The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders. The microbiota and the brain communicate with each other via various routes including the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans. Many factors can influence microbiota composition in early life, including infection, mode of birth delivery, use of antibiotic medications, the nature of nutritional provision, environmental stressors, and host genetics. At the other extreme of life, microbial diversity diminishes with aging. Stress, in particular, can significantly impact the microbiota-gut-brain axis at all stages of life. Much recent work has implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson’s disease, and Alzheimer’s disease. Animal models have been paramount in linking the regulation of fundamental neural processes, such as neurogenesis and myelination, to microbiome activation of microglia. Moreover, translational human studies are ongoing and will greatly enhance the field. Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.

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There is a growing recognition of the involvement of the gastrointestinal microbiota in the regulation of physiology and behaviour. Microbiota-derived metabolites play a central role in the communication between microbes and their host, with short-chain fatty acids (SCFAs) being perhaps the most studied. SCFAs are primarily derived from fermentation of dietary fibres and play a pivotal role in host gut, metabolic and immune function. All these factors have previously been demonstrated to be adversely affected by stress. Therefore, we sought to assess whether SCFA supplementation could counteract the enduring effects of chronic psychosocial stress. C57BL/6J male mice received oral supplementation of a mixture of the three principle SCFAs (acetate, propionate and butyrate). One week later, mice underwent 3 weeks of repeated psychosocial stress, followed by a comprehensive behavioural analysis. Finally, plasma corticosterone, faecal SCFAs and caecal microbiota composition were assessed. SCFA treatment alleviated psychosocial stress-induced alterations in reward-seeking behaviour, and increased responsiveness to an acute stressor and in vivo intestinal permeability. In addition, SCFAs exhibited behavioural test-specific antidepressant and anxiolytic effects, which were not present when mice had also undergone psychosocial stress. Stress-induced increases in body weight gain, faecal SCFAs and the colonic gene expression of the SCFA receptors free fatty acid receptors 2 and 3 remained unaffected by SCFA supplementation. Moreover, there were no collateral effects on caecal microbiota composition. Taken together, these data show that SCFA supplementation alleviates selective and enduring alterations induced by repeated psychosocial stress and these data may inform future research into microbiota-targeted therapies for stress-related disorders.

The gut harbors an enormous diversity of microbes that are essential for the maintenance of homeostasis in health and disease. A growing body of evidence supports the role of this microbiota in influencing host appetite and food intake. Individual species within the gut microbiota are under selective pressure arising from nutrients available and other bacterial species present. Each bacterial species within the gut aims to increase its own fitness, habitat, and survival via specific fermentation of dietary nutrients and secretion of metabolites, many of which can influence host appetite and eating behavior by directly affecting nutrient sensing and appetite and satiety-regulating systems. These include microbiota-produced neuroactives and short-chain fatty acids. In addition, the gut microbiota is able to manipulate intestinal barrier function, interact with bile acid metabolism, modulate the immune system, and influence host antigen production, thus indirectly affecting eating behavior. A growing body of evidence indicates that there is a crucial role for the microbiota in regulating different aspects of eating-related behavior, as well as behavioral comorbidities of eating and metabolic disorders. The importance of intestinal microbiota composition has now been shown in obesity, anorexia nervosa, and forms of severe acute malnutrition. Understanding the mechanisms in which the gut microbiota can influence host appetite and metabolism will provide a better understanding of conditions wherein appetite is dysregulated, such as obesity and other metabolic or eating disorders, leading to novel biotherapeutic strategies.

The gut microbiota is increasingly recognized as an important regulator of host immunity and brain health. The aging process yields dramatic alterations in the microbiota, which is linked to poorer health and frailty in elderly populations. However, there is limited evidence for a mechanistic role of the gut microbiota in brain health and neuroimmunity during aging processes. Therefore, we conducted fecal microbiota transplantation from either young (3-4 months) or old (19-20 months) donor mice into aged recipient mice (19-20 months). Transplant of a microbiota from young donors reversed agingassociated differences in peripheral and brain immunity, as well as the hippocampal metabolome and transcriptome of aging recipient mice. Finally, the young donor-derived microbiota attenuated selective age-associated impairments in cognitive behavior when transplanted into an aged host. Our results reveal that the microbiome may be a suitable therapeutic target to promote healthy aging.Aging triggers metabolic and immune alterations that lead to perturbation of brain function and behavior, including impairments in hippocampal-associated cognitive behavior 1 . Notably, the gut microbiota, encompassing the population of trillions of microorganisms, undergoes a parallel community shift, which has been correlated to changes in host frailty and cognition 2,3 .Animal models have shown specific roles for the microbiota in shaping hallmarks of aging in the gut 4,5 . Moreover, the consequences of an elderly-associated microbiota on a young host involve alterations in host immunity, neurogenesis and cognition [6][7][8][9] . Notably, transferring microbiota from young fish (African turquoise killifish) into middle-aged fish improves lifespan and motor behavior 10 . However, it is completely unknown whether microbiota from young donors can restore aging-associated impairments in mammals.To determine whether fecal microbiota transplantation (FMT) from young mice can ameliorate aging-induced neurocognitive and immune impairments, we collected fecal microbiota from naive young mice (3-4 months) and transplanted this into aged mice ('aged yFMT' , 19-20 months). A separate group of aged mice received fecal microbiota from naive old mice to control for handling during FMT administration ('aged oFMT' ,(19)(20). To allow aging-associated comparisons, naive young mice received the same yFMT mixture ('young yFMT'). We found aging-associated differences in microbiota (Fig. 1 and Supplementary Tables 1 and 2), immunity (Fig. 2 and Extended Data Figs. 2 and 3), hippocampal neurogenesis (Extended Data Fig. 2), hippocampal metabolomics (Fig. 3, Extended Data Fig. 7 and Supplementary Table 3) and transcriptomics (Fig. 2 and Extended Data Fig. 7), and behavior (Fig. 4 and Extended Data Fig. 5); some, but not all, of which were attenuated by microbiota transplantation from a young mouse into an aged host. Our research offers the possibility that a microbiota from a young individual may have beneficial effects when given to an aged host.

