How the gut microbiota and immune system maintain intestinal homeostasis in concert with the enteric nervous system (ENS) remains incompletely understood. To address this gap, we assessed small intestinal transit, enteric neuronal density, enteric neurogenesis, intestinal microbiota, immune cell populations and cytokines in wildtype and T-cell deficient germ-free mice colonized with specific pathogen-free (SPF) microbiota, conventionally raised SPF and segmented filamentous bacteria (SFB)-monocolonized mice. SPF microbiota increased small intestinal transit in a T cell-dependent manner. SPF microbiota increased neuronal density in the myenteric and submucosal plexuses of the ileum and colon, similar to conventionally raised SPF mice, independently of T cells. SFB increased neuronal density in the ileum in a T cell-dependent manner, but independently of T cells in the colon. SPF microbiota stimulated enteric neurogenesis (Sox2 expression in enteric neurons) in the ileum in a T cell-dependent manner, but in the colon this effect was T cell-independent. T cells regulated nestin expression in the ENS. SPF colonization increased Th17 cells, RORγT+ Treg cells, and IL-1β and IL-17A levels in the ileum and colon. By neutralizing IL-1β and IL-17A, we observed that they control microbiota-mediated enteric neurogenesis but were not involved in the regulation of motility. Together, these findings provide new insights into the microbiota-neuroimmune dialog that regulates intestinal physiology.

Clostridioides difficile is the leading cause of antibiotic-associated diarrhoea worldwide. In the USA, C. difficile infection (CDI) is the eighth leading cause for hospital readmission and seventh for mortality among all gastrointestinal disorders. Gastrointestinal dysmotility and/or diarrhoea occurs after the acute phase of CDI, but persistent gastrointestinal dysfunction post-infection supports contributions of neuroplasticity in the enteric nervous system (ENS), which has a key role in regulating intestinal motility and secretion, in the natural course of CDI. Here, our goal is to provide an up-to-date summary of how the ENS and extrinsic innervation of the gut are affected by CDI and how ENS responses contribute to CDI pathogenesis and outcomes. Enteric neurons and glia are targets of C. difficile toxins in humans and in preclinical model, and changes to the ENS and extrinsic innervation contribute to intestinal inflammation, damage and secretory diarrhoea. These findings suggest possible bidirectional interaction between CDI and the ENS. More studies focusing on understanding how various neurotransmitters and mediators released by the ENS and extrinsic neurons modulate immune responses to CDI could provide insight into novel pharmacological approaches to balance the host response, improve the management of CDI and prevent gastrointestinal dysfunction post-infection.

Intrinsic enteric neurons (iENs) form a crucial neuronal network within the myenteric and submucosal plexus of the gastrointestinal tract, primarily responsible for regulating gut peristalsis. The mechanisms by which iENs sense and integrate dietary and microbial signals to regulate intestinal homeostasis and inflammation remain unclear. Here, we showed that environmental sensor aryl hydrocarbon receptor (AHR) was expressed in different iEN subsets in the ileum and colon and that AHR ligands differentially modulated iEN activity in these regions. Genetic perturbation of Ahr in neurons increased iEN activation in the ileum but, conversely, decreased it in the colon in response to different intestinal pathogens. Furthermore, neuronal AHR deficiency enhanced the clearance of bacterial pathogens, which was associated with increased proliferation and abundance of group 3 innate lymphoid cells in the ileum. Together, our findings demonstrate the region-specific functions of AHR in neurons in response to infections.

Serotonin is one of the most potent gastrointestinal, peripheral, and neuronal signaling molecules and plays a key role in regulating energy metabolism. Accumulating evidence has shown the complex interplay between gut microbiota and host energy metabolism. In this review, we summarize recent findings on the role of gut microbiota in serotonin metabolism and discuss the complicated mechanisms by which serotonin, working in conjunction with the gut microbiota, affects total body energy metabolism in the host. Gut microbiota affects serotonin synthesis, storage, release, transport, and catabolism. In addition, serotonin plays an indispensable role in regulating host energy homeostasis through organ crosstalk and microbe-host communication, particularly with a wide array of serotonergic effects mediated by diverse serotonin receptors with unique tissue specificity. This fresh perspective will help broaden the understanding of serotonergic signaling in modulating energy metabolism, thus shedding light on the design of innovative serotonin-targeting strategies to treat metabolic diseases.

Undernourishment can significantly affect the serotonergic system, potentially increasing the risk of neuropsychiatric disorders such as depression and anxiety. Probiotic therapy has emerged as a potential modulator of the serotonergic system and brain-derived neurotrophic factor (BDNF). Our hypothesis posits that probiotic treatment positively influences the serotonergic system and BDNF levels in the prefrontal cortex (PFC) and hippocampus (HIP), mitigating the effects of malnutrition.

We conducted an experiment using 38 adult isogenic rats, divided into four groups: nourished control (n = 9), undernourished control (n = 9), nourished probiotic (n = 10), and undernourished probiotic (n = 10). The animals experienced undernourishment for 10 days, followed by probiotic supplementation while continuing food restriction for an additional 15 days. On the 25th day of the experiment, we euthanized the animals, microdissected their brains, and extracted samples from the HIP and PFC. We performed immunoblotting analysis to assess the expression levels of the following proteins: BDNF, tryptophan hydroxylase 2 enzyme, and 5-HT1A and 5-HT2C serotonergic receptors.

Our findings revealed the following effects of probiotic administration: tryptophan hydroxylase 2 expression increased in the PFC of nourished rats (P = 0.033) and in the HIP of undernourished rats (P = 0.013); improved 5-HT2C expression was observed in the PFC under both nutritional conditions (P < 0.01). The proBDNF levels were elevated in the HIP of undernourished rats (P = 0.001).

Probiotic administration effectively modulated the gut-microbiota-brain axis by enhancing serotonergic system proteins in the prefrontal cortex and hippocampus of both nourished and undernourished rats.

Gut microbiota not only affects the function of the gastrointestinal tract but also the function of other organs, including the brain. The microbiota-gut-brain axis reflects the constant bidirectional communication between the central nervous system and the gastrointestinal tract. Gut microbiota metabolites can cross brain barriers, the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSF) and influence neuropsychiatric disorders, including depression. In recent years, the communication between the microbiome and brain in depression has been extensively studied in humans and animal models. In this chapter, we summarise the current literature on the role of gut microbiota in depression, focusing in particular on brain barriers and bidirectional gut-brain communication.

