentado: 2021-01-01 hasta 2022-12-31
Obesity is a severe public health challenge globally and a significant determinant of disability and death. According to WHO, overweight and obesity have reached epidemic proportions in the European region, affecting almost 60% of adults and one in three school-aged children. Obesity substantially reduces health and well-being and, consequently, accounts for considerable costs that place a strain on national healthcare systems, economic productivity, and social resources. Besides, people with obesity often suffer from weight stigma that damages mental health and causes discrimination. Accordingly, addressing obesity is a priority for achieving the Sustainable Development Goals. In this sense, several policy frameworks and action plans to halt the rise in obesity have been set out; however, there have been consistent increases in the prevalence of overweight and obesity in the European Region, and no Member State is on track to reach the target of halting the rise in obesity by 2025. There is thus an urgent need to better understand the interplay between environmental obesity drivers (e.g. unhealthy diets) and individual response to such drivers (e.g. the response mediated by gut microbiota), to develop more effective interventions to combat obesity at population and individual levels.
To overcome the pandemic worldwide evolution of obesity and cardiometabolic diseases, research has increasingly focused its attention on interventions targeting the gut microbiota. These strategies arise from the increasing evidence demonstrating that alterations in the microbiota influence adiposity, insulin resistance, and other hallmarks of obesity and metabolic syndrome. Nonetheless, the key bacteria relevant for obesity and the precise mechanisms by which they contribute to define metabolic phenotypes are unknown. Growing evidence points to the intestinal immune system as an important contributor to systemic inflammation associated with obesity. The intestine is the largest immune organ of the body, and is inhabited by trillions of bacteria that, in turn, influence immune function. It is also the first to be exposed to the effects of dietary patterns, which can modulate the gut microbiota. Thus, the gut microbiota could be essential to moderate or aggravate the response of the intestinal immune system to diet, influencing metabolic homeostasis at both intestinal and peripheral levels.
The aim of the EU-funded MicroILCs project was to identify the key determinants of the gut ecosystem for the immune responses of the innate lymphoid cells (ILCs) in particular. Specifically, we have assessed the role of the microbiota in regulating ILCs as a possible driver of gut microbiota-mediated effects on obesity and metabolic dysfunction and, thereby, identified effective microbiota-based interventions to combat obesity.
To overcome the pandemic worldwide evolution of obesity and cardiometabolic diseases, research has increasingly focused its attention on interventions targeting the gut microbiota. These strategies arise from the increasing evidence demonstrating that alterations in the microbiota influence adiposity, insulin resistance, and other hallmarks of obesity and metabolic syndrome. Nonetheless, the key bacteria relevant for obesity and the precise mechanisms by which they contribute to define metabolic phenotypes are unknown. Growing evidence points to the intestinal immune system as an important contributor to systemic inflammation associated with obesity. The intestine is the largest immune organ of the body, and is inhabited by trillions of bacteria that, in turn, influence immune function. It is also the first to be exposed to the effects of dietary patterns, which can modulate the gut microbiota. Thus, the gut microbiota could be essential to moderate or aggravate the response of the intestinal immune system to diet, influencing metabolic homeostasis at both intestinal and peripheral levels.
The aim of the EU-funded MicroILCs project was to identify the key determinants of the gut ecosystem for the immune responses of the innate lymphoid cells (ILCs) in particular. Specifically, we have assessed the role of the microbiota in regulating ILCs as a possible driver of gut microbiota-mediated effects on obesity and metabolic dysfunction and, thereby, identified effective microbiota-based interventions to combat obesity.
