Gut microbial regulation of innate and adaptive immunity after traumatic brain injury

Acute care management of traumatic brain injury is focused on the prevention and reduction of secondary insults such as hypotension,hypoxia,intracranial hypertension,and detrimental inflammation.However,the imperative to balance multiple clinical concerns simultaneously often results in therapeutic strategies targeted to address one clinical concern causing unintended effects in other remote organ systems.Recently the bidirectional communication between the gastrointestinal tract and the brain has been shown to influence both the central nervous system and gastrointestinal tract homeostasis in health and disease.A critical component of this axis is the microorganisms of the gut known as the gut microbiome.Changes in gut microbial populations in the setting of central nervous system disease,including traumatic brain injury,have been reported in both humans and experimental animal models and can be further disrupted by off-target effects of patient care.In this review article,we will explore the important role gut microbial populations play in regulating brain-resident and peripheral immune cell responses after traumatic brain injury.We will discuss the role of bacterial metabolites in gut microbial regulation of neuroinflammation and their potential as an avenue for therapeutic intervention in the setting of traumatic brain injury.

Antihypertensive effects of whey protein hydrolysate involve reshaping the gut microbiome in spontaneously hypertension rats

Novel angiotensin-converting enzyme(ACE)inhibitory peptides were identified from whey protein hydrolysates(WPH)in vitro in our previous study and the antihypertensive abilities of WPH in vivo were further investigated in the current study.Results indicated that WPH significantly inhibited the development of high blood pressure and tissue injuries caused by hypertension.WPH inhibited ACE activity(20.81%,P<0.01),and reduced renin concentration(P<0.05),thereby reducing systolic blood pressure(SBP)(12.63%,P<0.05)in spontaneously hypertensive rats.The increased Akkermansia,Bacteroides,and Lactobacillus abundance promoted high short chain fatty acid content in feces after WPH intervention.These changes jointly contributed to low blood pressure.The heart weight and cardiomyocyte injuries(hypertrophy and degeneration)were alleviated by WPH.The proteomic results revealed that 19 protein expressions in the heart mainly associated with the wingless/integrated(Wnt)signaling pathway and Apelin signaling pathway were altered after WPH supplementation.Notably,WPH alleviated serum oxidative stress,indicated by the decreased malondialdehyde content(P<0.01),enhanced total antioxidant capacity(P<0.01)and superoxide dismutase activity(P<0.01).The current study suggests that WPH exhibit promising antihypertensive abilities in vivo and could be a potential alternative for antihypertensive dietary supplements.

Dynamic gut microbiome-metabolome in cationic bovine serum albumin induced experimental immune-complex glomerulonephritis and effect of losartan and mycophenolate mofetil on microbiota modulation

Dynamic changes in gut dysbiosis and metabolomic dysregulation are associated with immune-complex glomerulonephritis(ICGN).However,an in-depth study on this topic is currently lacking.Herein,we report an ICGN model to address this gap.ICGN was induced via the intravenous injection of cationized bovine serum albumin(c-BSA)into Sprague-Dawley(SD)rats for two weeks,after which mycophenolate mofetil(MMF)and losartan were administered orally.Two and six weeks after ICGN establishment,fecal samples were collected and 16S ribosomal DNA(rDNA)sequencing and untargeted metabolomic were conducted.Fecal microbiota transplantation(FMT)was conducted to determine whether gut normali-zation caused by MMF and losartan contributed to their renal protective effects.A gradual decline in microbial diversity and richness was accompanied by a loss of renal function.Approximately 18 genera were found to have significantly different relative abundances between the early and later stages,and Marvinbryantia and Allobaculum were markedly upregulated in both stages.Untargeted metabolomics indicated that the tryptophan metabolism was enhanced in ICGN,characterized by the overproduction of indole and kynurenic acid,while the serotonin pathway was reduced.Administration of losartan and MMF ameliorated microbial dysbiosis and reduced the accumulation of indoxyl conjugates in feces.FMT using feces from animals administered MMF and losartan improved gut dysbiosis by decreasing the Firmicutes/Bacteroidetes(F/B)ratio but did not improve renal function.These findings indicate that ICGN induces serous gut dysbiosis,wherein an altered tryptophan metabolism may contribute to its pro-gression.MMF and losartan significantly reversed the gut microbial and metabolomic dysbiosis,which partially contributed to their renoprotective effects.