The microbiota-gut-brain axis has major implications for human health including gastrointestinal physiology, brain function, and behavior. The immune system represents a key pathway of communication along this axis with the microbiome implicated in neuroinflammation in health and disease. In this review, we discuss the mechanisms as to how the gut microbiota interacts with the brain, focusing on innate and adaptive immunity that are often disrupted in gut-brain axis disorders. We also consider the implications of these observations and how they can be advanced by interdisciplinary research. Leveraging an increased understanding of how these interactions regulate immunity has the potential to usher in a new era of precision neuropsychiatric clinical interventions for psychiatric, neurodevelopmental, and neurological disorders.

Deoxynivalenol (DON) poses a threat to animal and human health, particularly causing damage to the nervous system. Intestinal flora can regulate the nervous system through the gut-brain axis; however, there is currently a lack of evidence on the effect of changing the intestinal flora on the damage to the nervous system caused by DON. Therefore, this study aims to investigate the effect of gut microbiota ablation on neurotoxicity induced by exposure to deoxynivalenol.

One hundred-twenty (120) specific pathogen-free (SPF) male C57BL/6j mice were randomly divided into four groups (control group, microbiota-uncleaned group + 5 mg/kg/BW DON, microbiota-cleared group, and microbiota-cleared group + 5 mg/kg/BW DON). The open field and Morris behavior tests were used to evaluate behavior changes after DON exposure. After 14 days of treatment, the mice were euthanized and brain tissues were collected for further analysis.

The tests showed that DON exposure led to anxiety and decreased learning ability in mice with no gut microbiota ablation. We also observed pathological changes including neuronal shrinkage, degeneration, and cortical edema in the mice with no microbiota ablation after DON exposure. In addition, the protein and mRNA levels of tight junction proteins and anti-inflammatory factors were decreased in the mice with no microbiota ablation after DON exposure compared with mice with ablated microbiota.

We concluded that the presence of microbiota plays a key role in the neurotoxicity induced by DON; thus, ablation of the intestinal microbiota can effectively improve brain damage caused by DON.

Perturbations in the intestinal microbiome are strongly linked to the pathogenesis of inflammatory bowel disease (IBD). Bacteria, fungi and viruses all make up part of a complex multi-kingdom community colonizing the gastrointestinal tract, often referred to as the gut microbiome. They can exert various effects on the host that can contribute to an inflammatory state. Advances in screening, multiomics and experimental approaches have revealed insights into host-microbiota interactions in IBD and have identified numerous mechanisms through which the microbiota and its metabolites can exert a major influence on the gastrointestinal tract. Looking into the future, the microbiome and microbiota-associated processes will be likely to provide unparalleled opportunities for novel diagnostic, therapeutic and diet-inspired solutions for the management of IBD through harnessing rationally designed microbial communities, powerful bacterial and fungal metabolites, individually or in combination, to foster intestinal health. In this Review, we examine the current understanding of the cross-kingdom gut microbiome in IBD, focusing on bacterial and fungal components and metabolites. We examine therapeutic and diagnostic opportunities, the microbial metabolism, immunity, neuroimmunology and microbiome-inspired interventions to link mechanisms of disease and identify novel research and therapeutic opportunities for IBD.

The crisis of metabolic and mental disorders continues to escalate worldwide. A growing body of research highlights the influence of tryptophan and its metabolites, such as serotonin, beyond their traditional roles in neural signaling. Serotonin acts as a key neurotransmitter within the brain-gut-microbiome axis, a critical bidirectional communication network affecting both metabolism and behavior. Emerging evidence suggests that the gut microbiome regulates brain function and behavior, particularly through microbial influences on tryptophan metabolism and the serotonergic system, both of which are essential for normal functioning. Additionally, sex differences exist in multiple aspects of serotonin-mediated modulation within the brain-gut-microbiome axis, affecting feeding and affective behaviors. This review summarizes the current knowledge from human and animal studies on the influence of tryptophan and its metabolite serotonin on metabolic and behavioral regulation involving the brain and gut microbiome, with a focus on sex differences and the role of sex hormones. We speculate that gut-derived tryptophan and serotonin play essential roles in the pathophysiology that modifies neural circuits, potentially contributing to eating and affective disorders. We propose the gut microbiome as an appealing therapeutic target for metabolic and affective disorders, emphasizing the importance of understanding sex differences in metabolic and behavioral regulation influenced by the brain-gut-microbiome axis. The therapeutic targeting of the gut microbiota and its metabolites may offer a viable strategy for treating serotonin-related disorders, such as eating and affective disorders, with potential differences in treatment efficacy between men and women. This review would promote research on sex differences in metabolic and behavioral regulation impacted by the brain-gut-microbiome axis.

The microbiota-gut-brain axis (MGBA) plays a significant role in the maintenance of brain structure and function. The MGBA serves as a conduit between the CNS and the ENS, facilitating communication between the emotional and cognitive centers of the brain via diverse pathways. In the initial stages of this review, we will examine the way how MGBA affects neurogenesis, neuronal dendritic morphology, axonal myelination, microglia structure, brain blood barrier (BBB) structure and permeability, and synaptic structure. Furthermore, we will review the potential mechanistic pathways of neuroplasticity through MGBA influence. The short-chain fatty acids (SCFAs) play a pivotal role in the MGBA, where they can modify the BBB. We will therefore discuss how SCFAs can influence microglia, neuronal, and astrocyte function, as well as their role in brain disorders such as Alzheimer's disease (AD), and Parkinson's disease (PD). Subsequently, we will examine the technical strategies employed to study MGBA interactions, including using germ-free (GF) animals, probiotics, fecal microbiota transplantation (FMT), and antibiotics-induced dysbiosis. Finally, we will examine how particular bacterial strains can affect brain structure and function. By gaining a deeper understanding of the MGBA, it may be possible to facilitate research into microbial-based pharmacological interventions and therapeutic strategies for neurological diseases.

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, which is characterized by inattention, impulsivity and hyperactivity. Although the etiology and pathogenesis of ADHD are not fully understood, existing studies have shown that it may be related to genetic factors, environmental factors, abnormal brain development, and psychosocial factors. In recent years, with the concept of microbioa-gut-brain axis (MGBA), more and more studies have begun to pay attention to the effect of gut microbiota on ADHD. Dietary structure can significantly change the diversity and abundance of gut microbiota. Therefore, dietary supplements or food additives to regulate gut microbiota have become one of the potential ways to treat ADHD. Peppers, as an important dietary component, have potential value in regulating gut microbiota. Among them, capsaicin (8-methyl N-vanillyl-6-noneamide, CAP), as a key active component of peppers, has been shown to have potential therapeutic effects on central nervous system (CNS) diseases such as Parkinson's disease, epilepsy, and depression. In addition, much attention has been paid to the beneficial effects of CAP on gut microbiota. Chili peppers contain not only CAP, but also rich in vitamin C and fatty acids, all of which may ameliorate ADHD by modulating the gut microbiota. This finding not only provides a potential treatment for ADHD, but also provides a new perspective to expand the research and clinical treatment of ADHD pathogenesis. Although current research on the potential therapeutic effects of chili peppers on ADHD is still at an early stage and requires further verification through larger-scale and more rigorous controlled studies, its potential clinical value cannot be ignored.

