Host-microbiota Relationship Research Articles

Maternal Immunoglobulin A protects against the development of necrotizing enterocolitis in preterm infants

Abstract Neonates are particularly susceptible to infection by colonizing microbes, and mammals protect their offspring via antibodies secreted into breast milk. Necrotizing Enterocolitis(NEC) is a disease of preterm infants characterized by intestinal epithelial damage and inflammation associated with the microbiota. The incidence of NEC is significantly lower in infants fed with maternal milk, though the mechanisms underlying this protective benefit are not clear. Here, we show that maternal Immunoglobulin A (IgA) is an important factor in protection against NEC. Analysis of IgA-binding within fecal samples from preterm infants indicated that breast milk was the predominant source of IgA in the first month of life and that a relative decrease in the fraction of bacteria bound by IgA is associated with the development of NEC. Sequencing of IgA-bound and unbound bacteria revealed that NEC was associated with increasing domination of the IgA unbound microbiota by Enterobacteriaceae, prior to disease onset. Further, we confirmed that IgA is critical in preventing NEC in a murine model, where we demonstrate that pups reared by IgA deficient mothers are susceptible to disease despite exposure to maternal milk. This study illustrates the importance of maternal IgA in shaping the host-microbiota relationship of preterm neonates and provides evidence that IgA is a critical factor in maternal milk necessary for the prevention of NEC.

The role of gut microbiota in intestinal and liver diseases.

The world-wide incidence of many immune-mediated and metabolic diseases, including those of the intestines and liver, is steadily increasing. Gut microbiota plays a central role in the pathogenesis of these diseases as it mediates environmental changes to the intestinal immune system. Various environmental factors including diet, food additives and medication also trigger the compositional and functional alterations of microbiota, that is, dysbiosis, and this dysbiosis is closely associated with many chronic inflammatory diseases. However, the causal relationship remains unclear for the majority of these diseases. In this review, we discuss essential epidemiological data, known pathogenetic factors including those of genetic and environmental nature, while mainly focusing on the role of gut microbiota in the development of selected intestinal and liver diseases. Using specific examples, we also briefly describe some of the most widely-used animal models including gnotobiotic models and their contribution to the research of pathogenetic mechanisms of the host-microbiota relationship.

Metronidazole Causes Skeletal Muscle Atrophy and Modulates Muscle Chronometabolism

Antibiotics lead to increased susceptibility to colonization by pathogenic organisms, with different effects on the host-microbiota relationship. Here, we show that metronidazole treatment of specific pathogen-free (SPF) mice results in a significant increase of the bacterial phylum Proteobacteria in fecal pellets. Furthermore, metronidazole in SPF mice decreases hind limb muscle weight and results in smaller fibers in the tibialis anterior muscle. In the gastrocnemius muscle, metronidazole causes upregulation of Hdac4, myogenin, MuRF1, and atrogin1, which are implicated in skeletal muscle neurogenic atrophy. Metronidazole in SPF mice also upregulates skeletal muscle FoxO3, described as involved in apoptosis and muscle regeneration. Of note, alteration of the gut microbiota results in increased expression of the muscle core clock and effector genes Cry2, Ror-β, and E4BP4. PPARγ and one of its important target genes, adiponectin, are also upregulated by metronidazole. Metronidazole in germ-free (GF) mice increases the expression of other core clock genes, such as Bmal1 and Per2, as well as the metabolic regulators FoxO1 and Pdk4, suggesting a microbiota-independent pharmacologic effect. In conclusion, metronidazole in SPF mice results in skeletal muscle atrophy and changes the expression of genes involved in the muscle peripheral circadian rhythm machinery and metabolic regulation.

The response of human bacteria to static magnetic field and radiofrequency electromagnetic field.

Cell phones and electronic appliances and devices are inseparable from most people in modern society and the electromagnetic field (EMF) from the devices is a potential health threat. Although the direct health effect of a cell phone and its radiofrequency (RF) EMF to human is still elusive, the effect to unicellular organisms is rather apparent. Human microbiota, including skin microbiota, has been linked to a very significant role in the health of a host human body. It is important to understand the response of human skin microbiota to the RF-EMF from cell phones and personal electronic devices, since this may be one of the potential mechanisms of a human health threat brought about by the disruption of the intimate and balanced host-microbiota relationship. Here, we investigated the response of both laboratory culture strains and isolates of skin bacteria under static magnetic field (SMF) and RF-EMF. The growth patterns of laboratory cultures of Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus epidermidis under SMF were variable per different species. The bacterial isolates of skin microbiota from 4 subjects with different cell phone usage history also showed inconsistent growth responses. These findings led us to hypothesize that cell phone level RF-EMF disrupts human skin microbiota. Thus, the results from the current study lay ground for more comprehensive research on the effect of RF-EMF on human health through the human-microbiota relationship.

