Microbiome Interconnectedness throughout Environments with Major Consequences for Healthy People and a Healthy Planet.

Microbiomes have highly important roles for ecosystem functioning and carry out key functions that support planetary health, including nutrient cycling, climate regulation, and water filtration. Microbiomes are also intimately associated with complex multicellular organisms such as humans, other animals, plants, and insects and perform crucial roles for the health of their hosts. Although we are starting to understand that microbiomes in different systems are interconnected, there is still a poor understanding of microbiome transfer and connectivity. In this review we show how microbiomes are connected within and transferred between different habitats and discuss the functional consequences of these connections. Microbiome transfer occurs between and within abiotic (e.g., air, soil, and water) and biotic environments, and can either be mediated through different vectors (e.g., insects or food) or direct interactions. Such transfer processes may also include the transmission of pathogens or antibiotic resistance genes. However, here, we highlight the fact that microbiome transmission can have positive effects on planetary and human health, where transmitted microorganisms potentially providing novel functions may be important for the adaptation of ecosystems.

Intestinal group 1 innate lymphoid cells drive macrophage-induced inflammation and endocrine defects in obesity and promote insulinemia.

Hypercaloric diets overactivate the intestinal immune system and disrupt the microbiome and epithelial cell functions, impairing glucose metabolism. The origins of this inflammatory cascade are poorly characterized. We investigated the involvement of intestinal proinflammatory group 1 innate lymphoid cells (ILC1s) in obesity progression and metabolic disruption. In obese mice, we studied longitudinally the ILC1s response to the diet and ILC1s depletion to address its role in obesity. ILC1s are required for the expansion of pro-inflammatory macrophages and ILC2s. ILC1s depletion induced the ILC3-IL-22 pathway, increasing mucin production, antimicrobial peptides, and neuroendocrine cells. These changes were translated into higher gut hormones and reduced insulinemia and adiposity. ILC1s depletion was also associated with a bloom in Akkermansia muciniphila and decreases in Bilophila spp. Intestinal-ILC1s are upstream activators of inflammatory signals, connecting immunity with the microbiome, the enteroendocrine system, and the intestinal barrier in the control of glucose metabolism and adiposity.

Microbiome Research as an Effective Driver of Success Stories in Agrifood Systems - A Selection of Case Studies.

Increasing knowledge of the microbiome has led to significant advancements in the agrifood system. Case studies based on microbiome applications have been reported worldwide and, in this review, we have selected 14 success stories that showcase the importance of microbiome research in advancing the agrifood system. The selected case studies describe products, methodologies, applications, tools, and processes that created an economic and societal impact. Additionally, they cover a broad range of fields within the agrifood chain: the management of diseases and putative pathogens; the use of microorganism as soil fertilizers and plant strengtheners; the investigation of the microbial dynamics occurring during food fermentation; the presence of microorganisms and/or genes associated with hazards for animal and human health (e.g., mycotoxins, spoilage agents, or pathogens) in feeds, foods, and their processing environments; applications to improve HACCP systems; and the identification of novel probiotics and prebiotics to improve the animal gut microbiome or to prevent chronic non-communicable diseases in humans (e.g., obesity complications). The microbiomes of soil, plants, and animals are pivotal for ensuring human and environmental health and this review highlights the impact that microbiome applications have with this regard.

The Allium Derivate Propyl Propane Thiosulfinate Exerts Anti-Obesogenic Effects in a Murine Model of Diet-Induced Obesity.

Allium species and their organosulfur-derived compounds could prevent obesity and metabolic dysfunction, as they exhibit immunomodulatory and antimicrobial properties. Here, we report the anti-obesogenic potential and dose-dependent effects (0.1 or 1 mg/kg/day) of propyl propane thiosulfinate (PTS) in a murine model of diet-induced obesity. The obesogenic diet increased body weight gain and adipocyte size, and boosted inflammatory marker (Cd11c) expression in the adipose tissue. Conversely, PTS prevented these effects in a dose-dependent manner. Moreover, the higher dose of PTS improved glucose and hepatic homeostasis, modulated lipid metabolism, and raised markers of the thermogenic capacity of brown adipose tissue. In the colon, the obesogenic diet reduced IL-22 levels and increased gut barrier function markers (Cldn3, Muc2, Reg3g, DefaA); however, the highest PTS dose normalized all of these markers to the levels of mice fed a standard diet. Gut microbiota analyses revealed no differences in diversity indexes and only minor taxonomic changes, such as an increase in butyrate producers, Intestimonas and Alistipes, and a decrease in Bifidobacterium in mice receiving the highest PTS dose. In summary, our study provides preclinical evidence for the protective effects of PTS against obesity, which if confirmed in humans, might provide a novel plant-based dietary product to counteract this condition.