The gut microbiome is a key partner of animals, influencing various aspects of their physiology and behaviors. Among the diverse behaviors regulated by the gut microbiome, locomotion is vital for survival and reproduction, although the underlying mechanisms remain unclear. Here, we reveal that the gut microbiome modulates the locomotor behavior of Drosophila larvae via a specific neuronal type in the brain. The crawling speed of germ-free (GF) larvae was significantly reduced compared to the conventionally reared larvae, while feeding and excretion behaviors were unaffected. Recolonization with Acetobacter and Lactobacillus can fully and partially rescue the locomotor defects in GF larvae, respectively, probably due to the highest abundance of Acetobacter as a symbiotic bacterium in the larval gut, followed by Lactobacillus. Moreover, the gut microbiome promoted larval locomotion, not by nutrition, but rather by enhancing the brain levels of tyrosine decarboxylase 2 (Tdc2), which is an enzyme that synthesizes octopamine (OA). Overexpression of Tdc2 rescued locomotion ability in GF larvae. These findings together demonstrate that the gut microbiome specifically modulates larval locomotor behavior through the OA signaling pathway, revealing a new mechanism underlying larval locomotion regulated by the gut microbiome.

Intestinal motility disorder is characterised by abnormal intestinal motility function, often resulting in symptoms such as diarrhoea and constipation. Probiotics are increasingly recognised as an effective treatment for gastrointestinal disorders, including intestinal motility disorders. In this study, we used senna extract to induce an animal model of intestinal dysfunction characterised by BDNF downregulation. By assessing relevant indicators of intestinal dyskinesia, we found that Bifidobacterium bifidum CCFM1359 effectively alleviated the dyskinesia. However, this alleviating effect was nullified when a TrkB receptor inhibitor was introduced, suggesting that Bifidobacterium bifidum CCFM1359 operates through the BDNF-TrkB pathway. Further analysis revealed that Bifidobacterium bifidum CCFM1359 likely exerts its beneficial effects by regulating intestinal microecology (increasing the relative abundance of Bifidobacterium bifidum and valeric acid content while decreasing Faecalibacterium and butyric acid content), reducing intestinal inflammation (upregulating the anti-inflammatory factor IL-10 and downregulating pro-inflammatory factors TNF-α and IL-1β), and remodelling intestinal nerves (upregulating S100β and the excitatory neurotransmitter ACh, while downregulating the inhibitory neurotransmitter nNOS). This study provides a theoretical basis for using probiotics to alleviate intestinal motility disorders.

Bidirectional regulation between neurons and immune cells in the intestine governs essential physiological processes, including digestion, metabolism and motility, while also controlling intestinal inflammation and maintaining tissue homeostasis. This review covers recent advances and future research challenges focused on the regulatory molecules and potential therapeutic targets in neuron-immune interactions within the intestine.

Recently identified molecular and cellular pathways have been shown to regulate neuron-immune cell cross talk in the context of maintaining tissue homeostasis, modulating inflammation, and promoting intestinal repair. Additionally, behaviors governed by the central nervous system, including feeding and stress responses, can play key roles in regulating intestinal immunity and inflammation.

This review emphasizes recent progress in understanding the complex interplay between the nervous system and intestinal immune system and outlines future research directions. These advances have the potential to lead to innovative therapies targeting gastrointestinal disorders including inflammatory bowel diseases, allergic responses and cancer.

As a result of a long evolutionary history, serotonin plays a variety of physiological roles, including neurological, cardiovascular, gastrointestinal, and endocrine functions. While many of these activities can be accommodated within the serotoninergic activity, recent findings have revealed an unsuspected role of serotonin in orchestrating host and microbial dialogue at the tryptophan dining table, to the benefit of local and systemic homeostasis. Herein we review the dual role of serotonin at the host-microbe interface and discuss how unraveling the interconnections among the host and microbial pathways of tryptophan degradation may help to accommodate the versatility of serotonin in physiology and pathology.

Glial cells are key players in the regulation of nervous system functioning in both the central and enteric nervous systems. Glial cells are dynamic and respond to environmental cues to modulate their activity. Increasing evidence suggests that these signals include those originating from the gut microbiota, the community of microorganisms, including bacteria, viruses, archaea, and protozoa, that inhabit the gut. The gut microbiota and the brain communicate in a bidirectional manner across multiple signaling pathways and interfaces that together comprise the microbiota-gut-brain axis. Here, we detail the role of glial cells, including astrocytes, microglia, and oligodendrocytes in the central nervous system, and glial cells in the enteric nervous system along this gut-brain axis. We review what is known regarding the modulation of glia by microbial signals, in particular by microbial metabolites which signal to the brain through systemic circulation and via the vagus nerve. In addition, we highlight what is yet to be discovered regarding the role of other gut microbiota signaling pathways in glial cell modulation and the challenges of research in this area.

A malignant tumor is a complex systemic disease involving the nervous system, which regulates nerve signals. Cancer neuroscience is a field that explores the interactions between tumors and the nervous system. The gastrointestinal tract is a typical peripheral organ with abundant neuroregulation and is regulated by the peripheral, enteric, and central nervous systems (PNS, ENS, and CNS, respectively). The physiological functions of the gastrointestinal tract are maintained via complex neuromodulation. Neuroregulatory imbalance is the primary cause of gastrointestinal diseases, including colorectal cancer (CRC). In CRC, there is a direct interaction between the nervous system and tumor cells. Moreover, this tumor-nerve interaction can indirectly regulate the tumor microenvironment, including the microbiota, immunity, and metabolism. In addition to the lower nerve centers, the stress response, emotion, and cognition represented by the higher nerve centers also participate in the occurrence and progression of CRC. Herein, we review some basic knowledge regarding cancer neuroscience and elucidate the mechanism underlying tumor-nerve interactions in CRC.

Tryptophan (Trp) metabolism is linked to health and disease, with indoleamine 2,3-dioxygenase 1 (IDO) being a key enzyme in its breakdown outside the liver. This process produces metabolites that influence metabolic and inflammatory responses. A distinctive feature of the gut is its involvement in three major Trp catabolic pathways: the IDO-driven kynurenine pathway, bacteria-produced indoles, and serotonin. Dysregulation of these pathways is associated with gastrointestinal and chronic inflammatory diseases. Understanding these mechanisms could reveal how gut function affects overall systemic health and disease susceptibility. Here, we review current insights into Trp metabolism, its impact on host physiology and cardiometabolic diseases, and its role in the gut-periphery connection, highlighting its relevance for therapeutic innovation.