Gut microbiota dysbiosis associated with glucose metabolism disorders and the metabolic syndrome in older adults.

Obesity and associated metabolic disorders have become highly prevalent diseases worldwide, and the human gut microbiota, due to its influence on host energy metabolism, has been attributed an important role therein. This pilot study explores host-microbiota relationships in men and women affected by various types of glucose metabolism disorder. Among 20 individuals aged 58 to 71 years with either normal glucose tolerance, prediabetes, or type 2 diabetes mellitus the gut bacterial communities were compared based on barcoded 454 sequencing of 16S rRNA genes amplified from stool samples. We found that specific microbiota groups were relatively enriched or reduced in different metabolic states. Further, positive or negative associations with clinical manifestations of metabolic disease suggest that these organisms indicate and possibly contribute to metabolic impairment or health. For instance, a higher prevalence of Erysipelotrichaceae and Lachnospiraceae was found associated with metabolic disorders, and the Holdemania and Blautia genera correlated with clinical indicators of an impaired lipid and glucose metabolism. The Bacteroidetes and groups therein, by contrast, displayed inverse relationships with metabolic disease parameters and were found relatively enriched in participants not diagnosed with metabolic syndrome or obesity. Further, the prevalence of specific Clostridia and Rikenellaceae members also pointed towards a healthier metabolic state. Links with diet as an intermediate factor included positive and negative associations of Lachnospiraceae with relative consumption rates of fat and carbohydrates, respectively, and positive associations of Turicibacteraceae with the consumption of protein. Identifying critical roles of major gut microbiota components in metabolic disorders has important translational implications regarding the prevention and treatment of metabolic diseases by means of preventing or reversing dysbiosis and by controlling exacerbating diet and life style factors particularly in sensitive population groups.

The Altered Schaedler Flora: Continued Applications of a Defined Murine Microbial Community.

The gastrointestinal (GI) microbiota forms a mutualistic relationship with the host through complex and dynamic interactions. Because of the complexity and interindividual variation of the GI microbiota, investigating how members of the microbiota interact with each other, as well as with the host, is daunting. The altered Schaedler flora (ASF) is a model community of eight microorganisms that was developed by R.P. Orcutt and has been in use since the late 1970s. The eight microorganisms composing the ASF were all derived from mice, can be cultured in vitro, and are stably passed through multiple generations (at least 15 years or more by the authors) in gnotobiotic mice continually bred in isolator facilities. With the limitations associated with conventional, mono- or biassociated, and germfree mice, use of mice colonized with a consortium of known bacteria that naturally inhabit the murine gut offers a powerful system to investigate mechanisms governing host-microbiota relationships, and how members of the GI microbiota interact with one another. The ASF community offers significant advantages to study homeostatic as well as disease-related interactions by taking advantage of a well-defined, limited community of microorganisms. For example, quantification and spatial distribution of individual members, microbial genetic manipulation, genomic-scale analysis, and identification of microorganism-specific host immune responses are all achievable using the ASF model. This review compiles highlights associated with the 37-year history of the ASF, including descriptions of its continued use in biomedical research to elucidate the complexities of host-microbiome interactions in health and disease.

Microbes taming mast cells: Implications for allergic inflammation and beyond

There is increasing awareness of a relationship between our microbiota and the pathogenesis of allergy and other inflammatory diseases. In investigating the mechanisms underlying microbiota modulation of allergy the focus has been on the induction phase; alterations in the phenotype and function of antigen presenting cells, induction of regulatory T cells and shifts in Th1/Th2 balance. However there is evidence that microbes can influence the effector phase of disease, specifically that certain potentially beneficial bacteria can attenuate mast cell activation and degranulation. Furthermore, it appears that different non-pathogenic bacteria can utilize distinct mechanisms to stabilize mast cells, acting locally though direct interaction with the mast cell at mucosal sites or attenuating systemic mast cell dependent responses, likely through indirect signaling mechanisms. The position of mast cells on the frontline of defense against pathogens also suggests they may play an important role in fostering the host–microbiota relationship. Mast cells are also conduits of neuro-immuo-endocrine communication, suggesting the ability of microbes to modulate cell responses may have implications for host physiology beyond immunology. Further investigation of mast cell regulation by non-pathogenic or symbiotic bacteria will likely lead to a greater understanding of host microbiota interaction and the role of the microbiome in health and disease.