Calling for a systems approach in microbiome research and innovation.

Microbiomes are all around us in natural and cultivated ecosystems, for example, soils, plants, animals and our own body. Microbiomes are essential players of biotechnological applications, and their functions drive human, animal, plant and environmental health. The rapidly developing microbiome research landscape was studied by a global mapping excercise and bibliometric analysis. Although microbiome research is performed in many different science fields, using similar concepts within and across fields, microbiomes are mostly investigated one ecosystem at-a-time. In order to fully understand microbiome impacts and leverage microbial functions, research needs to adopt a systems approach connecting microbiomes and research initiatives in divergent fields to create understanding on how microbiomes can be modulated for desirable functions as a basis of sustainable, circular bioeconomy.

Manipulation of the gut microbiome in gluten-intolerance.

PURPOSE OF REVIEW: Gluten is a complex mixture of highly immunogenic glutamine- and proline-rich proteins found in some cereals. In celiac disease (CeD), gluten triggers an autoimmune response due to its interaction with the human leukocyte antigen heterodimers that confer the genetic risk. The involvement of gluten in other disorders has also been investigated, but its role beyond CeD is still unclear. Here, we review the most recent evidence of the involvement of gluten in diseases and the opportunities of manipulating the gut microbiota to treat or prevent gluten-related conditions. RECENT FINDINGS: Most of the new studies have been conducted in the context of CeD, where important evidence has been gained on associations between the gut microbiota, genotype, and environmental factors such as breastfeeding and antibiotics. The role of the microbiota has been investigated in several prospective, observational and interventional studies with probiotics, which together showed that the gut microbiota could be targeted to ameliorate and aid in the prevention of CeD development. SUMMARY: Several studies have evidenced how genetic and environmental factors influence the gut microbiome with consequences in CeD. These findings could inspire the development of microbiota modulation strategies to support the prevention or treatment of CeD.

The Microbiota and the Gut-Brain Axis in Controlling Food Intake and Energy Homeostasis.

Obesity currently represents a major societal and health challenge worldwide. Its prevalence has reached epidemic proportions and trends continue to rise, reflecting the need for more effective preventive measures. Hypothalamic circuits that control energy homeostasis in response to food intake are interesting targets for body-weight management, for example, through interventions that reinforce the gut-to-brain nutrient signalling, whose malfunction contributes to obesity. Gut microbiota-diet interactions might interfere in nutrient sensing and signalling from the gut to the brain, where the information is processed to control energy homeostasis. This gut microbiota-brain crosstalk is mediated by metabolites, mainly short chain fatty acids, secondary bile acids or amino acids-derived metabolites and subcellular bacterial components. These activate gut-endocrine and/or neural-mediated pathways or pass to systemic circulation and then reach the brain. Feeding time and dietary composition are the main drivers of the gut microbiota structure and function. Therefore, aberrant feeding patterns or unhealthy diets might alter gut microbiota-diet interactions and modify nutrient availability and/or microbial ligands transmitting information from the gut to the brain in response to food intake, thus impairing energy homeostasis. Herein, we update the scientific evidence supporting that gut microbiota is a source of novel dietary and non-dietary biological products that may beneficially regulate gut-to-brain communication and, thus, improve metabolic health. Additionally, we evaluate how the feeding time and dietary composition modulate the gut microbiota and, thereby, the intraluminal availability of these biological products with potential effects on energy homeostasis. The review also identifies knowledge gaps and the advances required to clinically apply microbiome-based strategies to improve the gut-brain axis function and, thus, combat obesity.

The gut microbiota as a versatile immunomodulator in obesity and associated metabolic disorders.