The intestinal flora is involved in the maintenance of human health and the development of diseases, and is closely related to the brain. As an essential amino acid, tryptophan (TRP) participates in a variety of physiological functions in the body and affects the growth and health of the human body. TRP catabolites produced by the gut microbiota are important signaling molecules for microbial communities and host-microbe interactions, and play an important role in maintaining health and disease pathogenesis.

The review first demonstrates the evidence of TRP metabolism in stroke and the relationship between gut microbiota and TRP metabolism. Furthermore, the review reveals that food homologous plants (FHP) bioactive compounds have been shown to regulate various metabolic pathways of the gut microbiota, including the biosynthesis of valine, leucine, isoleucine, and vitamin B6 metabolism. The most notable metabolic alteration is in TRP metabolism.

The interaction between gut microbiota and TRP metabolism offers a plausible explanation for the notable bioactivities of FHP in the treatment of ischemic stroke (IS). This review enhances the comprehension of the underlying mechanisms associated with the bioactivity of FHP on IS.

The sedative and hypnotic properties of 5,7,3',4',5'-pentamethoxyflavone (PMF), a monomer extracted from the leaves of Murraya paniculata (L.) Jack, have been reported. However, the role of PMFs in the development of anxiety remains uncertain. An anxiety model was developed using chronic unpredictable mild stimulation (CUMS). Kunming mice were randomly allocated to the following groups: control, CUMS, PMF (50 mg/kg), PMF (100 mg/kg), and diazepam (3 mg/kg). The anxiolytic effects of PMFs were evaluated using elevated plus maze (EPM) test and open field test (OFT). Enzyme-linked immunosorbent assay (ELISA) kits were used to analyze the serum levels of corticosterone (CORT), 5-hydroxytryptamine (5-HT), gamma-aminobutyric acid (GABA), and cyclic adenosine monophosphate (cAMP) in the hippocampus. High-throughput-16S rRNA sequencing was performed to investigate its effect on the composition of the gut microbiota. Subsequently, western blotting was performed to assess the expression of GABAergic synaptic-associated proteins. PMF effectively mitigated CUMS-induced anxiety-like behavior. Further examination revealed that PMF treatment ameliorated dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis and increased 5-HT and GABA levels in the hippocampus. Notably, the ability of PMF to maintain the stability of GABAergic synapses by enhancing the species composition of the gut microbiota and acting on the adenosine a2a receptor (A2AR)/gephyrin/gamma-aminobutyric acid A receptor alpha 2 (GABRA2) pathway revealed a previously unrecognized mechanism for the anxiolytic effect of PMF. These findings suggest that PMF enhances the expression of A2AR, preserves GABAergic synaptic stability, and reduces anxiety by modulating the microbiota composition. Thus, it holds promise as an anxiolytic agent.

Yeast β-glucan (YBG), an indigestible polysaccharide from yeast cell walls, is multifunctional. It plays a pivotal role in regulating gut microbiota (GM) and boosting the immune system, which is central to research on inflammation, cancer, and metabolic diseases. By modulating the GM, YBG exhibits various prebiotic effects, including hypoglycemic, hypolipidemic, and immune-regulating properties. Additionally, acting as a bioreactor modulator, it activates immune responses, demonstrating potential in anti-infection and anticancer applications. This article synthesizes the latest data from in vitro, in vivo, and clinical studies. It comprehensively evaluates the therapeutic potential of YBG, starting from its structure-function relationship. It particularly focuses on the application prospects of yeast β-glucan in probiotic-like effects, anti-infectious properties, and anti-cancer activity, and explores the underlying mechanisms of these actions. The aim of this article is to elucidate the positive impact of YBG on health by modulating the gut microbiota and enhancing immune responses. Simultaneously, it identifies critical areas for future research to provide theoretical support for its development in biomedical applications.

As a multifunctional ecosystem, the human digestive system contains a complex network of microorganisms, collectively known as gut microbiota. This consortium composed of more than 1013 microorganisms and Firmicutes and Bacteroidetes are the dominant microbes. Gut microbiota is increasingly recognized for its critical role in physiological processes beyond digestion. Gut microbiota participates in a symbiotic relationship with the host and takes advantage of intestinal nutrients and mutually participates in the digestion of complex carbohydrates and maintaining intestinal functions.

We reviewed the neuroactive components produced by gut microbiota. Interestingly, microbiota plays a crucial role in regulating the activity of the intestinal lymphatic system, regulation of the intestinal epithelial barrier, and maintaining the tolerance to food immunostimulating molecules. The gut-brain axis is a two-way communication pathway that links the gut microbiota to the central nervous system (CNS) and importantly is involved in neurodevelopment, cognition, emotion and synaptic transmissions. The connections between gut microbiota and CNS are via endocrine system, immune system and vagus nerve.

The gut microbiota produces common neurotransmitters and neuromodulators of the nervous system. These compounds play a role in neuronal functions, immune system regulation, gastrointestinal homeostasis, permeability of the blood brain barrier and other physiological processes. This review investigates the essential aspects of the neurotransmitters and neuromodulators produced by gut microbiota and their implications in health and disease.

It has recently become clear that the gut microbiota influence intestinal motility, intestinal barrier function, and mucosal immune function; therefore, the gut microbiota are deeply involved in the maintenance of intestinal homeostasis. The effects of the gut microbiota on the enteric nervous system (ENS) in the adult intestine, however, remain poorly understood. In the current study, we investigated the effects of the gut microbiota on the ENS. Male C57BL/6 SPF mice at 12 weeks of age were given a cocktail of four antibiotics (ABX) orally to induce dysbiosis (ABX mice). As early as six hours after ABX administration, the weight of the cecum of ABX mice increased to be significantly greater than that of vehicle-treated animals; moreover, ABX-induced dysbiosis reduced the density of enteric nerve fibers (marked by tubulin-β3 immunoreactivity) in the lamina propria of the proximal colon to approximately 60% that of control. TAK242, a TLR4 antagonist, significantly lowered the nerve fiber density in the lamina propria of the proximal colonic mucosa to approximately 60% that of vehicle-treated SPF mice. We thus developed and tested the hypothesis that mucosal glia expressing TLR4 are activated by enteric bacteria and release neurotrophic factors that contribute to the maintenance of enteric neural circuits. Neurotrophic factors in the mucosa of the SPF mouse proximal colon were examined immunohistochemically. Ciliary neurotrophic factor (CNTF) was abundantly expressed in the lamina propria; most of the CNTF immunoreactivity was observed in mucosal glia (marked by S100β immunoreactivity). Administration of CNTF (subcutaneously, 0.3 mg/kg, 3 doses, 2 hours apart) to ABX mice significantly increased mucosal nerve fiber density in the ABX mouse proximal colon to nearly control levels. The effect of CNTF on enteric mucosal nerve fibers was examined in isolated preparations of proximal colon of ABX mice. As it did in vivo, exposure to CNTF in vitro significantly increased enteric mucosal nerve fiber density in the ABX-treated colon. In conclusion, our evidence suggests that gut microbiota constitutively activate TLR4 signaling in enteric mucosal glia, which secrete CNTF in response. The resulting bacterial-driven glial release of CNTF helps to maintain the integrity of enteric mucosal nerve fibers.