First, we have investigated the gut-resident ILC1s’ involvement in obesity progression and metabolic disruption. To address this gold, we have evaluated the ILC1s response to an obesogenic diet and the consequences of the ILC1s depletion in a murine model of diet-induced obesity longitudinally. In the intestine, ILC1s depletion avoided the increases in M1 macrophages, known to drive a pro-inflammatory response. Additionally, ILC1s depletion increased protective responses such as mucin production, antimicrobial peptides, and neuroendocrine cells. Ultimately, we associated these improvements in gut homeostasis with higher gut hormone secretion and reduced insulinemia and adiposity. Moreover, ILC1s depletion reset microbial and metabolomic profiles to a healthier symbiotic state.
Second, we have identified the properties of a novel isolated bacteria as a next-generation probiotic in a murine model of diet-induced obesity. In particular, we have proven that the anti-obesogenic properties of this bacterial strain depend on its immunomodulatory effect on intestinal ILC1. Besides, by using in vitro approaches, we have discovered the potential for microbiota strategies to modulate the phenotypic plasticity of intestinal ILC1 and the potential impact of this cross-talk on metabolic health.
The results obtained in the MicroILCs have significantly improved our understanding of the role of gut-resident ILC in response to hypercaloric diets and the opportunities for their modulation by probiotics for obesity management. In particular, based on our results, we can state two main conclusions:
(i) We have described the contribution of intestinal ILC1s to the activation of macrophage-induced inflammation and the downstream consequences for the microbiota, gut barrier function, and the enteroendocrine system responsible for metabolic dysregulation in obesity.
(ii) We have identified the anti-obesogenic properties of a new isolated bacterial that prevents obesity by buffering the increases in ILC induced by obesogenic diets. Besides, our in vitro experiments underscore a complex dialog between bacteria, gut-resident M2 macrophages, and ILC1s that deserves further investigation.
These results have been presented in several contexts, like International Conferences, scientific manuscripts and also in seminars and social media.
Second, we have identified the properties of a novel isolated bacteria as a next-generation probiotic in a murine model of diet-induced obesity. In particular, we have proven that the anti-obesogenic properties of this bacterial strain depend on its immunomodulatory effect on intestinal ILC1. Besides, by using in vitro approaches, we have discovered the potential for microbiota strategies to modulate the phenotypic plasticity of intestinal ILC1 and the potential impact of this cross-talk on metabolic health.
The results obtained in the MicroILCs have significantly improved our understanding of the role of gut-resident ILC in response to hypercaloric diets and the opportunities for their modulation by probiotics for obesity management. In particular, based on our results, we can state two main conclusions:
(i) We have described the contribution of intestinal ILC1s to the activation of macrophage-induced inflammation and the downstream consequences for the microbiota, gut barrier function, and the enteroendocrine system responsible for metabolic dysregulation in obesity.
(ii) We have identified the anti-obesogenic properties of a new isolated bacterial that prevents obesity by buffering the increases in ILC induced by obesogenic diets. Besides, our in vitro experiments underscore a complex dialog between bacteria, gut-resident M2 macrophages, and ILC1s that deserves further investigation.
These results have been presented in several contexts, like International Conferences, scientific manuscripts and also in seminars and social media.
We have highlighted the importance of intestinal ILCs as mediators of the inflammatory response that causes an obesogenic diet at the intestinal level. In addition, we have investigated that manipulating the microbiota can be a strategy to re-equilibrate the function of ILCs under conditions where homeostasis is disrupted, as occurs with obesogenic diets. Remarkably, the administration of beneficial bacteria (probiotics) is a good approach to re-establish the dysregulated immune response and, together with healthier lifestyle habits, promote metabolic health and reduce complications in obesity.
The following steps to increase the impact of the results obtained within the MicroILCs project are scaling up the production of the probiotic bacteria here characterized and validating its efficacy in human studies. These complementary studies will undoubtedly pave the way for its industrial exploitation, and thus, society will benefit from these advances in the future.
The following steps to increase the impact of the results obtained within the MicroILCs project are scaling up the production of the probiotic bacteria here characterized and validating its efficacy in human studies. These complementary studies will undoubtedly pave the way for its industrial exploitation, and thus, society will benefit from these advances in the future.