A Metal-Polyphenol-Based Antidepressant for Alleviating Colitis-Associated Mental Disorders. Advanced materials (Deerfield Beach, Fla.) Emerging evidence suggests that patients with inflammatory bowel diseases (IBDs) are predisposed to psychosocial disturbances, such as depression and anxiety. Regrettably, clinical antidepressants exhibit unsatisfactory therapeutic efficacy in IBD-associated psychosocial disturbances, primarily attributed to the inherent intestinal disorders and intricate bidirectional relationship between the gut and the brain. Herein, we report a metal-polyphenol-based antidepressant to alleviate mental disorders in dextran sulfate sodium-induced experimental acute colitis mice via modulating the microbiota-gut-brain axis. The antidepressant, termed CSMTC, comprises a core of melittin-encapsulated natural antioxidant enzymes (i.e., catalase and superoxide dismutase) and a protective shell composed of tannic acid-cerium ion network. Upon oral administration to colitis mice, CSMTC can effectively restore colonic redox balance, reinforce the intestinal barrier, modulate gut microbiota composition, maintain the blood-brain barrier integrity, and regulate systemic immune responses. Notably, behavioral test results reveal that CSMTC significantly alleviates the colitis-associated mental disorder (e.g., depression-like behavior) via the microbiota-gut-brain axis by reducing neuroinflammation, enhancing hippocampal neural plasticity, modulating hippocampal immune responses, and restoring neurotransmitter homeostasis. This work may have implications for the development of new nanodrugs for treating inflammation-associated complications. 10.1002/adma.202410993

The gut-brain axis and pain signalling mechanisms in the gastrointestinal tract. Nature reviews. Gastroenterology & hepatology Visceral pain is a major clinical problem and one of the most common reasons patients with gastrointestinal disorders seek medical help. Peripheral sensory neurons that innervate the gut can detect noxious stimuli and send signals to the central nervous system that are perceived as pain. There is a bidirectional communication network between the gastrointestinal tract and the nervous system that mediates pain through the gut-brain axis. Sensory neurons detect mechanical and chemical stimuli within the intestinal tissues, and receive signals from immune cells, epithelial cells and the gut microbiota, which results in peripheral sensitization and visceral pain. This Review focuses on molecular communication between these non-neuronal cell types and neurons in visceral pain. These bidirectional interactions can be dysregulated during gastrointestinal diseases to exacerbate visceral pain. We outline the anatomical pathways involved in pain processing in the gut and how cell-cell communication is integrated into this gut-brain axis. Understanding how bidirectional communication between the gut and nervous system is altered during disease could provide new therapeutic targets for treating visceral pain. 10.1038/s41575-024-01017-9

Intestinal Epithelial Serotonin as a Novel Target for Treating Disorders of Gut-Brain Interaction and Mood. Gastroenterology BACKGROUND & AIMS:Mood disorders and disorders of gut-brain interaction (DGBI) are highly prevalent, commonly comorbid, and lack fully effective therapies. Although selective serotonin reuptake inhibitors (SSRIs) are first-line pharmacological treatments for these disorders, they may impart adverse effects, including anxiety, anhedonia, dysmotility, and, in children exposed in utero, an increased risk of cognitive, mood, and gastrointestinal disorders. SSRIs act systemically to block the serotonin reuptake transporter and enhance serotonergic signaling in the brain, intestinal epithelium, and enteric neurons. Yet, the compartments that mediate the therapeutic and adverse effects of SSRIs are unknown, as is whether gestational SSRI exposure directly contributes to human DGBI development. METHODS:We used transgenic, surgical, and pharmacological approaches to study the effects of intestinal epithelial serotonin reuptake transporter or serotonin on mood and gastrointestinal function, as well as relevant communication pathways. We also conducted a prospective birth cohort study to assess effects of gestational SSRI exposure on DGBI development. RESULTS:Serotonin reuptake transporter ablation targeted to the intestinal epithelium promoted anxiolytic and antidepressive-like effects without causing adverse effects on the gastrointestinal tract or brain; conversely, epithelial serotonin synthesis inhibition increased anxiety and depression-like behaviors. Afferent vagal pathways were found to be conduits by which intestinal epithelial serotonin affects behavior. In utero SSRI exposure is a significant and specific risk factor for development of the DGBI, functional constipation, in the first year of life, irrespective of maternal depressive symptoms. CONCLUSION:These findings provide fundamental insights into how the gastrointestinal tract modulates emotional behaviors, reveal a novel gut-targeted therapeutic approach for mood modulation, and suggest a new link in humans between in utero SSRI exposure and DGBI development. 10.1053/j.gastro.2024.11.012

Microbiota-neuroepithelial signalling across the gut-brain axis. Nature reviews. Microbiology Research over the past two decades has established a remarkable ability of the gut microbiota to modulate brain activity and behaviour. Conversely, signals from the brain can influence the composition and function of the gut microbiota. This bidirectional communication across the gut microbiota-brain axis, involving multiple biochemical and cellular mediators, is recognized as a major brain-body network that integrates cues from the environment and the body's internal state. Central to this network is the gut sensory system, formed by intimate connections between chemosensory epithelial cells and sensory nerve fibres, that conveys interoceptive signals to the central nervous system. In this Review, we provide a broad overview of the pathways that connect the gut and the brain, and explore the complex dialogue between microorganisms and neurons at this emerging intestinal neuroepithelial interface. We highlight relevant microbial factors, endocrine cells and neural mechanisms that govern gut microbiota-brain interactions and their implications for gastrointestinal and neuropsychiatric health. 10.1038/s41579-024-01136-9

The gut-brain axis underlying hepatic encephalopathy in liver cirrhosis. Nature medicine Up to 50-70% of patients with liver cirrhosis develop hepatic encephalopathy (HE), which is closely related to gut microbiota dysbiosis, with an unclear mechanism. Here, by constructing gut-brain modules to assess bacterial neurotoxins from metagenomic datasets, we found that phenylalanine decarboxylase (PDC) genes, mainly from Ruminococcus gnavus, increased approximately tenfold in patients with cirrhosis and higher in patients with HE. Cirrhotic, not healthy, mice colonized with R. gnavus showed brain phenylethylamine (PEA) accumulation, along with memory impairment, symmetrical tremors and cortex-specific neuron loss, typically found in patients with HE. This accumulation of PEA was primarily driven by decreased monoamine oxidase-B activity in both the liver and serum due to cirrhosis. Targeting PDC or PEA reversed the neurological symptoms induced by R. gnavus. Furthermore, fecal microbiota transplantation from patients with HE to germ-free cirrhotic mice replicated these symptoms and further corroborated the efficacy of targeting PDC or PEA. Clinically, high baseline PEA levels were linked to a sevenfold increased risk of HE after intrahepatic portosystemic shunt procedures. Our findings expand the understanding of the gut-liver-brain axis and identify a promising therapeutic and predictive target for HE. 10.1038/s41591-024-03405-9