Antibiotics are safe, effective drugs and continue to save millions of lives and prevent long-term illness worldwide. A large body of epidemiological, interventional and experimental evidence shows that exposure to antibiotics has long-term negative effects on human health. We reviewed the literature data on the links between antibiotic exposure, gut dysbiosis, and chronic disease (notably with regard to the "developmental origins of health and disease" ("DOHaD") approach). Molecular biology studies show that the systemic administration of antibiotic to infants has a rapid onset but also often a long-lasting impact on the microbial composition of the gut. Along with other environmental factors (e.g., an unhealthy "Western" diet and sedentary behavior), antibiotics induce gut dysbiosis, which can be defined as the disruption of a previously stable, functionally complete microbiota. Gut dysbiosis many harmful long-term effects on health. Associations between early-life exposure to antibiotics have been reported for chronic diseases, including inflammatory bowel disease, celiac disease, some cancers, metabolic diseases (obesity and type 2 diabetes), allergic diseases, autoimmune disorders, atherosclerosis, arthritis, and neurodevelopmental, neurodegenerative and other neurological diseases. In mechanistic terms, gut dysbiosis influences chronic disease through direct effects on mucosal immune and inflammatory pathways, plus a wide array of direct or indirect effects of short-chain fatty acids, the enteric nervous system, peristaltic motility, the production of hormones and neurotransmitters, and the loss of intestinal barrier integrity (notably with leakage of the pro-inflammatory endotoxin lipopolysaccharide into the circulation). To mitigate dysbiosis, the administration of probiotics in patients with chronic disease is often (but not always) associated with positive effects on clinical markers (e.g., disease scores) and biomarkers of inflammation and immune activation. Meta-analyses are complicated by differences in probiotic composition, dose level, and treatment duration, and large, randomized, controlled clinical trials are lacking in many disease areas. In view of the critical importance of deciding whether or not to prescribe antibiotics (especially to children), we suggest that the DOHaD concept can be logically extended to "gastrointestinal origins of health and disease" ("GOHaD") or even "microbiotic origins of health and disease" ("MOHaD").

The Dobbs decision of the United States Supreme Court and the actions of several state legislatures have made it risky, if not outright dangerous, to teach factual material concerning human embryology. At some state universities, for instance, if a professor's lecture is felt to teach or discuss abortion (as it might when teaching about tubal pregnancies, hydatidiform moles, or eneuploidy), that instructor risks imprisonment for up to 14 years (Gyori, 2023). Some states' new censorship rules have thus caused professors to drop modules on abortion from numerous science and humanities courses. In most states, instructors can still teach about human embryonic development and not risk putting their careers or livelihoods in jeopardy. However, even in many of these institutions, students can bring a professor to a disciplinary hearing by claiming that the instructor failed to provide ample trigger warnings on such issues. This essay attempts to provide some strategies wherein human embryology and the ethical issues surrounding it might be taught and students may be given resources to counter unscientific falsehoods about fertilization and human development. This essay provides evidence for teaching the following propositions. Mis-information about human biology and medicine is rampant on the internet, and there are skills that can be taught to students that will help them determine which sites should trusted. This is a skill that needs to be taught as part of science courses.

Major depressive disorder (MDD) is a severe mental health condition characterized by persistent depression, impaired cognition, and reduced activity. Increasing evidence suggests that gut microbiota (GM) imbalance is closely linked to the emergence and advancement of MDD, highlighting the potential significance of regulating the "Microbiota-Gut-Brain" (MGB) axis to impact the development of MDD. Natural products (NPs), characterized by broad biological activities, low toxicity, and multi-target characteristics, offer unique advantages in antidepressant treatment by regulating MGB axis.

This review was aimed to explore the intricate relationship between the GM and the brain, as well as host responses, and investigated the mechanisms underlying the MGB axis in MDD development. It also explored the pharmacological mechanisms by which NPs modulate MGB axis to exert antidepressant effects and addressed current research limitations. Additionally, it proposed new strategies for future preclinical and clinical applications in the MDD domain.

To study the effects and mechanism by which NPs exert antidepressant effects through mediating the MGB axis, data were collected from Web of Science, PubMed, ScienceDirect from initial establishment to March 2024. NPs were classified and summarized by their mechanisms of action.

NPs, such as flavonoids,alkaloids,polysaccharides,saponins, terpenoids, can treat MDD by regulating the MGB axis. Its mechanism includes balancing GM, regulating metabolites and neurotransmitters such as SCAFs, 5-HT, BDNF, inhibiting neuroinflammation, improving neural plasticity, and increasing neurogenesis.

NPs display good antidepressant effects, and have potential value for clinical application in the prevention and treatment of MDD by regulating the MGB axis. However, in-depth study of the mechanisms by which antidepressant medications affect MGB axis will also require considerable effort in clinical and preclinical research, which is essential for the development of effective antidepressant treatments.

Gastrointestinal microbes modulate peristalsis and stimulate the enteric nervous system (ENS), whose development, as in the central nervous system (CNS), continues into the murine postweaning period. Given that adult CNS function depends on stimuli received during critical periods of postnatal development, we hypothesized that adult ENS function, namely motility, depends on microbial stimuli during similar critical periods. We gave fecal microbiota transplantation (FMT) to germ-free mice at weaning or as adults and found that only the mice given FMT at weaning recovered normal transit, while those given FMT as adults showed limited improvements. RNA sequencing (RNA-seq) of colonic muscularis propria revealed enrichments in neuron developmental pathways in mice exposed to gut microbes earlier in life, while mice exposed later-or not at all-showed exaggerated expression of inflammatory pathways. These findings highlight a microbiota-dependent sensitive period in ENS development, pointing to potential roles of the early-life microbiome in later-life dysmotility.

