The role of gut microbiota in the gut-brain axis: current challenges and perspectives

Brain and the gastrointestinal (GI) tract are intimately connected to form a bidirectional neurohumoral communication system. The communication between gut and brain, knows as the gut-brain axis, is so well established that the functional status of gut is always related to the condition of brain. The researches on the gut-brain axis were traditionally focused on the psychological status affecting the function of the GI tract. However, recent evidences showed that gut microbiota communicates with the brain via the gut-brain axis to modulate brain development and behavioral phenotypes. These recent fi ndings on the new role of gut microbiota in the gut-brain axis implicate that gut microbiota could associate with brain functions as well as neurological diseases via the gut-brain axis. To elucidate the role of gut microbiota in the gut-brain axis, precise identification of the composition of microbes constituting gut microbiota is an essential step. However, identifi cation of microbes constituting gut microbiota has been the main technological challenge currently due to massive amount of intestinal microbes and the diffi culties in culture of gut microbes. Current methods for identifi cation of microbes constituting gut microbiota are dependent on omics analysis methods by using advanced high tech equipment. Here, we review the association of gut microbiota with the gut-brain axis, including the pros and cons of the current high throughput methods for identifi cation of microbes constituting gut microbiota to elucidate the role of gut microbiota in the gut-brain axis.     

Therapeutic potential of melatonin in colorectal cancer: Focus on lipid metabolism and gut microbiota

Colorectal cancer (CRC) is one of the most common gastrointestinal malignancies. The occurrence and development of CRC are complicated processes. Obesity and dysbacteriosis have been increasingly regarded as the main risk factors for CRC. Understanding the etiology of CRC from multiple perspectives is conducive to screening for some potential drugs or new treatment strategies to limit the serious side effects of conventional treatment and prolong the survival of CRC patients. Melatonin, a natural indoleamine, is mainly produced by the pineal gland, but it is also abundant in other tissues, including the gastrointestinal tract, retina, testes, lymphocytes, and Harder's glands. Melatonin could participate in lipid metabolism by regulating adipogenesis and lipolysis. Additionally, many studies have focused on the potential beneficial effects of melatonin in CRC, such as promotion of apoptosis; inhibition of cell proliferation, migration, and invasion; antioxidant activity; and immune regulation. Meaningfully, gut microbiota is the main determinant of all aspects of health and disease (including obesity and tumorigenesis). The gut microbiota is of great significance for understanding the relationship between obesity and increased risk of CRC. Although the current understanding of how the melatonin-mediated gut microbiota coordinates a variety of physiological and pathological activities is fairly comprehensive, there are still many unknown topics to be explored in the face of a complex nutritional status and a changeable microbiota. This review summarizes the potential links among melatonin, lipid metabolism, gut microbiota, and CRC to promote the development of melatonin as a preventive and therapeutic agent for CRC.     

Gut microbiota in patients after surgical treatment for colorectal cancer

Colorectal cancer (CRC) is a common disease worldwide that is strongly associated with the gut microbiota. However, little is known regarding the gut microbiota after surgical treatment. 16S rRNA gene sequencing was used to evaluate differences in gut microbiota among colorectal adenoma patients, CRC patients, CRC postoperative patients and healthy controls by comparing gut microbiota diversity, overall composition and taxonomic signature abundance. The gut microbiota of CRC patients, adenoma patients and healthy controls developed in accordance with the adenoma-carcinoma sequence, with impressive shifts in the gut microbiota before or during the development of CRC. The gut microbiota of postoperative patients and CRC patients differed significantly. Subdividing CRC postoperative patients according to the presence or absence of newly developed adenoma which based on the colonoscopy findings revealed that the gut microbiota of newly developed adenoma patients differed significantly from that of clean intestine patients and was more similar to the gut microbiota of carcinoma patients than to the gut microbiota of healthy controls. The alterations of the gut microbiota between the two groups of postoperative patients corresponded to CRC prognosis. More importantly, we used the different gut microbiota as biomarkers to distinguish postoperative patients with or without newly developed adenoma, achieving an AUC value of 0.72. These insights on the changes in the gut microbiota of CRC patients after surgical treatment may allow the use of the microbiota as non-invasive biomarkers for the diagnosis of newly developed adenomas and to help prevent cancer recurrence in postoperative patients.     

