Focus: Microbiome: The Hoops,Hopes, and Hypes of Human Microbiome Research

Recent developments in sequencing methods and bioinformatics analysis tools have greatly enabled the culture-independent analysis of complex microbial communities associated with environmental samples, plants, and animals. This has led to a spectacular increase in the number of studies on both membership and functionalities of these hitherto invisible worlds, in particular those of the human microbiome. The wide variety in available microbiome tools and platforms can be overwhelming, and making sound conclusions from scientific research can be challenging. Here, I will review 1) the methodological and analytic hoops a good microbiome study has to jump through, including DNA extraction and choice of bioinformatics tools, 2) the hopes this field has generated for diseases such as autism and inflammatory bowel diseases, and 3) some of the hypes that it has created, e.g., by confusing correlation and causation, and the recent pseudoscientific commercialization of microbiome research.     

Focus: Microbiome: Human Microbiota and Ophthalmic Disease

The human ocular surface, consisting of the cornea and conjunctiva, is colonized by an expansive, diverse microbial community. Molecular-based methods, such as 16S rRNA sequencing, has allowed for more comprehensive and precise identification of the species composition of the ocular surface microbiota compared to traditional culture-based methods. Evidence suggests that the normal microbiota plays a protective immunological role in preventing the proliferation of pathogenic species and thus, alterations in the homeostatic microbiome may be linked to ophthalmic pathologies. Further investigation of the ocular surface microbiome, as well as the microbiome of other areas of the body such as the oral mucosa and gut, and their role in the pathophysiology of diseases is a significant, emerging field of research, and may someday enable the development of novel probiotic approaches for the treatment and prevention of ophthalmic diseases.     

Focus: Microbiome: The Impact of the Gut Microbiota on Drug Metabolism and Clinical Outcome

The significance of the gut microbiota as a determinant of drug pharmacokinetics and accordingly therapeutic response is of increasing importance with the advent of modern medicines characterised by low solubility and/or permeability, or modified-release. These physicochemical properties and release kinetics prolong drug residence times within the gastrointestinal tract, wherein biotransformation by commensal microbes can occur. As the evidence base in support of this supplementary metabolic “organ” expands, novel opportunities to engineer the microbiota for clinical benefit have emerged. This review provides an overview of microbe-mediated alteration of drug pharmacokinetics, with particular emphasis on studies demonstrating proof of concept in vivo. Additionally, recent advances in modulating the microbiota to improve clinical response to therapeutics are explored.     

Focus: Microbiome: Unraveling the Dynamics of the Human Vaginal Microbiome

Four Lactobacillus species, namely L. crispatus, L. iners, L. gasseri, and L. jensenii, commonly dominate the vaginal communities of most reproductive-age women. It is unclear why these particular species, and not others, are so prevalent. Historically, estrogen-induced glycogen production by the vaginal epithelium has been proffered as being key to supporting the proliferation of vaginal lactobacilli. However, the ‘fly in the ointment’ (that has been largely ignored) is that the species of Lactobacillus commonly found in the human vagina cannot directly metabolize glycogen. It would appear that this riddle has been solved as studies have demonstrated that vaginal lactobacilli can metabolize the products of glycogen depolymerization by α-amylase, and fortunately, amylase activity is found in vaginal secretions. These amylases are presumed to be host-derived, but we suggest that other bacterial populations in vaginal communities could also be sources of amylase in addition to (or instead of) the host. Here we briefly review what is known about human vaginal bacterial communities and discuss how glycogen-derived resources and resource competition might shape the composition and structure of these communities.     

Focus: Microbiome: Integrative Therapies in Anxiety Treatment with Special Emphasis on the Gut Microbiome

Over the past decade, research has shown that diet and gut health affects symptoms expressed in stress related disorders, depression, and anxiety through changes in the gut microbiota. Psycho-behavioral function and somatic health interaction have often been ignored in health care with resulting deficits in treatment quality and outcomes. While mental health care requires the professional training in counseling, psychotherapy and psychiatry, complimentary therapeutic strategies, such as attention to a nutritional and diverse diet and supplementation of probiotic foods, may be integrated alongside psychotherapy treatment models. Development of these alternative strategies is predicated on experimental evidence and diligent research on the biology of stress, fear, anxiety-related behaviors, and the gut-brain connection. This article provides a brief overview on biological markers of anxiety and the expanding nutritional literature relating to brain health and mental disorders. A case study demonstrates an example of a biopsychosocial approach integrating cognitive psychotherapy, dietary changes, and mindfulness activities, in treating symptoms of anxiety. This case study shows a possible treatment protocol to explore the efficacy of targeting the gut-brain-axis that may be used as an impetus for future controlled studies.     