Depression is a global health concern affecting nearly 280 million individuals. It not only imposes a significant burden on economies and healthcare systems but also manifests complex physiological connections and consequences. Agmatine, a putative neuromodulator derived primarily from beneficial gut microbes specially Lactobacillus, has emerged as a potential therapeutic agent for mental health. The microbiota-gut-brain axis is involved in the development of depression through the peripheral nervous system, endocrine system, and immune system and may be a key factor in the effect of agmatine. Therefore, this study aimed to investigate the potential mechanism of agmatine in antibiotic-induced dysbiosis and depression-like behavior in rats, focusing on its modulation of the gut-brain axis. Depression-like behavior associated with dysbiosis was induced through a seven-day regimen of the broad-spectrum antibiotic, comprising ampicillin and metronidazole and validated through microbial, biochemical, and behavioral alterations. On day 8, antibiotic-treated rats exhibited loose fecal consistency, altered fecal microbiota, and depression-like behavior in forced swim test. Pro-inflammatory cytokines were elevated, while agmatine and monoamine levels decreased in the hippocampus and prefrontal cortex. Antibiotic administration disrupted tight junction proteins in the ileum, affecting gut architecture. Oral administration of agmatine alone or combined with probiotics significantly reversed antibiotic-induced dysbiosis, restoring gut microbiota and mitigating depression-like behaviors. This intervention also restored neuro-inflammatory markers, increased agmatine and monoamine levels, and preserved gut integrity. The study highlights the regulatory role of endogenous agmatine in the gut-brain axis in broad-spectrum antibiotic induced dysbiosis and associated depression-like behavior.

Irritable bowel syndrome (IBS) is a condition that significantly impacts the lifestyle, health, and habits of numerous individuals worldwide. Its diagnosis and classification are based on the Rome criteria, updated periodically to reflect new research findings in this field. IBS can be classified into different types based on symptoms, each with distinct treatment approaches and some differences in their pathophysiology. The exact pathological background of IBS remains unclear, with many aspects still unknown. Recent research developments suggest that disorders in the brain-gut-microbiota axis are key contributors to the symptoms and severity of IBS. The central nervous system (CNS) interacts bidirectionally with intestinal processes within the lumen and the intestinal wall, with the autonomic nervous system, particularly the vagus nerve, playing an important role. However, the enteric nervous system (ENS) is also crucial in the pathophysiological pathway of IBS. The apeline-corticotropin-releasing factor (CRF)-toll-like receptor 4 (TLR4) signaling route via enteric glia and serotonin production in enteroendocrine cells at the enteric barrier are among the most well-understood new findings that affect IBS through the ENS. Additionally, the microbiota regulates neuronal signals, modifying enteric function by altering the number of enteric bacteria and other mechanisms. Given the limited therapeutic options currently available, it is essential to identify new treatment targets, with the brain-gut axis, particularly the enteric nervous system, being a promising focus. This study aims to delineate the molecular mechanisms that induce IBS and to suggest potential targets for future research and treatment of this potentially debilitating disease.

Cardiovascular disease (CVD) may be inherited, as recently shown with the identification of single nucleotide polymorphisms (SNPs or "snips") on a 250 kb DNA fragment that encodes 92 proteins associated with CVD. CVD is also triggered by microbial dysbiosis, microbial metabolites, metabolic disorders, and inflammatory intestinal epithelial cells (IECs). The epithelial cellular adhesion molecule (Ep-CAM) and trefoil factor 3 (TFF3) peptide keeps the gut wall intact and healthy. Variations in Ep-CAM levels are directly linked to changes in the gut microbiome. Leptin, plasminogen activator inhibitor 1 (PAI1), and alpha-1 acid glycoprotein 1 (AGP1) are associated with obesity and may be used as biomarkers. Although contactin 1 (CNTN1) is also associated with obesity and adiposity, it regulates the bacterial metabolism of tryptophan (Trp) and thus appetite. A decrease in CNTN1 may serve as an early warning of CVD. Short-chain fatty acids (SCFAs) produced by gut microbiota inhibit pro-inflammatory cytokines and damage vascular integrity. Trimethylamine N-oxide (TMAO), produced by gut microbiota, activates inflammatory Nod-like receptors (NLRs) such as Nod-like receptor protein 3 (NLRP3), which increase platelet formation. Mutations in the elastin gene (ELN) cause supra valvular aortic stenosis (SVAS), defined as the thickening of the arterial wall. Many of the genes expressed by human cells are regulated by gut microbiota. The identification of new molecular markers is crucial for the prevention of CVD and the development of new therapeutic strategies. This review summarizes the causes of CVD and identifies possible CVD markers.

The emerging function of short-chain fatty acids (SCFAs) in Parkinson's disease (PD) has been investigated in this article. SCFAs, which are generated via the fermentation of dietary fiber by gut microbiota, have been associated with dysfunction of the gut-brain axis and, neuroinflammation. These processes are integral to the development of PD. This article examines the potential therapeutic implications of SCFAs in the management of PD, encompassing their capacity to modulate gastrointestinal permeability, neuroinflammation, and neuronal survival, by conducting an extensive literature review. As a whole, this article emphasizes the potential therapeutic utility of SCFAs as targets for the management and treatment of PD.

Neurodegenerative diseases are global health challenges characterized by the progressive degeneration of nerve cells, leading to cognitive and motor impairments. The brain-gut-bone axis, a complex network that modulates multiple physiological systems, has gained increasing attention owing to its profound effects on the occurrence and development of neurodegenerative diseases. No comprehensive review has been conducted to clarify the triangular relationship involving the brain-gut-bone axis and its potential for innovative therapies for neurodegenerative disorders. In light of this, a new perspective is aimed to propose on the interplay between the brain, gut, and bone systems, highlighting the potential of their dynamic communication in neurodegenerative diseases, as they modulate multiple physiological systems, including the nervous, immune, endocrine, and metabolic systems. Therapeutic strategies for maintaining the balance of the axis, including brain health regulation, intestinal microbiota regulation, and improving skeletal health, are also explored. The intricate physiological interactions within the brain-gut-bone axis pose a challenge in the development of effective treatments that can comprehensively target this system. Furthermore, the safety of these treatments requires further evaluation. This review offers a novel insights and strategies for the prevention and treatment of neurodegenerative diseases, which have important implications for clinical practice and patient well-being.