Lactobacillus from fermented bamboo shoots prevents inflammation in DSS-induced colitis mice via modulating gut microbiome and serum metabolites

Fermented bamboo shoots(FBS)is a region-specific food widely consumed in Southwestern China,with Lactobacillus as the predominant fermenting bacteria.However,the probiotic potential of Lactobacillus derived from FBS reminds largely unexplored,especially for diseases with a low prevalence in areas consuming FBS,namely,inflammatory bowel disease.In this study,Lactiplantibacillus pentosus YQ001 and Lentilactobacillus senioris YQ005 were screening by in vitro probiotic tests to further investigate the probioticlike bioactivity in dextran sulfate sodium(DSS)-induced ulcerative colitis(UC)mouse.They exhibited more positive probiotic effects than Lactobacillus rhamnosus GG in preventing intestinal inflammatory response.The results revealed that both strains improved the abundance of deficient intestinal microbiota in UC mice,including Muribaculaceae and Akkermansia.In the serum metabolome,they modulated the DSS-disturbed levels of metabolites,with significant increment of cinnamic acid.Meanwhile,they reduced the expression levels of interleukin-1β(IL-1β),interleukin-6(IL-6)inflammatory factors and increased zonula occludens-1(ZO-1),Occludin,and cathelicidin-related antimicrobial peptide(CRAMP)in the colon.Consequently,these results demonstrated that Lactobacillus spp.isolates derived from FBS showed promising probiotic activity based on the gut microbiome homeostasis modulation,anti-inflammation and intestinal barrier protection in UC mice.

Distinct gut microbiomes in Thai patients with colorectal polyps

BACKGROUND Colorectal polyps that develop via the conventional adenoma-carcinoma sequence[e.g.,tubular adenoma(TA)]often progress to malignancy and are closely associated with changes in the composition of the gut microbiome.There is limited research concerning the microbial functions and gut microbiomes associated with colorectal polyps that arise through the serrated polyp pathway,such as hyperplastic polyps(HP).Exploration of microbiome alterations asso-ciated with HP and TA would improve the understanding of mechanisms by which specific microbes and their metabolic pathways contribute to colorectal carcinogenesis.AIM To investigate gut microbiome signatures,microbial associations,and microbial functions in HP and TA patients.METHODS Full-length 16S rRNA sequencing was used to characterize the gut microbiome in stool samples from control participants without polyps[control group(CT),n=40],patients with HP(n=52),and patients with TA(n=60).Significant differences in gut microbiome composition and functional mechanisms were identified between the CT group and patients with HP or TA.Analytical techniques in this study included differential abundance analysis,co-occurrence network analysis,and differential pathway analysis.RESULTS Colorectal cancer(CRC)-associated bacteria,including Streptococcus gallolyticus(S.gallolyticus),Bacteroides fragilis,and Clostridium symbiosum,were identified as characteristic microbial species in TA patients.Mediterraneibacter gnavus,associated with dysbiosis and gastrointestinal diseases,was significantly differentially abundant in the HP and TA groups.Functional pathway analysis revealed that HP patients exhibited enrichment in the sulfur oxidation pathway exclusively,whereas TA patients showed dominance in pathways related to secondary metabolite biosynthesis(e.g.,mevalonate);S.gallolyticus was a major contributor.Co-occurrence network and dynamic network analyses revealed co-occurrence of dysbiosis-associated bacteria in HP patients,whereas TA patients exhibited co-occurrence of CRC-associated bacteria.Furthermore,the co-occurrence of SCFA-producing bacteria was lower in TA patients than HP patients.CONCLUSION This study revealed distinct gut microbiome signatures associated with pathways of colorectal polyp development,providing insights concerning the roles of microbial species,functional pathways,and microbial interactions in colorectal carcinogenesis.

Metabolic syndrome’s new therapy:Supplement the gut microbiome

This letter to the editor discusses the publication on gut microbiome supple-mentation as therapy for metabolic syndrome.Gut microbiome dysbiosis disrupts intestinal bacterial homeostasis and is related to chronic inflammation,insulin resistance,cardiovascular diseases,type 2 diabetes mellitus,and obesity.Previous research has found that increasing the abundance of beneficial microbiota in the gut modulates metabolic syndrome by reducing chronic inflammation and insulin resistance.Prebiotics,probiotics,synbiotics,and postbiotics are often used as supplements to increase the number of beneficial microbes and thus the produc-tion of short-chain fatty acids,which have positive effects on the gut microbiome and metabolic syndrome.In this review article,the author summarizes the available supplements to increase the abundance of beneficial gut microbiota and reduce the abundance of harmful microbiota in patients with metabolic disorders.Our group is also researching the role of the gut microbiota in chronic liver disease.This article will be of great help to our research.At the end of the letter,the mechanism of the gut microbiota in chronic liver disease is discussed.