Gut microbiota of a long‐distance migrant demonstrates resistance against environmental microbe incursions

Migratory animals encounter suites of novel microbes as they move between disparate sites during their migrations, and are frequently implicated in the global spread of pathogens. Although wild animals have been shown to source a proportion of their gut microbiota from their environment, the susceptibility of migrants to enteric infections may be dependent upon the capacity of their gut microbiota to resist incorporating encountered microbes. To evaluate migrants’ susceptibility to microbial invasion, we determined the extent of microbial sourcing from the foraging environment and examined how this influenced gut microbiota dynamics over time and space in a migratory shorebird, the Red‐necked stint Calidris ruficollis. Contrary to previous studies on wild, nonmigratory hosts, we found that stint on their nonbreeding grounds obtained very little of their microbiota from their environment, with most individuals sourcing only 0.1% of gut microbes from foraging sediment. This microbial resistance was reflected at the population level by only weak compositional differences between stint flocks occupying ecologically distinct sites, and by our finding that stint that had recently migrated 10,000 km did not differ in diversity or taxonomy from those that had inhabited the same site for a full year. However, recent migrants had much greater abundances of the genus Corynebacterium, suggesting a potential microbial response to either migration or exposure to a novel environment. We conclude that the gut microbiota of stint is largely resistant to invasion from ingested microbes and that this may have implications for their susceptibility to enteric infections during migration.     

肠道菌群及其代谢产物与结肠腺瘤性息肉相关性的研究进展

结肠癌（colorectal cancer,CRC）是常见的消化道恶性肿瘤,其发病率和病死率都极高。从结肠息肉发展到结肠癌一般需要10～15年,且大多遵循息肉‒腺瘤‒癌症的发展过程,结肠腺瘤性息肉（colorectal adenomatous polyps,CAP）被认为是结肠癌的癌前病变。有研究显示肠道菌群的改变与肠道腺瘤性息肉样变及癌症的发生发展有密切的相关性。根据肠道菌群在不同病理状态下的富集程度,可以进一步分析其与结肠病变之间的关系。本文就肠道菌群的构成,CAP患者粪便和腺瘤组织中肠道菌群富集的改变,以及肠道菌群代谢产物对CAP患者的影响等内容进行综述,为结肠腺瘤性息肉的早期诊断和治疗提供依据。     

Gut microbes as future therapeutics in treating inflammatory and infectious diseases: Lessons from recent findings

The human gut microbiota has been the interest of extensive research in recent years and our knowledge on using the potential capacity of these microbes are growing rapidly. Microorganisms colonized throughout the gastrointestinal tract of human are coevolved through symbiotic relationship and can influence physiology, metabolism, nutrition and immune functions of an individual. The gut microbes are directly involved in conferring protection against pathogen colonization by inducing direct killing, competing with nutrients and enhancing the response of the gut-associated immune repertoire. Damage in the microbiome (dysbiosis) is linked with several life-threatening outcomes viz. inflammatory bowel disease, cancer, obesity, allergy, and auto-immune disorders. Therefore, the manipulation of human gut microbiota came out as a potential choice for therapeutic intervention of the several human diseases. Herein, we review significant studies emphasizing the influence of the gut microbiota on the regulation of host responses in combating infectious and inflammatory diseases alongside describing the promises of gut microbes as future therapeutics.     

Faecal microbial biomarkers in early diagnosis of colorectal cancer

Colorectal cancer (CRC) is ranked as the second most common cause of cancer deaths and the third most common cancer globally. It has been described as a ‘silent disease’ which is often easily treatable if detected early—before progression to carcinoma. Colonoscopy, which is the gold standard for diagnosis is not only expensive but is also an invasive diagnostic procedure, thus, effective and non-invasive diagnostic methods are urgently needed. Unfortunately, the current methods are not sensitive and specific enough in detecting adenomas and early colorectal neoplasia, hampering treatment and consequently, survival rates. Studies have shown that imbalances in such a relationship which renders the gut microbiota in a dysbiotic state are implicated in the development of adenomas ultimately resulting in CRC. The differences found in the makeup and diversity of the gut microbiota of healthy individuals relative to CRC patients have in recent times gained attention as potential biomarkers in early non-invasive diagnosis of CRC, with promising sensitivity, specificity and even cost-effectiveness. This review summarizes recent studies in the application of these microbiota biomarkers in early CRC diagnosis, limitations encountered in the area of the faecal microbiota studies as biomarkers for CRC, and future research exploits that address these limitations.     