Staphylococcus epidermidis Contributes to Healthy Maturation of the Nasal Microbiome by Stimulating Antimicrobial Peptide Production

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Asthma Severity, Psychophysiological Indicators of Arousal, and Immune Function in Asthma Patients Undergoing Biofeedback-Assisted Relaxation

Asthma is characterized by airway hyper-responsiveness, inflammation, and reversible obstruction. Respiratory tract infection, allergies, air pollution, and psychosocial factors impact the severity and frequency of asthma symptoms. Pharmacotherapy and self-care are the major components in the management of asthma, but behavioral interventions also have the potential to affect asthma morbidity. We conducted a small, randomized controlled study, examining the effects of biofeedback-assisted relaxation in 16 nonsmokers with nonsteroid-dependent mild asthma. Data were collected on asthma symptoms, pulmonary function, indicators of arousal, and cellular immune factors. The trained group evidenced a decrease in forehead muscle tension in comparison to the controls, but no changes in peripheral skin temperature. Decreases in asthma severity and bronchodilator medication usage for the experimental group were observed. Pulmonary function testing revealed a significant difference between groups in FEV₁/FVC at posttest, with the E group having a higher ratio than the controls. The cellular immune data showed no significant group differences in total white blood cell or lymphocyte counts, but decreases over time were observed. Significant differences were observed in the numbers of neutrophils and basophils in the trained group compared to controls, which supports the concept of decreased inflammation. Results of delayed-type hypersensitivity skin testing suggested enhanced function, but they were not conclusive. These findings, though limited by size of population, suggest a positive effect of biofeedback-assisted relaxation in young, nonsteroid-dependent asthmatics. The mechanisms underlying linkages between psychological, behavioral, and immune responses in asthma require further study.     

Focus: Microbiome: Distinct Ecological Niche of Anal,Oral, and Cervical Mucosal Microbiomes in Adolescent Women

Human body sites represent ecological niches for microorganisms, each providing variations in microbial exposure, nutrient availability, microbial competition, and host immunological responses. In this study, we investigated the oral, anal, and cervical microbiomes from the same 20 sexually active adolescent females, using culture-independent, next-generation sequencing. DNA from each sample was amplified for the bacterial 16S rRNA gene and sequenced on an Illumina platform using paired-end reads. Across the three anatomical niches, we found significant differences in bacterial community composition and diversity. Overall anal samples were dominated with Prevotella and Bacteriodes, oral samples with Streptococcus and Prevotella, and cervical samples with Lactobacillus. The microbiomes of a few cervical samples clustered with anal samples in weighted principal coordinate analyses, due in part to a higher proportion of Prevotella in those samples. Additionally, cervical samples had the lowest alpha diversity. Our results demonstrate the occurrence of distinct microbial communities across body sites within the same individual.     

Focus: Microbiome: Treating Obesity and Metabolic Syndrome with Fecal Microbiota Transplantation

The worldwide prevalence of metabolic syndrome, which includes obesity and its associated diseases, is rising rapidly. The human gut microbiome is recognized as an independent environmental modulator of host metabolic health and disease. Research in animal models has demonstrated that the gut microbiome has the functional capacity to induce or relieve metabolic syndrome. One way to modify the human gut microbiome is by transplanting fecal matter, which contains an abundance of live microorganisms, from a healthy individual to a diseased one in the hopes of alleviating illness. Here we review recent evidence suggesting efficacy of fecal microbiota transplant (FMT) in animal models and humans for the treatment of obesity and its associated metabolic disorders.     

Unexpected guests in the tumor microenvironment:microbiome in cancer

Although intestinal microbiome have been established as an important biomarker and regulator of cancer development and therapeutic response,less is known about the role of microbiome at other body sites in cancer.Emerging evidence has revealed that the local microbiota make up an important part of the tumor microenvironment across many types of cancer,espe-cially in cancers arising from mucosal sites,including the lung,skin and gastrointestinal tract.The populations of bacteria that reside specifically within tumors have been found to be tumor-type specific,and mechanistic studies have demonstrated that tumor-associated microbiota may directly regulate cancer initiation,pro-gression and responses to chemo-or immuno-thera-pies.This review aims to provide a comprehensive review of the important literature on the microbiota in the cancerous tissue,and their function and mechanism of action in cancer development and treatment.     