Obesity has reached epidemic proportions and is associated with chronic-low-grade inflammation and metabolic morbidities. Energy-dense diets and a sedentary lifestyle are determinants of obesity. The gut microbiome is a novel biological factor involved in obesity via interactions with the host and the diet. The gut microbiome act as a synergistic force protecting or aggravating the effects of the diet on the metabolic phenotype. The role of the microbiome in the regulation of intestinal and systemic immunity is one of the mechanisms by which it contributes to the host's response to the diet and to the pathophysiology of diet-induced obesity. Here, we review the mechanisms whereby "obesogenic" diets and the microbiome impact immunity, locally and systemically, focusing on the consequences in the gut-adipose tissue axis. We also review the structural and microbial metabolites that influence immunity and how advances in this field could help design microbiome-informed strategies to tackle obesity-related disorders more effectively.

Implication of the Gut Microbiota in Metabolic Inflammation Associated with Nutritional Disorders and Obesity.

SCOPE: More than a decade ago, the concept of "metabolic endotoxemia" is elaborated on the fact that some bacterial components, classified as microbial associated membrane pathogens (MAMPs) can pass through the gut barrier and create a systemic low tone inflammation. METHODS AND RESULTS: The translocation of lipopolysaccharides and its contribution to systemic inflammation are largely studied in murine models of obesity, allowing to unravel the molecular pathways involved in the process. Many different pathological contexts evoke the loss of gut barrier as an event contributing to inflammation and thereby driving metabolic and behavioral alterations. CONCLUSION: This review describes the role of nutrition as a modulator of metabolic regulation and focuses on the contribution of the gut microbiota in the process of the production of a large diversity of bioactive metabolites. The two first sections of the review will be dedicated to the impact of nutritional disorders on both the gut microbiota composition and on metabolic inflammation. The last and more prominent section will describe the role of different nutrient-derived gut metabolites on the gut barrier integrity, metabolic inflammation, and peripheral tissue alterations during obesity or associated complications.

Bifidobacterium pseudocatenulatum CECT 7765 reverses the adverse effects of diet-induced obesity through the gut-bone axis.

Obesity and the associated chronic metabolic diseases (e.g., type-2 diabetes) adversely affect bone metabolism and health. Gut microbiota is considered to be involved in the pathophysiology of obesity and also represents a therapeutic target. This study has investigated the contribution of diet-induced obesity to alterations in bone health and metabolism and whether these could be restored by oral administration of Bifidobacterium pseudocatenulatum CECT 7765. To do so, adult male wild-type C57BL-6 mice were fed either a standard or high-fat diet (HFD), supplemented or not with B. pseudocatenulatum CECT 7765 (109 CFU/day) for 14 weeks. Effects on bone mass density (BMD), bone mineral content, bone remodeling, bone structure and gene expression were assessed. In HFD-fed mice, bone microstructural properties at the distal femur showed deteriorated trabecular architecture in bone volumetric fraction, trabecular number and trabecular pattern factor. Besides, the HFD reduced the volumetric bone mineral density in the trabecular bone, but not in the cortical bone. All these bone microstructural alterations found in obese mice were reversed by B. pseudocatenulatum CECT 7765. Administration of the bacterium increased (p < .05) the Wnt/ß-catenin pathway gene expression, which could mediate effects on BMD. Bifidobacterium pseudocatenulatum CECT 7765 supplementation increased (p < .05) serum osteocalcin (OC, bone formation parameter), and decreased serum C-terminal telopeptide (CTX) (p < .01) and parathormone (PTH) (p < .05) (both bone resorption parameters). It also altered the microstructure of the femur. In summary, HFD interfered with the normal bone homeostasis leading to increased bone loss. In obese mice, B. pseudocatenulatum CECT 7765 lowered bone mass loss and enhanced BMD by decreasing bone resorption and increasing bone formation.

Breast-Milk Microbiota Linked to Celiac Disease Development in Children: A Pilot Study From the PreventCD Cohort.