Microbiota dysbiosis and barrier dysfunction in inflammatory bowel disease and colorectal cancers: exploring a common ground hypothesis

Inflammatory bowel disease (IBD) is a multifactorial disease which arises as a result of the interaction of genetic, environmental, barrier and microbial factors leading to chronic inflammation in the intestine. Patients with IBD had a higher risk of developing colorectal carcinoma (CRC), of which the subset was classified as colitis-associated cancers. Genetic polymorphism of innate immune receptors had long been considered a major risk factor for IBD, and the mutations were also recently observed in CRC. Altered microbial composition (termed microbiota dybiosis) and dysfunctional gut barrier manifested by epithelial hyperpermeability and high amount of mucosa-associated bacteria were observed in IBD and CRC patients. The findings suggested that aberrant immune responses to penetrating commensal microbes may play key roles in fueling disease progression. Accumulative evidence demonstrated that mucosa-associated bacteria harbored colitogenic and protumoral properties in experimental models, supporting an active role of bacteria as pathobionts (commensal-derived opportunistic pathogens). Nevertheless, the host factors involved in bacterial dysbiosis and conversion mechanisms from lumen-dwelling commensals to mucosal pathobionts remain unclear. Based on the observation of gut leakiness in patients and the evidence of epithelial hyperpermeability prior to the onset of mucosal histopathology in colitic animals, it was postulated that the epithelial barrier dysfunction associated with mucosal enrichment of specific bacterial strains may predispose the shift to disease-associated microbiota. The speculation of leaky gut as an initiating factor for microbiota dysbiosis that eventually led to pathological consequences was proposed as the “common ground hypothesis”, which will be highlighted in this review. Overall, the understanding of the core interplay between gut microbiota and epithelial barriers at early subclinical phases will shed light to novel therapeutic strategies to manage chronic inflammatory disorders and colitis-associated cancers.     

Microbial community in human gut: a therapeutic prospect and implication in health and diseases

The interest in the working and functionality of the human gut microbiome has increased drastically over the years. Though the existence of gut microbes has long been speculated for long over the last few decades, a lot of research has sprung up in studying and understanding the role of gut microbes in the human digestive tract. The microbes present in the gut are highly instrumental in maintaining the metabolism in the body. Further research is going on in this field to understand how gut microbes can be employed as potential sources of novel therapeutics; moreover, probiotics have also elucidated their significant place in this direction. As regards the clinical perspective, microbes can be engineered to afford defence mechanisms while interacting with foreign pathogenic bodies. More investigations in this field may assist us to evaluate and understand how these cells communicate with human cells and promote immune interactions. Here we elaborate on the possible implication of human gut microbiota into the immune system as well as explore the probiotics in the various human ailments. Comprehensive information on the human gut microbiome at the same platform may contribute effectively to our understanding of the human microbiome and possible mechanisms of associated human diseases.     

Impact of microbial transformation of food on health - from fermented foods to fermentation in the gastro-intestinal tract

Fermentation of food components by microbes occurs both during certain food production processes and in the gastro-intestinal tract. In these processes specific compounds are produced that originate from either biotransformation reactions or biosynthesis, and that can affect the health of the consumer. In this review, we summarize recent advances highlighting the potential to improve the nutritional status of a fermented food by rational choice of food-fermenting microbes. The vast numbers of microbes residing in the human gut, the gut microbiota, also give rise to a broad array of health-active molecules. Diet and functional foods are important modulators of the gut microbiota activity that can be applied to improve host health. A truly multidisciplinary approach is required to increase our understanding of the molecular mechanisms underlying health beneficial effects that arise from the interaction of diet, microbes and the human body.     