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Background: The human gut microbiota has emerged as a key factor in the development of obesity. Certain probiotic strains have shown anti-obesity effects. The objective of this study was to investigate whether Bifidobacterium longum APC1472 has anti-obesity effects in high-fat diet (HFD)-induced obese mice and whether B. longum APC1472 supplementation reduces body-mass index (BMI) in healthy overweight/obese individuals as the primary outcome. B. longum APC1472 effects on waist-to-hip ratio (W/H ratio) and on obesity-associated plasma biomarkers were analysed as secondary outcomes. Methods: B. longum APC1472 was administered to HFD-fed C57BL/6 mice in drinking water for 16 weeks. In the human intervention trial, participants received B. longum APC1472 or placebo supplementation for 12 weeks, during which primary and secondary outcomes were measured at the beginning and end of the intervention. Findings: B. longum APC1472 supplementation was associated with decreased bodyweight, fat depots accumulation and increased glucose tolerance in HFD-fed mice. While, in healthy overweight/obese adults, the supplementation of B. longum APC1472 strain did not change primary outcomes of BMI (0.03, 95% CI [-0.4, 0.3]) or W/H ratio (0.003, 95% CI [-0.01, 0.01]), a positive effect on the secondary outcome of fasting blood glucose levels was found . Interpretation: This study shows a positive translational effect of B. longum APC1472 on fasting blood glucose from a preclinical mouse model of obesity to a human intervention study in otherwise healthy overweight and obese individuals. This highlights the promising potential of B. longum APC1472 to be developed as a valuable supplement in reducing specific markers of obesity.

The ghrelin receptor [growth hormone secretagogue receptor (GHSR)‐1a] represents a promising pharmacologic target for the treatment of metabolic disorders, including obesity and cachexia, via central appetite modulation. The GHSR‐1a has a complex pharmacology, highlighted by G‐protein–dependent and—independent downstream signaling pathways and high basal constitutive activity. The functional selectivity and signaling bias of many GHSR‐1a–specific ligands has not been fully characterized. In this study, we investigated the pharmacologic properties of ghrelin, MK‐0677, L692,585, and [d‐Lys3]‐growth hormone–releasing peptide‐6 (Dlys), JMV2959, and [d‐Arg(1),d‐Phe(5),d‐Trp(7, 9), Leu(11)]‐substance P (SP‐analog). We investigated their effect on basal GHSR‐1a constitutive signaling, ligand‐directed downstream GHSR‐1a signaling, functional selectivity, and signaling bias. Dlys behaved as a partial antagonist with a strong bias toward GHSR‐1a–β‐arrestin signaling, whereas JMV2959 acted as a full unbiased GHSR‐1a antagonist. Moreover, the SP‐analog behaved as an inverse agonist increasing G‐protein–dependent signaling, but only at high concentrations, whereas, at low concentrations, the SP‐analog attenuated β‐arrestin–dependent signaling. Considering the limited success in the clinical development of GHSR‐1a–targeted drugs so far, these findings provide a novel insight into the pharmacologic characteristics of GHSR‐1a ligands and their signaling bias, which has important implications in the design of novel, more selective GHSR‐1a ligands with predictable functional outcome and selectivity for preclinical and clinical drug development.—Ramirez, V. T., van Oeffelen, W. E. P. A., Torres‐Fuentes, C., Chruścicka, B., Druelle, C., Golubeva, A. V., van de Wouw, M., Dinan, T. G., Cryan, J. F., Schellekens, H. Differential functional selectivity and downstream signaling bias of ghrelin receptor antagonists and inverse agonists. FASEB J. 33, 518–531 (2019). http://www.fasebj.org