Neurotransmitters, including 5-hydroxytryptamine (5-HT), dopamine (DA), gamma-aminobutyric acid (GABA), and glutamate, are essential transductors in the Gut-Brain Axis (GBA), playing critical roles both peripherally and centrally. Accumulating evidence suggests that the gut microbiota modulates intestinal neurotransmitter metabolism and gut-to-brain signaling, shedding light on the crucial role of the gut microbiota in brain function and the pathogenesis of various neuropsychiatric diseases, such as major depression disorder (MDD), anxiety, addiction and Parkinson's disease (PD). Despite the exciting findings, the mechanisms underlying the modulation of neurotransmitter metabolism and function by the gut microbiota are still being elucidated. In this review, we aim to provide a comprehensive overview of the existing knowledge about the role of the gut microbiota in neurotransmitter metabolism and function in animal and clinical experiments. Moreover, we will discuss the potential mechanisms through which gut microbiota-derived neurotransmitters contribute to the pathogenesis of neuropsychiatric diseases, thus highlighting a novel therapeutic target for these conditions.

This cross-sectional study aims to analyze the differences in gut flora between patients with epilepsy with and without cognitive impairment and normal subjects.

One hundred patients with epilepsy who came to our hospital from 2020.12 to 2022.12 (epilepsy group) were selected, and another 100 family members of the patients were selected as the control group (control group). Patients with epilepsy were further classified by the MMSE scale into 62 patients with combined cognitive impairment (Yes group) and 38 patients without cognitive impairment (No group). Detection of gut flora in feces by 16 S rRNA high-throughput sequencing. Logistic regression was used to analyze risk factors for cognitive dysfunction in patients with epilepsy.

There were more significant differences in the structure and composition of the gut flora between patients in the epilepsy group and the control group, but no significant differences in diversity analysis (P > 0.05). Actinobacteriota, Faecalibacterium and Collinsella were significantly lower in the Yes group than in the No group (P < 0.05), and the Alpha diversity index was numerically slightly smaller than in the No group, with the PCoA analysis demonstrating a more dispersed situation in both groups. Five metabolic pathways, including glycolysis and heterolactic fermentation, were upregulated in the Yes group. LEfSe analysis showed that five groups of bacteria, including Coriobacteriaceae and Collinsella, were selected as marker species for the presence or absence of comorbid cognitive impairment. Of these, Collinsella, Oscillospirales, and Ruminococcaceae have a greater impact on epilepsy combined with cognitive impairment.

There was an imbalance in the gut flora of patients with epilepsy compared to healthy controls. The gut flora of patients with epilepsy with cognitive dysfunction differs significantly from that of patients without cognitive dysfunction. Collinsella, Oscillospirales, and Ruminococcaceae have a greater impact on epilepsy with cognitive dysfunction and can be used as an indicator for the observation of epilepsy with cognitive dysfunction.

The human microbiome is a complex and dynamic system that plays important roles in human health and disease. However, there remain limitations and theoretical gaps in our current understanding of the intricate relationship between microbes and humans. In this narrative review, we integrate the knowledge and insights from various fields, including anatomy, physiology, immunology, histology, genetics, and evolution, to propose a systematic framework. It introduces key concepts such as the 'innate and adaptive genomes', which enhance genetic and evolutionary comprehension of the human genome. The 'germ-free syndrome' challenges the traditional 'microbes as pathogens' view, advocating for the necessity of microbes for health. The 'slave tissue' concept underscores the symbiotic intricacies between human tissues and their microbial counterparts, highlighting the dynamic health implications of microbial interactions. 'Acquired microbial immunity' positions the microbiome as an adjunct to human immune systems, providing a rationale for probiotic therapies and prudent antibiotic use. The 'homeostatic reprogramming hypothesis' integrates the microbiome into the internal environment theory, potentially explaining the change in homeostatic indicators post-industrialization. The 'cell-microbe co-ecology model' elucidates the symbiotic regulation affecting cellular balance, while the 'meta-host model' broadens the host definition to include symbiotic microbes. The 'health-illness conversion model' encapsulates the innate and adaptive genomes' interplay and dysbiosis patterns. The aim here is to provide a more focused and coherent understanding of microbiome and highlight future research avenues that could lead to a more effective and efficient healthcare system.

The traditional Chinese medicine (TCM) Xiaoer-Feire-Qing granules (XEFRQ) has been used to treat pyretic pulmonary syndrome (PPS) in children for many years. The function of the lungs is considered to be closely related to the large intestine in TCM.

We aimed to investigate the effects of XEFRQ on PPS and the underlying mechanisms via network pharmacology and animal experiments.

The TCMSP platform was used to identify the ingredients and potential targets of XEFRQ. The GeneCards, OMIM, and TTD databases were used to predict PPS-associated targets. Cytoscape 3.9.1 was employed to construct the protein-protein interaction network, and target prediction was performed by GO and KEGG analyses. For the animal experiment, a PPS model was constructed by three cycles of nasal drip of Streptococcus pneumoniae (STP; 0.5 mL/kg). The animals were randomly divided into the following four groups according to their weight (n = 10 rats per group): the blank group, the model group, the XEFRQ-L (16.3 g/kg) group, and the XEFRQ-H (56.6 g/kg) group. Rats in the blank group and the model group were given 0.5% CMC-Na by gavage. The general conditions of the rats were observed, and their food-intake, body weight, and body temperature were recorded for 14 days. After the intervention of 14 days, serum was collected to detect inflammatory cytokines (TNF-α, IL-1β, and PGE2) and neurotransmitters (5-HT, SP, and VIP). H&E staining was used to observe the pathological morphology of lung and colon tissue. AQP3 expression was detected by Western blot. In addition, the gut microbiota in cecal content samples were analyzed by 16S rDNA high-throughput sequencing.

Our network analysis revealed that XEFRQ may alleviate PPS injury by affecting the levels of inflammatory cytokines and neurotransmitters and mitigating STP-induced PPS.In vivo validation experiments revealed that XEFRQ improved STP-induced PPS and reduced the expression of inflammatory cytokines and neurotransmitters. Notably, XEFRQ significantly decreased the protein expression levels of AQP3, which was associated with dry stool. Our gut microbiota analysis revealed that the relative abundance of [Eubacterium]_ruminantium_group, Colidextribacter, Romboutsia, and Oscillibacter was decreased, which means XEFRQ exerts therapeutic effects against PPS associated with these bacteria.

Our results demonstrate that XEFRQ alleviates PPS by affecting the lungs and intestines, further guiding its clinical application.