Role of SCFAs in gut microbiome and glycolysis for colorectal cancer therapy

Increased risk of colorectal cancer (CRC) is associated with altered intestinal microbiota as well as short-chain fatty acids (SCFAs) reduction of output The energy source of colon cells relies mainly on three SCFAs, namely butyrate (BT), propionate, and acetate, while CRC transformed cells rely mainly on aerobic glycolysis to provide energy. This review summarizes recent research results for dysregulated glucose metabolism of SCFAs, which could be initiated by gut microbiome of CRC. Moreover, the relationship between SCFA transporters and glycolysis, which may correlate with the initiation and progression of CRC, are also discussed. Additionally, this review explores the linkage of BT to transport of SCFAs expressions between normal and cancerous colonocyte cell growth for tumorigenesis inhibition in CRC. Furthermore, the link between gut microbiota and SCFAs in the metabolism of CRC, in addition, the proteins and genes related to SCFAs-mediated signaling pathways, coupled with their correlation with the initiation and progression of CRC are also discussed. Therefore, targeting the SCFA transporters to regulate lactate generation and export of BT, as well as applying SCFAs or gut microbiota and natural compounds for chemoprevention may be clinically useful for CRCs treatment. Future research should focus on the combination these therapeutic agents with metabolic inhibitors to effectively target the tumor SCFAs and regulate the bacterial ecology for activation of potent anticancer effect, which may provide more effective application prospect for CRC therapy.     

Gut microbiota alterations are distinct for primary colorectal cancer and hepatocellular carcinoma

Colorectal cancer(CRC)and hepatocellular carcinoma(HCC)are the second and third most common causes of death by cancer,respectively.The etiologies of the two cancers are either infectious insult or due to chronic use of alcohol,smoking,diet,obesity and diabetes.Patho-logical changes in the composition of the gut microbiota that lead to intestinal inflammation are a common factor for both HCC and CRC.However,the gut microbiota of the cancer patient evolves with disease pathogenesis in unique ways that are affected by etiologies and envi-ronmental factors.in this review,we examine the chan-ges that occur in the composition of the gut microbiota across the stages of the HCC and CRC.Based on the idea that the gut microblota are an additional"lifeline"and contribute to the tumor microenvironment,we can observe from previously published literature how the microbiota can cause a shift in the balance from normal→ inflammation → diminished inflammation from early to later disease stages.This pattern leads to the hypothesis that tumor survival depends on a less pro-inflammatory tumor microenvironment.The differences observed in the gut microbiota composition between different disease etiologies as well as between HCC and CRC suggest that the tumor microenvironment is unique for each case.     

Gut microbiome in tumorigenesis and therapy of colorectal cancer

Colorectal cancer (CRC) is the malignant tumor with the highest incidence in the digestive system, and the gut microbiome plays a crucial role in CRC tumorigenesis and therapy. The gastrointestinal tract is the organ harboring most of the microbiota in humans. Changes in the gut microbiome in CRC patients suggest possible host–microbe interactions, thereby hinting the potential tumorigenesis, which provides new perspective for preventing, diagnosing, or treating CRC. In this review, we discuss the effects of gut microbiome dysbiosis on CRC, and reveal the mechanisms by which gut microbiome dysbiosis leads to CRC. Gut microbiome modulation with the aim to reverse the established gut microbial dysbiosis is a novel strategy for the prevention and treatment of CRC. In addition, this review summarizes that probiotic antagonize CRC tumorigenesis by protecting intestinal barrier function, inhibiting cancer cell proliferation, resisting oxidative stress, and enhancing host immunity. Finally, we highlight clinical applications of the gut microbiome, such as gut microbiome analysis-based biomarker screening and prediction, and microbe modulation-based CRC prevention, treatment enhancement, and treatment side effect reduction. This review provides the reference for the clinical application of gut microbiome in the prevention and treatment of CRC.     

Focus: Microbiome: Striking a Balance with Help from our Little Friends – How the Gut Microbiota Contributes to Immune Homeostasis

The trillions of microbes that inhabit the human gut (the microbiota) together with the host comprise a complex ecosystem, and like any ecosystem, health relies on stability and balance. Some of the most important members of the human microbiota are those that help maintain this balance via modulation of the host immune system. Gut microbes, through both molecular factors (such as capsular components) and by-products of their metabolism (such as Short Chain Fatty Acids (SCFAs)), can influence both innate and adaptive components of the immune system, in ways that can drive both effector, and regulatory responses. Here we review how commensal microbes can specifically promote a dynamic balance of these immune responses in the mammalian gut.     