Monitoring host responses to the gut microbiota.

The gastrointestinal (GI) ecosystem is increasingly understood to be a fundamental component of health, and has been identified as a new focal point for diagnosing, correcting and preventing countless disorders. Shotgun DNA sequencing has emerged as the dominant technology for determining the genetic and microbial composition of the gut microbiota. This technology has linked microbiota dysbioses to numerous GI diseases including inflammatory bowel disease, obesity and allergy, and to non-GI diseases like autism and depression. The importance of establishing causality in the deterioration of the host-microbiota relationship is well appreciated; however, discovery of candidate molecules and pathways that underlie mechanisms remains a major challenge. Targeted approaches, transcriptional assays, cytokine panels and imaging analyses, applied to animals, have yielded important insight into host responses to the microbiota. However, non-invasive, hypothesis-independent means of measuring host responses in humans are necessary to keep pace with similarly unbiased sequencing efforts that monitor microbes. Mass spectrometry-based proteomics has served this purpose in many other fields, but stool proteins exist in such diversity and dynamic range as to overwhelm conventional proteomics technologies. Focused analysis of host protein secretion into the gut lumen and monitoring proteome-level dynamics in stool provides a tractable route toward non-invasively evaluating dietary, microbial, surgical or pharmacological intervention efficacies. This review is intended to guide GI biologists and clinicians through the methods currently used to elucidate host responses in the gut, with a specific focus on mass spectrometry-based shotgun proteomics applied to the study of host protein dynamics within the GI ecosystem.

Type I interferon signalling in the intestinal epithelium affects Paneth cells, microbial ecology and epithelial regeneration

ObjectiveIntestinal epithelial cells (IECs) at the internal/external interface orchestrate the mucosal immune response. Paneth cells secrete antimicrobial peptides and inflammatory mediators, protect from pathogens and shape the commensal microbiota. Prompted...

Gut Microbiota, Low-grade Inflammation, and Metabolic Syndrome

The intestinal tract is inhabited by a large diverse community of bacteria collectively referred to as the gut microbiota. Alterations in gut microbiota composition are associated with a variety of disease states including obesity, diabetes, and inflammatory bowel disease (IBD). Transplant of microbiota from diseased persons (or mice) to germfree mice transfers some aspects of disease phenotype, indicating that altered microbiota plays a role in disease establishment and manifestation. There are myriad potential mechanisms by which alterations in gut microbiota might promote disease, including increasing energy harvest, production of toxic metabolites, and molecular mimicry of host proteins. However, our research indicates that an overarching mechanism by which an aberrant microbiota negatively impacts health is by driving chronic inflammation. More specifically, we hypothesize that the histopathologically evident gut inflammation that defines IBD is a severe but relatively rare outcome of an altered host-microbiota relationship, while a much more common consequence of such disturbances is "low-grade" inflammation characterized by elevated proinflammatory gene expression that associates with, and may promote, metabolic syndrome. In this context, a variety of chronic inflammatory diseases may stem from inability of the mucosal immune system to properly manage a stable healthy relationship with the gut microbiota. While one's ability to manage their gut microbiota is dictated in part by genetics, it can be markedly influenced by the composition of the microbiota one inherits from their early environment. Moreover, the host-microbiota relationship can be perturbed by instigator bacteria or dietary components, which may prove to play a role in promoting chronic inflammatory disease states.

Experimental Approaches for Defining Functional Roles of Microbes in the Human Gut

The complex and intimate relationship between humans and their gut microbial communities is becoming less obscure, due in part to large-scale gut microbial genome-sequencing projects and culture-independent surveys of the composition and gene content of these communities. These studies build upon, and are complemented by, experimental efforts to define underlying mechanisms of host-microbe interactions in simplified model systems. This review highlights the intersection of these approaches. Experimental studies now leverage the advances in high-throughput DNA sequencing that have driven the explosion of microbial genome and community profiling projects, and the loss-of-function and gain-of-function strategies long employed in model organisms are now being extended to microbial genes, species, and communities from the human gut. These developments promise to deepen our understanding of human gut host-microbiota relationships and are readily applicable to other host-associated and free-living microbial communities.