Update on the gut microbiome in health and diseases

The Human Microbiome Project,Earth Microbiome Project,and next-generation sequencing have advanced novel genome association,host genetic linkages,and pathogen identification.The microbiome is the sum of the microbes,their genetic information,and their ecological niche.This study will describe how millions of bacteria in the gut affect the human body in health and disease.The gut microbiome changes in relation with age,with an increase in Bacteroidetes and Firmicutes.Host and environmental factors affecting the gut microbiome are diet,drugs,age,smoking,exercise,and host genetics.In addition,changes in the gut microbiome may affect the local gut immune system and systemic immune system.In this study,we discuss how the microbiome may affect the metabolism of healthy subjects or may affect the pathogenesis of metabolism-generating metabolic diseases.Due to the high number of publications on the argument,from a methodologically point of view,we decided to select the best papers published in referred journals in the last 3 years.Then we selected the previously published papers.The major goals of our study were to elucidate which microbiome and by which pathways are related to healthy and disease conditions.

The Effect of Macronutrient Restrictions on Gut Microbiome and Biochemical Parameters of Wistar Albino Rats

Macronutrients serve as a source of energy for both gut microbiota and its host. An increase or decrease in macronutrients can either increase or decrease the composition of gut microbiota, leading to gut dysbiosis which has been implicated in many diseases state including non-communicable diseases. To achieve this, seven diets were formulated by restricting 60% of each macronutrient. These diets were fed on 42 albino rats (Wistar), divided into 7 groups of 6 rats each. Group 1 was fed on a normal laboratory chow diet (ND), group 2 received a fat-restricted diet (FRD), group 3 received a protein-restricted diet, (PFD), group 4 received a carbohydrate-restricted diet (CRD), group 5 received a protein and fat-restricted diet (PFRD), group 6 re-ceived a carbohydrate and fat-restricted diet (CFRD) and group 7 received a carbohydrate and protein-restricted diet (CPRD). Feed and water intake were given ad libitum and daily weight and food intake were recorded. The experiment went on for 4 weeks after which animals were sacrificed and intestinal content and blood were collected for analysis (gut microbial composition, glucose, insulin levels, serum lipid, and enzyme). Compared to the control group results showed a decrease in Bacteroides (40.50 - 14.00 CFU), HDL (68.20 - 40.40 mg/dl), and AST (66.62 - 64.74 U/L) in FRD. An increase in AST (66.6 - 69.43 U/L), Bifidobacterial (59.50 - 92.00 CFU) and decreased Bacteroides (40.5 - 19.5 CFU) for PRD was also recorded. CRD reduced Lactobacillus (73 - 33.5 CFU), total bacterial count (129 - 48 CFU), HDL (68.2 - 30.8 mg/dl), and cholesterol (121.44 - 88.65 mg/dl) whereas intestinal composition of E. coli (30.5 - 51.5 CFU) increased. PFRD increased Lactobacillus (73.00 - 102.5 CFU), Bifidobacterial (59.5 - 100 CFU), HDL (68.2 - 74.7 mg/dl), and Triglyceride (111.67 - 146.67 mg/dl) concentration. Meanwhile, a reduction in Bifidobacterial (59.5 - 41.5 CFU), and an increasing of AST (66.62 - 70.30 U/l) were recorded for CFRD. However, Bacteroides (40.5 69.5 CFU), LDL (30.95 - 41.98 mg/dl) increased and Bifidobacterial (59.5 - 38.00 CFU) and HDL (68.2 - 53.5 mg/dl) decreased for CPRD. This work, therefore, concludes that macronutrient restriction causes significant changes in serum marker and enzyme profile, and gut microbial composition which can cause gut dysbiosis and later on could expose the host to inflammatory diseases in the long run.