Celiac disease (CeD) is an immune-mediated disorder triggered by exposure to dietary gluten proteins in genetically predisposed individuals. In addition to the host genome, the microbiome has recently been linked to CeD risk and pathogenesis. To progress in our understanding of the role of breast milk microbiota profiles in CeD, we have analyzed samples from a sub-set of mothers (n = 49) included in the PreventCD project, whose children did or did not develop CeD. The results of the microbiota data analysis indicated that neither the BMI, HLA-DQ genotype, the CeD condition nor the gluten-free diet of the mothers could explain the human milk microbiota profiles. Nevertheless, we found that origin country, the offspring's birth date and, consequently, the milk sampling date influenced the abundance and prevalence of microbes in human milk, undergoing a transition from an anaerobic to a more aerobic microbiota, including potential pathogenic species. Furthermore, certain microbial species were more abundant in milk samples from mothers whose children went on to develop CeD compared to those that remained healthy. These included increases in facultative methylotrophs such as Methylobacterium komagatae and Methylocapsa palsarum as well as in species such as Bacteroides vulgatus, that consumes fucosylated-oligosaccharides present in human milk, and other breast-abscess associated species. Theoretically, these microbiota components could be vertically transmitted from mothers-to-infants during breastfeeding, thereby influencing CeD risk.

Microbiome response to diet: focus on obesity and related diseases.

Numerous studies in humans and animal models describe disturbances of the gut microbial ecosystem associated with adiposity and hallmarks of the metabolic syndrome, including hepatic and cardiovascular diseases. The manipulation of the microbiome, which is largely influenced by the diet, appears as an innovative therapeutic tool to prevent or control obesity and related diseases. This review describes the impact of nutrients on the gut microbiota composition and/or function and when available, the consequences on host physiology. A special emphasis is made on the contribution of bacterial-derived metabolites in the regulation of key gut functions that may explain their systemic effect.

Brain-Sparing Sympathofacilitators Mitigate Obesity without Adverse Cardiovascular Effects.

Anti-obesity drugs in the amphetamine (AMPH) class act in the brain to reduce appetite and increase locomotion. They are also characterized by adverse cardiovascular effects with origin that, despite absence of any in vivo evidence, is attributed to a direct sympathomimetic action in the heart. Here, we show that the cardiac side effects of AMPH originate from the brain and can be circumvented by PEGylation (PEGyAMPH) to exclude its central action. PEGyAMPH does not enter the brain and facilitates SNS activity via theß2-adrenoceptor, protecting mice against obesity by increasing lipolysis and thermogenesis, coupled to higher heat dissipation, which acts as an energy sink to increase energy expenditure without altering food intake or locomotor activity. Thus, we provide proof-of-principle for a novel class of exclusively peripheral anti-obesity sympathofacilitators that are devoid of any cardiovascular and brain-related side effects.

Aerobic dehydrogenation of amines to nitriles catalyzed by triazolylidene ruthenium complexes with O2 as terminal oxidant.

Pyridyl-substituted mesoionic triazolylidene ruthenium cymene complexes catalyze the oxidation of both aromatic and aliphatic amines to nitriles with high activity and selectivity under benign conditions using dioxygen as the terminal oxidant. Modification on the pyridyl moiety of the ligand scaffold has negligible effect on the catalytic performance, while substituents on the triazolylidene directly affect the catalytic fitness of the metal center, leading to distinct catalytic profiles. Pre-dissociation of the cymene ligand and formation of a solvento analogue further enhances the catalytic activity towards nitrile formation. Variation of reaction conditions provided valuable mechanistic insights and resulted in a highly efficient protocol for nitrile formation with maximum turnover numbers around 10 000. The turnover frequency reaches up to 400 h-1, providing one of the fastest catalytic systems known to date for this transformation.

Nutritional interest of dietary fiber and prebiotics in obesity: Lessons from the MyNewGut consortium.

The aim of EU project MyNewGut is to contribute to future public health-related recommendations supported by new insight in gut microbiome and nutrition-host relationship. In this Opinion Paper, we first revisit the concept of dietary fiber, taking into account their interaction with the gut microbiota. This paper also summarizes the main effects of dietary fibers with prebiotic properties in intervention studies in humans, with a particular emphasis on the effects of arabinoxylans and arabinoxylo-oligosaccharides on metabolic alterations associated with obesity. Based on the existing state of the art and future development, we elaborate the steps required to propose dietary guidelines related to dietary fibers, taking into account their interaction with the gut microbiota.

The Janus Face of Cereals: Wheat-Derived Prebiotics Counteract the Detrimental Effect of Gluten on Metabolic Homeostasis in Mice Fed a High-Fat/High-Sucrose Diet.