Temporal variations in early gut microbial colonization are associated with allergen‐specific immunoglobulin E but not atopic eczema at 2 years of age

Intestinal microbiota undergoes substantial development during the first 2 years of life, important for intestinal immunologic development and maturation influencing systemic immune responses. We aimed to investigate, using a prospective study design, whether allergen-specific IgE (sIgE) and atopic eczema are associated with variations in gut microbial colonization patterns in an unselected population during the first 2 years of life. Faeces from 94 infants were repeatedly sampled from 10 days, 4 months, 1 and 2 years postnatal and analysed for 12 different bacterial species by quantitative real-time PCR. Venous blood samples from the infants were collected at 2 years of age and were analysed for sIgE for 12 specific allergens. The temporal gut colonization patterns for 42 sIgE-positive (sIgE≥0.35 kU/L) and 52 sIgE-negative children (sIgE<0.1 kU/L) were then compared. The association between colonization pattern and phenotype as atopic eczema according to UK Working Party (UKWP) criteria were also described. Subjects with atopic sensitization had lower levels of Escherichia coli at 4 months and 1 year, higher levels of Bifidobacterium longum at 1 year and lower levels of Bacteroides fragilis at 2 years. For E. coli and B. longum, the differences were only transient and had disappeared by 2 years of age. For other species, there were no differences in colonization patterns, and we found no association between colonization pattern and atopic eczema. We found temporal and transient variations in gut microbial colonization patterns associated with differences in sIgE sensitization at 2 years of age. A full understanding of the principles and mechanisms that underlie intestinal microbial colonization and diversity and host-microbiota relationships will be pivotal for the development of therapeutic approaches that manipulate the intestinal microbiota to maintain human health. [ ISRCTN28090297].

Restoration of host–microbiota homeostasis for attaining healthy aging: the role of milk and fermented milk

Intestinal microbiota and gut-associated lymphoreticular tissue are in a dynamic equilibrium, the rupture of which causes a condition of dysbiosis in the host. Among many natural foods, milk, because of its composition, is able to influence the host–microbiota relationship. Donkey’s and goat’s milk represents a good alternative to human milk. Healthy effects of both kinds of milk have been reported in either in vitro or in vivo experiments. When administered to elderly subjects, donkey’s milk increased the release of interleukins 6 and 8, while goat’s milk exerted opposite effects. With special reference to fermented cow’s milk, a symbiotic (Gorbach and Goldin) when administered to another group of elderly people, behaved as donkey’s milk upregulating interleukins 6, 8 and also 1. In conclusion, the ability of milk and fermented milk to modulate the altered immune response in senescence needs to be exploited more for maintaining healthy aging.

The immune system and the gut microbiota: friends or foes?

The mammalian intestine is home to a complex community of trillions of bacteria that are engaged in a dynamic interaction with the host immune system. Determining the principles that govern host-microbiota relationships is the focus of intense research. Here, we describe how the intestinal microbiota is able to influence the balance between pro-inflammatory and regulatory responses and shape the host's immune system. We suggest that improving our understanding of the intestinal microbiota has therapeutic implications, not only for intestinal immunopathologies but also for systemic immune diseases.

Gut microbiota and lipopolysaccharide content of the diet influence development of regulatory T cells: studies in germ-free mice

BackgroundMammals are essentially born germ-free but the epithelial surfaces are promptly colonized by astounding numbers of bacteria soon after birth. The most extensive microbial community is harbored by the distal intestine. The gut microbiota outnumber ~10 times the total number of our somatic and germ cells. The host-microbiota relationship has evolved to become mutually beneficial. Studies in germ-free mice have shown that gut microbiota play a crucial role in the development of the immune system. The principal aim of the present study was to elucidate whether the presence of gut microbiota and the quality of a sterile diet containing various amounts of bacterial contaminants, measured by lipopolysaccharide (LPS) content, can influence maturation of the immune system in gnotobiotic mice.ResultsWe have found that the presence of gut microbiota and to a lesser extent also the LPS-rich sterile diet drive the expansion of B and T cells in Peyer's patches and mesenteric lymph nodes. The most prominent was the expansion of CD4+ T cells including Foxp3-expressing T cells in mesenteric lymph nodes. Further, we have observed that both the presence of gut microbiota and the LPS-rich sterile diet influence in vitro cytokine profile of spleen cells. Both gut microbiota and LPS-rich diet increase the production of interleukin-12 and decrease the production of interleukin-4. In addition, the presence of gut microbiota increases the production of interleukin-10 and interferon-γ.ConclusionOur data clearly show that not only live gut microbiota but also microbial components (LPS) contained in sterile diet stimulate the development, expansion and function of the immune system. Finally, we would like to emphasize that the composition of diet should be regularly tested especially in all gnotobiotic models as the LPS content and other microbial components present in the diet may significantly alter the outcome of experiments.