Exploring the relationship between gut microbial ecology and inflammatory disease:An insight into health and immune function

The immune system,host brain development,and general metabolism are all influenced by the gut bacteria.Bacteria make up the majority of the gut microbiota in mammals.The mouse has been the most often used animal model in preclinical biological research.In mice,Firmicutes and Clostridiales are prominent.On the other hand,Bacteroidaceae,Prevotellaceae,and Firmicutes are commonly found in humans.In this review,we performed a detailed study by focusing on a comparison between human and murine gut microbiomes,role of the microbiome and their secreted metabolites in regulating gut immunity to maintain homeostasis,and changes in the microbial composition in the dysbiotic state.

Gut microbiome in alcohol use disorder:Implications for health outcomes and therapeutic strategies-a literature review

Alcohol use disorder(AUD)represents a major public health issue which affects millions of people globally and consist a chronic relapsing condition associated with substantial morbidity and mortality.The gut microbiome plays a crucial role in maintaining overall health and has emerged as a significant contributor to the pathophysiology of various psychiatric disorders.Recent evidence suggests that the gut microbiome is intimately linked to the development and progression of AUD,with alcohol consumption directly impacting its composition and function.This review article aims to explore the intricate relationship between the gut microbiome and AUD,focusing on the implications for mental health outcomes and potential therapeutic strategies.We discuss the bidirectional communication between the gut microbiome and the brain,highlighting the role of microbiotaderived metabolites in neuroinflammation,neurotransmission,and mood regulation.Furthermore,we examine the influence of AUD-related factors,such as alcohol-induced gut dysbiosis and increased intestinal permeability,on mental health outcomes.Finally,we explore emerging therapeutic avenues targeting the gut microbiome in the management of AUD,including prebiotics,probiotics,and fecal microbiota transplantation.Understanding the complex interplay between the gut microbiome and AUD holds promise for developing novel interventions that could improve mental health outcomes in individuals with AUD.

Colonization and development of the gut microbiome in calves

Colonization and development of the gut microbiome are crucial for the growth and health of calves.In this review,we summarized the colonization,beneficial nutrition,immune function of gut microbiota,function of the gut barrier,and the evolution of core microbiota in the gut of calves of different ages.Homeostasis of gut microbiome is beneficial for nutritional and immune system development of calves.Disruption of the gut microbiome leads to digestive diseases in calves,such as diarrhea and intestinal inflammation.Microbiota already exists in the gut of calf fetuses,and the colonization of microbiota continues to change dynamically under the influence of various factors,which include probiotics,diet,age,and genotype.Colonization depends on the interaction between the gut microbiota and the immune system of calves.The abundance and diversity of these commensal microbiota stabilize and play a critical role in the health of calves.

Impact of gut microbiome in the development and treatment of pancreatic cancer:Newer insights

The gut microbiome plays an important role in the variation of pharmacologic response.This aspect is especially important in the era of precision medicine,where understanding how and to what extent the gut microbiome interacts with drugs and their actions will be key to individualizing therapy.The impact of the composition of the gut microbiome on the efficacy of newer cancer therapies such as immune checkpoint inhibitors and chimeric antigen receptor T-cell treatment has become an active area of research.Pancreatic adenocarcinoma(PAC)has a poor prognosis even in those with potentially resectable disease,and treatment options are very limited.Newer studies have concluded that there is a synergistic effect for immunotherapy in combination with cytotoxic drugs,in the treatment of PAC.A variety of commensal microbiota can affect the efficacy of conventional chemotherapy and immunotherapy by modulating the tumor microenvironment in the treatment of PAC.This review will provide newer insights on the impact that alterations made in the gut microbial system have in the development and treatment of PAC.

Gut microbiome therapeutic modulation to alleviate drug-induced hepatic damage in COVID-19 patients

Coronavirus disease 2019(COVID-19)infection caused by the severe acute respiratory syndrome coronavirus 2 virus,its symptoms,treatment,and post-COVID-19 effects have been a major focus of research since 2020.In addition to respiratory symptoms,different clinical variants of the virus have been associated with dynamic symptoms and multiorgan diseases,including liver abnormalities.The release of cytokines by the activation of innate immune cells during viral infection and the high doses of drugs used for COVID-19 treatment are considered major drivers of liver injury in COVID-19 patients.The degree of hepatic inflammation in patients suffering from chronic liver disease and having COVID-19 could be severe and can be estimated through different liver chemistry abnormality markers.Gut microbiota influences liver chemistry through its metabolites.Gut dysbiosis during COVID-19 treatment can promote liver inflammation.Here,we highlighted the bidirectional association of liver physiology and gut microbiota(gut-liver axis)and its potential to manipulate drug-induced chemical abnormalities in the livers of COVID-19 patients.