SCOPE: Cereals are important sources of carbohydrates, but also contain nutrients that could impact adiposity. The contribution of gluten to obesity and the effects of prebiotics-arabinoxylo-oligosaccharides (AXOS) and fructo-oligosaccharides (FOS)-that can be extracted from gluten-containing cereals are analyzed. METHODS AND RESULTS: Mice are fed a control diet, Western diet (WD, consisting of high fat/high sucrose), or WD with 5% gluten. Prebiotics are tested in the WD with gluten. Gluten does not increase body weight and has a minor effect on ileal inflammation. Gluten decreases the expression of browning markers in the fat and increases the triglycerides synthesis in the muscle. AXOS decreases body weight and adiposity in fat pads muscle and liver. AXOS promotes gluten cleavage by the induction of prolyl endopeptidase that is translated into a reduction of gluten immunogenic peptides. Gluten has minor effects on cecal microbiota composition, whereas prebiotics increased Bifidobacterium, Butyricicoccus, Prevotella, and Parasutterella, which are all negatively correlated to the cecal content of gluten peptides. CONCLUSION: While gluten may affect metabolic homeostasis, these effects are lessened when gluten is consumed along with cereal-derived fibers. If confirmed in humans, the authors bring new arguments to eat fiber-rich cereals to promote a healthy diet.

High-fat diet induces depression-like behaviour in mice associated with changes in microbiome, neuropeptide Y, and brain metabolome.

Objectives: The biological mechanisms linking diet-related obesity and depression remain unclear. Therefore, we examined the impact of high-fat diet (HFD) on murine behaviour, intestinal microbiome, brain metabolome, neuropeptide Y (NPY) expression, and dipeptidyl peptidase-4 (DPP-4) activity.Methods: Male C57Bl/6J mice were fed an HFD (60 kJ% from fat) or control diet (12 kJ% from fat) for 8 weeks, followed by behavioural phenotyping. Caecal microbiome was analysed by 16S rDNA sequencing, brain metabolome by 1H nuclear magnetic resonance, NPY expression by PCR and immunoassay, and dipeptidyl peptidase-4 (DPP-4) activity by enzymatic assay. The effect of a 4-week treatment with imipramine (7 mg/kg/day) and the DPP-4 inhibitor sitagliptin (50 mg/kg/day) on HFD-induced behavioural changes was also tested.Results: HFD led to a depression-like phenotype as revealed by reduced sociability and sucrose preference. In the caecum, HFD diminished the relative abundance of Bacteroidetes and increased the relative abundance of Firmicutes and Cyanobacteria. In the brain, HFD modified the metabolome of prefrontal cortex and striatum, changing the relative concentrations of molecules involved in energy metabolism (e.g. lactate) and neuronal signalling (e.g. γ-aminobutyric acid). The expression of NPY in hypothalamus and hippocampus was decreased by HFD, whereas plasma NPY and DPP-4-like activity were increased. The HFD-induced anhedonia remained unaltered by imipramine and sitagliptin.Discussion: The depression-like behaviour induced by prolonged HFD in mice is associated with distinct alterations of intestinal microbiome, brain metabolome, NPY system, and DPP-4-like activity. Importantly, the HFD-evoked behavioural disturbance remains unaltered by DPP-4 inhibition and antidepressant treatment with imipramine.

The Potential Role of the Dipeptidyl Peptidase-4-Like Activity From the Gut Microbiota on the Host Health.

The Dipeptidyl peptidase-4 (DPP-4) activity influences metabolic, behavioral and intestinal disorders through the cleavage of key hormones and peptides. Some studies describe the existence of human DPP-4 homologs in commensal bacteria, for instance in Prevotella or Lactobacillus. However, the role of the gut microbiota as a source of DPP-4-like activity has never been investigated. Through the comparison of the DPP-4 activity in the cecal content of germ-free mice (GFM) and gnotobiotic mice colonized with the gut microbiota of a healthy subject, we bring the proof of concept that a significant DPP-4-like activity occurs in the microbiota. By analyzing the existing literature, we propose that DPP-4-like activity encoded by the intestinal microbiome could constitute a novel mechanism to modulate protein digestion as well as host metabolism and behavior.