Every facet of biological anthropology, including development, ageing, diseases, and even health maintenance, is influenced by gut microbiota's significant genetic and metabolic capabilities. With current advancements in sequencing technology and with new culture-independent approaches, researchers can surpass older correlative studies and develop mechanism-based studies on microbiome-host interactions. The microbiota-gut-brain axis (MGBA) regulates glial functioning, making it a possible target for the improvement of development and advancement of treatments for neurodegenerative diseases (NDDs). The gut-brain axis (GBA) is accountable for the reciprocal communication between the gastrointestinal and central nervous system, which plays an essential role in the regulation of physiological processes like controlling hunger, metabolism, and various gastrointestinal functions. Lately, studies have discovered the function of the gut microbiome for brain health-different microbiota through different pathways such as immunological, neurological and metabolic pathways. Additionally, we review the involvement of the neurotransmitters and the gut hormones related to gut microbiota. We also explore the MGBA in neurodegenerative disorders by focusing on metabolites. Further, targeting the blood-brain barrier (BBB), intestinal barrier, meninges, and peripheral immune system is investigated. Lastly, we discuss the therapeutics approach and evaluate the pre-clinical and clinical trial data regarding using prebiotics, probiotics, paraprobiotics, fecal microbiota transplantation, personalised medicine, and natural food bioactive in NDDs. A comprehensive study of the GBA will felicitate the creation of efficient therapeutic approaches for treating different NDDs.

Spinal cord injury (SCI) results in numerous systemic dysfunctions, including intestinal dysmotility and enteric nervous system (ENS) atrophy. The ENS has capacity to recover following perturbation, yet intestinal pathologies persist. With emerging evidence demonstrating SCI-induced alterations to gut microbiome composition, we hypothesized that microbiome modulation contributes to post-injury enteric recovery. Here, we show that intervention with the dietary fiber, inulin, prevents SCI-induced ENS atrophy and dysmotility in mice. While SCI-associated microbiomes and specific injury-sensitive gut microbes are not sufficient to modulate intestinal dysmotility after injury, intervention with microbially-derived short-chain fatty acid (SCFA) metabolites prevents ENS dysfunctions in injured mice. Notably, inulin-mediated resilience is dependent on IL-10 signaling, highlighting a critical diet-microbiome-immune axis that promotes ENS resilience post-injury. Overall, we demonstrate that diet and microbially-derived signals distinctly impact ENS survival after traumatic spinal injury and represent a foundation to uncover etiological mechanisms and future therapeutics for SCI-induced neurogenic bowel.

The study of the brain-gut axis and its impact on cognitive function and in the development of neurodegenerative diseases is a very timely topic of interest to researchers. This review summarizes information on the basic mechanisms of gut-brain communication. We then discuss the roles of the gut microbiome as a neuroprotective factor in neurodegeneration. The gut microbiota is extremely important in maintaining the body's homeostasis, shaping the human immune system and the proper functioning of the brain. The intestinal microflora affects the processes of neuroplasticity, synaptogenesis, and neuronal regeneration. This review aims to explain changes in the composition of the bacterial population of the intestinal microflora among patients with Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Abnormalities in gut microflora composition are also noted in stress, depression, or autism spectrum development. New observations on psychobiotic supplementation in alleviating the symptoms of neurodegenerative diseases are also presented.

Portal vein tumor thrombus (PVTT) is a major risk factor of recurrence of hepatocellular carcinoma (HCC) after hepatectomy. Whether postoperative adjuvant immunotherapy and molecular targeted therapy (I-O and MTT) is effective in reducing the risk of recurrence of HCC with minimal portal invasion after hepatectomy and improving prognosis is unknown.

We collected the data of HCC with Vp1 or Vp2 PVTT patients who underwent hepatectomy at our center between January 2019 and June 2022 from the hospital database. We utilized propensity score matching (PSM) to establish a 1:1 match between the postoperative group treated with I-O and MTT and the postoperative group without I-O and MTT. To compare the recurrence-free survival (RFS) and overall survival (OS) between the two groups, we employed the Kaplan-Meier method. Additionally, we conducted Cox regression analysis to identify the prognostic factors that influence patient prognosis. To account for different high-risk factors, subgroup analyses were carried out.

Among the 189 patients included in the study, 42 patients received postoperative adjuvant I-O and MTT. After PSM, the 1, 2-years RFS were 59.2%, 21.3% respectively in the I-O and MTT group and 40.8%, 9.6% respectively in the non-I-O and MTT group. The median RFS was 13.2 months for the I-O and MTT group better than 7.0 months for the non-I-O and MTT group (P = 0.028). 1, 2-years OS were 89.8%, 65.8% respectively in the I-O and MTT group and 42.4%, 27.7% respectively in the non-I-O and MTT group. The median OS was 23.5 months for the I-O and MTT group better than 17.2 months for the non-I-O and MTT group (P = 0.027). Multivariate analysis showed that postoperative adjuvant I-O and MTT was a prognostic protective factor associated with OS and RFS. The most frequent AE observed in this study was pruritus, and rare AEs included decreased platelet, hypothyroidism, proteinuria, myocarditis and hypoadrenocorticism. The incidence of GRADE ≥3 AE with no deaths recorded.

The study suggested that postoperative adjuvant I-O and MTT strategy was beneficial to improve the prognosis of HCC patients with PVTT patients, while the therapy was safe and reliable.

The gastrointestinal (GI) tract, home to the largest microbial population in the human body, plays a crucial role in overall health through various mechanisms. Recent advancements in research have revealed the potential implications of gut-brain and vice-versa communication mediated by gut-microbiota and their microbial products in various diseases including type-2 diabetes and Alzheimer's disease (AD). AD is the most common type of dementia where most of cases are sporadic with no clearly identified cause. However, multiple factors are implicated in the progression of sporadic AD which can be classified as non-modifiable (e.g., genetic) and modifiable (e.g. Type-2 diabetes, diet etc.). Present review focusses on key players particularly the modifiable factors such as Type-2 diabetes (T2D) and diet and their implications in microbiota-gut-brain (MGB) and brain-gut (BG) communication and cognitive functions of healthy brain and their dysfunction in Alzheimer's Disease. Special emphasis has been given on elucidation of the mechanistic aspects of the impact of diet on gut-microbiota and the implications of some of the gut-microbial products in T2D and AD pathology. For example, mechanistically, HFD induces gut dysbiosis with driven metabolites that in turn cause loss of integrity of intestinal barrier with concomitant colonic and systemic chronic low-grade inflammation, associated with obesity and T2D. HFD-induced obesity and T2D parallel neuroinflammation, deposition of Amyloid β (Aβ), and ultimately cognitive impairment. The review also provides a new perspective of the impact of diet on brain-gut and microbiota-gut-brain communication in terms of transcription factors as a commonly spoken language that may facilitates the interaction between gut and brain of obese diabetic patients who are at a higher risk of developing cognitive impairment and AD. Other commonality such as tyrosine kinase expression and functions maintaining intestinal integrity on one hand and the phagocytic clarence by migratory microglial functions in brain are also discussed. Lastly, the characterization of the key players future research that might shed lights on novel potential pharmacological target to impede AD progression are also discussed.