Maintenance of gut microbiome stability for optimum intestinal health in pigs——a review

Pigs are exposed to various challenges such as weaning,environmental stressors,unhealthy diet,diseases and infections during their lifetime which adversely affects the gut microbiome.The inability of the pig microbiome to return to the pre-challenge baseline may lead to dysbiosis resulting in the outbreak of diseases.Therefore,the maintenance of gut microbiome diversity,robustness and stability has been influential for optimum intestinal health after perturbations.Nowadays human and animal researches have focused on more holistic approaches to obtain a robust gut microbiota that provides protection against pathogens and improves the digestive physiology and the immune system.In this review,we present an overview of the swine gut microbiota,factors affecting the gut microbiome and the importance of microbial stability in promoting optimal intestinal health.Additionally,we discussed the current understanding of nutritional interventions using fibers and pre/probiotics supplementation as non-antibiotic alternatives to maintain microbiota resilience to replace diminished species.

Emerging role of the gut microbiome in post-infectious irritable bowel syndrome:A literature review

Post-infectious irritable bowel syndrome(PI-IBS)is a particular type of IBS,with symptom onset after an acute episode of infectious gastroenteritis.Despite infectious disease resolution and clearance of the inciting pathogen agent,10%of patients will develop PI-IBS.In susceptible individuals,the exposure to pathogenic organisms leads to a marked shift in the gut microbiota with prolonged changes in host-microbiota interactions.These changes can affect the gut-brain axis and the visceral sensitivity,disrupting the intestinal barrier,altering neuromuscular function,triggering persistent low inflammation,and sustaining the onset of IBS symptoms.There is no specific treatment strategy for PI-IBS.Different drug classes can be used to treat PI-IBS similar to patients with IBS in general,guided by their clinical symptoms.This review summarizes the current evidence for microbial dysbiosis in PI-IBS and analyzes the available data regarding the role of the microbiome in mediating the central and peripheral dysfunctions that lead to IBS symptoms.It also discusses the current state of evidence on therapies targeting the microbiome in the management of PI-IBS.The results of microbial modulation strategies used in relieving IBS symptomatology are encouraging.Several studies on PI-IBS animal models reported promising results.However,published data that describe the efficacy and safety of microbial targeted therapy in PI-IBS patients are scarce.Future research is required.

Characterization of oral and gut microbiome and plasma metabolomics in COVID-19 patients after 1-year follow-up

Background:Due to the outbreak and rapid spread of coronavirus disease 2019(COVID-19),more than 160 million patients have become convalescents worldwide to date.Significant alterations have occurred in the gut and oral microbiome and metabonomics of patients with COVID-19.However,it is unknown whether their characteristics return to normal after the 1-year recovery.Methods:We recruited 35 confirmed patients to provide specimens at discharge and 1 year later,as well as 160healthy controls.A total of 497 samples were prospectively collected,including 219 tongue-coating,129 stool and 149 plasma samples.Tongue-coating and stool samples were subjected to 16S rRNA sequencing,and plasma samples were subjected to untargeted metabolomics testing.Results:The oral and gut microbiome and metabolomics characteristics of the 1-year convalescents were restored to a large extent but did not completely return to normal.In the recovery process,the microbial diversity gradually increased.Butyric acid-producing microbes and Bifidobacterium gradually increased,whereas lipopolysaccharideproducing microbes gradually decreased.In addition,sphingosine-1-phosphate,which is closely related to the inflammatory factor storm of COVID-19,increased significantly during the recovery process.Moreover,the predictive models established based on the microbiome and metabolites of patients at the time of discharge reached high efficacy in predicting their neutralizing antibody levels one year later.Conclusions:This study is the first to characterize the oral and gut microbiome and metabonomics in 1-year convalescents of COVID-19.The key microbiome and metabolites in the process of recovery were identified,and provided new treatment ideas for accelerating recovery.And the predictive models based on the microbiome and metabolomics afford new insights for predicting the recovery situation which benefited affected individuals and healthcare.