The Microbiome in Early Life: Self‐Completion and Microbiota Protection as Health Priorities

This minireview considers the benefits of refocusing attention away from treating the patient as a mammalian human to managing the complete patient: a majority microbial superorganism. Under the “completed self” model for formation of the human‐microbial superorganism, the single, most pivotal sign in distinguishing a life course of health versus that filled with disease is self‐completion (i.e., seeding of the minority mammalian human by the majority microbial portion of the symbiont). From a disease prevention perspective, microbial seeding at birth and subsequent nurturing of the microbiota are significant steps to reduce the risk of both noncommunicable diseases (e.g., type 1 diabetes) and certain infectious diseases. Management of the microbiome during pregnancy, birth, and shortly thereafter appears to be the most significant critical window for healthy superorganism formation. However, the bolus for microbiota seeding at birth and the nurturing process are subject to environmental influences and disruption, such as exposure to toxic chemicals and drugs, infections, and other physical and psychological stressors. Additionally, childhood and adult corrective measures, such as fecal transplantation and administration of prebiotics and probiotics, while potentially useful, may have limitations that are yet to be fully defined. This minireview considers (1) basic features of management of the microbiome to facilitate self‐completion, (2) protection of the microbiota from environmental hazards, and (3) the benefits of using a superorganism focus for health management beginning with pregnancy and extending throughout childhood and adult life     

Overview of the rules of the microbial engagement in the gut microbiome: a step towards microbiome therapeutics

Human gut microbiome is a diversified, resilient, immuno-stabilized, metabolically active and physiologically essential component of the human body. Scientific explorations have been made to seek in-depth information about human gut microbiome establishment, microbiome functioning, microbiome succession, factors influencing microbial community dynamics and the role of gut microbiome in health and diseases. Extensive investigations have proposed the microbiome therapeutics as a futuristic medicine for various physiological and metabolic disorders. A comprehensive outlook of microbial colonization, host–microbe interactions, microbial adaptation, commensal selection and immuno-survivability is still required to catalogue the essential genetic and physiological features for the commensal engagement. Evolution of a structured human gut microbiome relies on the microbial flexibility towards genetic, immunological and physiological adaptation in the human gut. Key features for commensalism could be utilized in developing tailor-made microbiome-based therapy to overcome various physiological and metabolic disorders. This review describes the key genetics and physiological traits required for host–microbe interaction and successful commensalism to institute a human gut microbiome.     

Focus: Health Equity: Asthma Prevalence and its Risk Factors Among a Multi-Ethnic Adult Population

Asthma is a substantial global health problem characterized by chronic airway inflammation, leading to intermittent symptoms. This study aims to establish the prevalence and risk factors of asthma in a multi-ethnic adult population. Data for the study were extracted from the Singapore Mental Health Study 2016, a population-based, cross-sectional, epidemiological study of Singapore residents aged 18 years and above. The data relating to asthma prevalence was captured using the modified World Mental Health Composite International Diagnostic Interview (CIDI) version 3.0 chronic conditions checklist. The prevalence of lifetime asthma in this population was 11.9% (95% CI, 10.83-13.12). Those of Malay and Indian ethnicity (versus Chinese), ex-smokers (versus never smoked) and those who were overweight and obese (versus normal weight) were more likely to be associated with asthma. Participants belonging to the age group of 35 years and above (versus 18-34 years of age), male gender (versus female) were less likely to be associated with lifetime asthma. Asthma was also more likely to be associated with bipolar disorder. Those with current asthma (ie, those who had received treatment during the past 12 months) were significantly associated with lower health-related quality of life in the physical component score (PCS) than those without asthma. The high prevalence and association with lowered health-related quality of life makes asthma a significant public health concern. Our study’s findings can help create awareness and encourage integrated approaches for managing asthma in the health sector.     

Impact of feed restriction and housing hygiene conditions on specific and inflammatory immune response,the cecal bacterial community and the survival of young rabbits