Dysbiosis Signature of Fecal Microbiota in Colorectal Cancer Patients

The human gut microbiota is a complex system that is essential to the health of the host. Increasing evidence suggests that the gut microbiota may play an important role in the pathogenesis of colorectal cancer (CRC). In this study, we used pyrosequencing of the 16S rRNA gene V3 region to characterize the fecal microbiota of 19 patients with CRC and 20 healthy control subjects. The results revealed striking differences in fecal microbial population patterns between these two groups. Partial least-squares discriminant analysis showed that 17 phylotypes closely related to Bacteroides were enriched in the gut microbiota of CRC patients, whereas nine operational taxonomic units, represented by the butyrate-producing genera Faecalibacterium and Roseburia, were significantly less abundant. A positive correlation was observed between the abundance of Bacteroides species and CRC disease status (R?=?0.462, P?=?0.046?<?0.5). In addition, 16 genera were significantly more abundant in CRC samples than in controls, including potentially pathogenic Fusobacterium and Campylobacter species at genus level. The dysbiosis of fecal microbiota, characterized by the enrichment of potential pathogens and the decrease in butyrate-producing members, may therefore represent a specific microbial signature of CRC. A greater understanding of the dynamics of the fecal microbiota may assist in the development of novel fecal microbiome-related diagnostic tools for CRC.     

肠道微生物与过敏性疾病关系研究进展

目前,过敏性疾病的防治主要依赖于使用抗生素,然而抗生素的滥用已造成了严重的危害。近年来随着肠道微生物相关研究的不断深入以及人们对过敏性疾病的日益关注与重视,肠道微生物与过敏性疾病间的关系逐渐受到科学家们的关注。调整肠道菌群结构可能为过敏性疾病的防治提供新的思路。目前对肠道微生物与过敏性疾病间的相关性报道相对较少且未有深层次的剖析。本文总结了关于肠道微生物与过敏性疾病关系的研究起源、发展与现状,旨在为过敏性疾病的防治提供新策略。     

Altitudinal variation of the gut microbiota in wild house mice

The maintenance of oxygen homeostasis in the gut is critical for the maintenance of a healthy gut microbiota. However, few studies have explored how the concentration of atmospheric oxygen affects the gut microbiota in natural populations. High‐altitude environments provide an opportunity to study the potential effects of atmospheric oxygen on the composition and function of the gut microbiota. Here, we characterized the caecal microbial communities of wild house mice (Mus musculus domesticus) in two independent altitudinal transects, one in Ecuador and one in Bolivia, from sea level to nearly 4,000 m. First, we found that differences in altitude were associated with differences in the gut microbial community after controlling for the effects of body mass, diet, reproductive status and population of origin. Second, obligate anaerobes tended to show a positive correlation with altitude, while all other microbes tended to show a negative correlation with altitude. These patterns were seen independently in both transects, consistent with the expected effects of atmospheric oxygen on gut microbes. Prevotella was the most‐enriched genus at high elevations in both transects, consistent with observations in high‐altitude populations of pikas, ruminants and humans, and also consistent with observations of laboratory mice exposed to hypoxic conditions. Lastly, the renin–angiotensin system, a recently proposed microbiota‐mediated pathway of blood pressure regulation, was the top predicted metagenomic pathway enriched in high altitudes in both transects. These results suggest that high‐altitude environments affect the composition and function of the gut microbiota in wild mammals.     

Modulation of the gut microbiota by nutrients with prebiotic properties: consequences for host health in the context of obesity and metabolic syndrome

The gut microbiota is increasingly considered as a symbiotic partner for the maintenance of health. The homeostasis of the gut microbiota is dependent on host characteristics (age, gender, genetic background...), environmental conditions (stress, drugs, gastrointestinal surgery, infectious and toxic agents...). Moreover, it is dependent on the day-to-day dietary changes. Experimental data in animals, but also observational studies in obese patients, suggest that the composition of the gut microbiota is a factor characterizing obese versus lean individuals, diabetic versus non diabetic patients, or patients presenting hepatic diseases such as non alcoholic steatohepatitis. Interestingly, the changes in the gut microbes can be reversed by dieting and related weight loss. The qualitative and quantitative changes in the intake of specific food components (fatty acids, carbohydrates, micronutrients, prebiotics, probiotics), have not only consequences on the gut microbiota composition, but may modulate the expression of genes in host tissues such as the liver, adipose tissue, intestine, muscle. This in turn may drive or lessen the development of fat mass and metabolic disturbances associated with the gut barrier function and the systemic immunity. The relevance of the prebiotic or probiotic approaches in the management of obesity in humans is supported by few intervention studies in humans up to now, but the experimental data obtained with those compounds help to elucidate novel potential molecular targets relating diet with gut microbes. The metagenomic and integrative metabolomic approaches could help elucidate which bacteria, among the trillions in human gut, or more specifically which activities/genes, could participate to the control of host energy metabolism, and could be relevant for future therapeutic developments.