Gut microbiome and nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD)has become the most prevalent chronic liver disease globally and imposed a heavy economic burden on society and individuals.To date,the pathological process of NAFLD is not yet fully elucidated.Compelling evidences have demonstrated the pivotal role of gut microbiota in the pathogenesis of NAFLD,and gut dysbiosis has been commonly observed in patients with NAFLD.Gut dysbiosis impairs gut permeability,allowing the translocation of bacterial products such as lipopolysaccharides(LPS),short-chain fatty acids(SCFAs),and ethanol to the liver via portal blood flow.This review aimed to shed light on the underlying mechanisms by which gut microbiota influences the development and progression of NAFLD.In addition,the potential application of gut microbiome as a non-invasive diagnostic tool and a novel therapeutical target was reviewed.

Rethinking neurodegenerative diseases:neurometabolic concept linking lipid oxidation to diseases in the central nervous system

Currently,there is a lack of effective medicines capable of halting or reve rsing the progression of neurodegenerative disorde rs,including amyotrophic lateral sclerosis,Parkinson s disease,multiple sclerosis,or Alzheimer s disease.Given the unmet medical need,it is necessary to reevaluate the existing para digms of how to to rget these diseases.When considering neurodegenerative diseases from a systemic neurometabolic perspective,it becomes possible to explain the shared pathological features.This innovative approach presented in this paper draws upon exte nsive research conducted by the authors and researchers worldwide.In this review,we highlight the importance of metabolic mitochondrial dysfunction in the context of neurodegenerative diseases.We provide an overview of the risk factors associated with developing neurodegenerative disorders,including genetic,epigenetic,and environmental fa ctors.Additionally,we examine pathological mechanisms implicated in these diseases such as oxidative stress,accumulation of misfolded proteins,inflammation,demyelination,death of neurons,insulin resistance,dysbiosis,and neurotransmitter disturbances.Finally,we outline a proposal for the restoration of mitochondrial metabolism,a crucial aspect that may hold the key to facilitating curative therapeutic interventions for neurodegenerative disorders in forthcoming advancements.

Biodiversity metrics on ecological networks: Demonstrated with animal gastrointestinal microbiomes

Biodiversity has become a terminology familiar to virtually every citizen in modern societies.It is said that ecology studies the economy of nature,and economy studies the ecology of humans;then measuring biodiversity should be similar with measuring national wealth.Indeed,there have been many parallels between ecology and economics,actually beyond analogies.For example,arguably the second most widely used biodiversity metric,Simpson(1949)’s diversity index,is a function of familiar Gini-index in economics.One of the biggest challenges has been the high“diversity”of diversity indexes due to their excessive“speciation”-there are so many indexes,similar to each country’s sovereign currency-leaving confused diversity practitioners in dilemma.In 1973,Hill introduced the concept of“numbers equivalent”,which is based on Renyi entropy and originated in economics,but possibly due to his abstruse interpretation of the concept,his message was not widely received by ecologists until nearly four decades later.What Hill suggested was similar to link the US dollar to gold at the rate of$35 per ounce under the Bretton Woods system.The Hill numbers now are considered most appropriate biodiversity metrics system,unifying Shannon,Simpson and other diversity indexes.Here,we approach to another paradigmatic shift-measuring biodiversity on ecological networks-demonstrated with animal gastrointestinal microbiomes representing four major invertebrate classes and all six vertebrate classes.The network diversity can reveal the diversity of species interactions,which is a necessary step for understanding the spatial and temporal structures and dynamics of biodiversity across environmental gradients.

Probiotics administration alleviates cognitive impairment and circadian rhythm disturbance induced by sleep deprivation

Gut microbiome is indispensable for maintaining normal brain function.Specifically,gut microbiota plays a causal role in sleep deprivation(SD)-induced cognitive impairment.In this study,neurobehavioral effects of the Bifidobacterium breve strain(CCFM1025)were assessed in sleep-deprived mice.CCFM1025 improved the body weight and food and water intake of the mice.It also alleviated SD-induced cognitive behavioural abnormalities(in the novel object recognition test),but did not show beneficial effects on mood-and spatial memory-related behaviours.CCFM1025 significantly altered the gut microbial composition and genome function.Key microbial metabolites that may regulate sleep function were also identified,such as isovaleric acid andγ-aminobutyric acid in the gut and purine metabolites in the serum.Those metabolites may participate in gutbrain communication by acting on the striatal melatonin system,for example to increase melatonin levels,and by regulating the expression of circadian clock genes such as those encoding the adenosine A2A receptor and period circadian regulator 1.Collectively,administration of probiotics alleviated cognitive impairment and circadian rhythm disturbance induced by SD via modulation of gut microbiome and its metabolites.These findings may help guide the treatment of insomnia or other sleep disorders via dietary strategies.