Limiting the post-weaning intake of the young rabbit is known to improve its resistance to digestive disorders, whereas a degradation of its housing hygiene is assumed to have a negative impact on its health. This study aims at providing insights into the mechanism of digestive health preservation regarding both host (growth and immune response) and its symbiotic digestive microbiota. A 2×2 factorial design from weaning (day 28) to day 64 was set up: ad libitum intake or restricted intake at 70% of ad libitum, and high v. low hygiene of housing (n=105 per group). At day 36 and day 45, 15 animals/group were subcutaneously immunized with ovalbumin (OVA) to assess their specific immune response. Blood was sampled at 36, 45, 57 and 64 days of age to determine total and anti-OVA immunoglobulin type G (IgG) and haptoglobin levels. The cecal bacterial community was explored (18 per group) by 454 pyrosequencing of genes coding for the 16S ribosomal RNA, whereas cecal pH, NH₃ and volatile fatty acid (VFA) concentrations were measured to characterize fermentative activity. A 30% reduction in feed intake reduced the growth by only 17% (P<0.001), and improved the feed conversion ratio by 15% (P<0.001), whereas the degradation of hygiene conditions slightly decreased the feed intake in ad libitum fed rabbits (−3.5%, P<0.02). As poor hygiene conditions did not affect weight gain, feed conversion was improved from day 42 (P<0.05). Restricted feeding led to a lower mortality between day 28 and day 40 (P=0.047), whereas degraded hygiene conditions decreased overall morbidity (7.8% v. 16.6%; P<0.01). Both a reduced intake and low hygiene conditions of housing affected microbiota composition and especially dominant genera belonging to the Ruminococcaceae family (P<0.01). Moreover, low hygiene was associated with a higher Ruminococcaceae/Lachnospiraceae ratio (3.7 v. 2.4; P<0.05). Cecal total VFA and pH were increased (+19%; P<0.001) and decreased (−0.1 pH unit; P<0.05), respectively, in feed-restricted rabbits. Neither specific anti-OVA IgG nor haptoglobin was affected by treatments. Total IgG concentrations were the highest in animals raised in poor hygiene conditions after 8 days of restriction, but decreased after 19 days of restriction in high hygiene conditions (−2.15%; P<0.05). In conclusion, the degradation of hygiene conditions failed to induce a systematic specific and inflammatory response in rabbit, but reduced morbidity instead. Our results suggest that the microbiota composition would be a helpful source of biomarkers of digestive health.     

昆虫肠道防御及微生物稳态维持机制

在长期的进化过程中,昆虫形成了独特的肠道防御系统,主要由物理屏障和免疫系统共同作用来抵御外来微生物的入侵。如大部分后生动物一样,昆虫肠道上皮细胞无时无刻不与微生物接触,其种类从有益的共生菌、随食物进入的微生物到影响宿主生命的病原菌。在这样一种复杂的环境中,为了实现防御肠道病原微生物的同时又能维持共生微生物稳定的目的,宿主肠道上皮细胞必须在免疫应激和免疫耐受之间保持一种稳态平衡。Duox-ROS免疫系统和免疫缺陷(immune deficiency,Imd)信号通路作为肠道免疫反应的基本途径,必然参与调节此过程。本文从昆虫肠道防御组成、肠道免疫信号通路作用分子机制以及肠道免疫系统在肠道微生物群落稳态维持中的作用的最新研究进展进行综述。     

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

Conventional anticancer chemotherapy has been historically thought to act through direct killing of tumor cells. This concept stems from the fact that cytotoxic drugs interfere with DNA synthesis and replication. Accumulating evidence, however, indicates that the antitumor activities of chemotherapy also rely on several off-target effects, especially directed to the host immune system, that cooperate for successful tumor eradication. Chemotherapeutic agents stimulate both the innate and adaptive arms of the immune system through several modalities: (i) by promoting specific rearrangements on dying tumor cells, which render them visible to the immune system; (ii) by influencing the homeostasis of the hematopoietic compartment through transient lymphodepletion followed by rebound replenishment of immune cell pools; (iii) by subverting tumor-induced immunosuppressive mechanisms and (iv) by exerting direct or indirect stimulatory effects on immune effectors. Among the indirect ways of immune cell stimulation, some cytotoxic drugs have been shown to induce an immunogenic type of cell death in tumor cells, resulting in the emission of specific signals that trigger phagocytosis of cell debris and promote the maturation of dendritic cells, ultimately resulting in the induction of potent antitumor responses. Here, we provide an extensive overview of the multiple immune-based mechanisms exploited by the most commonly employed cytotoxic drugs, with the final aim of identifying prerequisites for optimal combination with immunotherapy strategies for the development of more effective treatments against cancer.     

It takes guts to grow a brain: Increasing evidence of the important role of the intestinal microflora in neuro- and immune-modulatory functions during development and adulthood

A new study entitled "Normal gut microbiota modulates brain development and behavior", published in the Proceedings of the National Academy of Sciences, requires that we reconsider the notion that the brain is an immune-privileged site. The authors demonstrate that intestinal microbiota must be present within a set time-frame for normal synaptogenesis to occur in the brain. In the absence of intestinal microbiota, histopathological and behavioral abnormalities arise. These observations necessitate a new look at the many interconnections of the immune system and the brain, suggesting new frontiers for research and new therapeutic strategies for neurodevelopmental diseases.     

肠道菌群与肠黏膜免疫及相关肠道疾病的研究进展

肠道菌群与肠黏膜免疫之间存在密切的关系,二者相互促进、相互影响,共同维持肠道微生态的平衡,二者失衡可造成肠道器质性及功能性的病变。对肠道菌群、肠黏膜免疫及相关肠道疾病的研究进展作一综述。