Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
Importance of microbial colonization of the gut in early life to the development of immunity
Introduction
The human gut microbiota, shaped by the long co-evolutionary history of symbiotic host–microbe interaction, plays an important role in maintaining human health by preventing colonization by pathogens, degrading dietary and in situ-produced compounds, producing nutrients, and maintaining the normal mucosal immunity [1], [2], [3]. Other important functions have begun to emerge over recent years suggesting that the effects of the commensal microbiota may be more profound; influencing processes as complex as lipid metabolism of the host [4], predisposition to obesity [5], [6], immune development and homeostasis, inflammation, repair and angiogenesis [7], [8], [9], [10]. The inter-relationships between the microbiota and the host are clearly important in relation to health and imbalance between these systems appears to drive a wide range of mucosal and systemic immune-mediated disorders including inflammatory bowel diseases, autoimmune and allergic conditions. In this review we discuss current data linking the human commensal microbiota to immunological development and function and highlight the potential consequences of microbe–host dialogue in early life to human health.
Section snippets
A single mucosal immune system, innate and adaptive components
The mucosal immune system relies on cells of both the innate and adaptive immune systems that function concertedly to neutralize potentially dangerous infectious agents and maintain tolerance to dietary antigens and commensal bacteria [11]. Innate immune signalling is mediated by innate or natural immune cells expressing germ-line receptors of limited repertoires that respond promptly following pattern recognition of bacterial structures (pathogen-associated molecular patterns or PAMPs) and
Describing the human gut microbiota
Historically, culture-based techniques characterizing microbial diversity dominated the field and as a result the most predominant species isolated from the human gut were considered to be Bacteroides spp., Bifidobacterium spp., Eubacterium spp., Peptostreptococcus spp., and Fusobacterium spp. [13]. These techniques, essentially based on fecal sampling and plating on specific selective media under anaerobic (up to 99.9% of colonic bacteria are obligate anaerobes) and aerobic conditions
Early colonization of the GIT
The mammalian fetal intestine is essentially sterile and the first exposure to maternal microbiota occurs during passage through the birth canal during the first hours of delivery. In the beginning of colonization, the microbiota of the newborn is heterogeneous [23]. In the cultivated microbiota of vaginally delivered and breast-fed infants, the majority of the fecal population is represented by bifidobacteria, with smaller numbers of Escherichia coli, bacteroides and clostridia [24]. In
Genomic and metagenomic approaches to functionality of the human microbiota
The major drawback of descriptive microbial diversity studies is their limited value in discerning the functional role of the majority of bacteria in the human gut. To address this several new approaches have been proposed. The human gut microbiome initiative, which aims to generate draft genome sequences of hundreds of gut bacteria as well as new metagenomic analyses have been proposed as routes of analysing the functional diversity of the human gut microbiota [40], [41]. Studies utilizing
Microbial colonization and development of immunity
Extensive intercellular signalling between lymphoid cell types is a key feature of a highly regulated innate and adaptive immune system. These interactions occur within germinal centres (GCs) and secondary lymphoid follicles (LFs) associated with the structurally complex gut-associated lymphoid tissues (GALT). There is increasing awareness that the GALT plays a role in shaping the repertoire of the gut microbiota and vice versa. In young mammals GC and LF regions of the GALT are incompletely
Microbial colonization, gut barrier and maintenance of immune tolerance
Several lines of evidence from various animal and disease models support the view that there is intensive communication between the host and gut bacteria. The net outcome of this communication, in immunological terms, is dictated largely by the nature of the bacterium. In healthy individuals commensal non-harmful bacteria induce immunological tolerance, contrasting with the response generated by pathogenic bacteria, which is characterized by strong pro-inflammatory reactions that trigger immune
The IgA barrier—milk and B1 cells in young mammals
The presence of microbial-reactive IgA in the lumen strongly augments the physical barrier function of the developing and adult gut and plays a key role in shaping the immune response to microbial colonization. The intestinal IgA shields the commensal flora from both the innate and the systemic immune system [49]. This function is likely to be very critical in early life when mechanisms of immune regulation are not fully operational. In the absence of IgA, gut commensal bacteria overgrow, have
IgA barrier—T cell-dependent
In the maturing gut, high affinity neutralising IgA is generated in a T cell-dependent fashion within the organised follicular structures of the GALT. The major inductive sites in the small intestine are LFs, either solitary or clustered as in Peyer's patches (PP). These follicles are covered by a specialised follicle associated epithelium (FAE) containing M cells (microfold cells) that take up intact macromolecules, particles and pathogens, and deliver them by transepithelial transport to
Commensal bacteria, signalling through extra- and intra-cellular recognition receptors
Although exclusion and immune suppression are key features of immune tolerance to commensal bacteria, the expansion and function of the immune system is built upon recognition and sampling. These later events are critical for immune education. A wide range of TLRs [67] and non-TLRs [68] for PAMP recognition have been characterised on gut epithelial cells, associated DCs, monocytes and macrophages [69]; lineages involved in microbial-immune surveillance. Yet there is a paradox, the commensal
DCs and mesenteric lymph nodes in microbe/host interaction
The development of the GALT sees an increasingly vital sentinel role for cellular components of the innate system including DCs, macrophages and epithelial cells that together monitor the microbial environment and coordinate immune responses to danger signals [80]. A subpopulation of DCs (CX3CR1+) populate the entire lamina propria as well as the dome regions of the PP [81]. These DCs are responsible for continuous antigen acquisition from the intestinal lumen and transport of this antigen for
Tregs and mucosal tolerance
In the steady state, prior to acute infection and inflammation, DCs are in an immature state and not fully differentiated to carry out their known roles as inducers of immunity. However, these immature cells are not inactive. They continuously circulate through tissues and into lymphoid organs, capturing self-antigens as well as innocuous environmental and microbial proteins. Recent experiments have provided direct evidence of antigen-loaded immature DCs in vivo that silence T cells either by
Childhood infections and vaccination
Vaccination is the most effective means of preventing infectious diseases and is largely responsible for the eradication of diseases such as polio-myelitis, smallpox and diphtheria that, in early periods of history, caused high mortality amongst children. Whilst disease control in this way is absolutely essential much of the ongoing work in vaccine development aims to derive ‘good vaccines’ with improved biological efficacy [60]. Commonly used vaccines promote antibody responses but have little
Hygiene hypothesis-link between gut microbiota and disease
Microorganisms colonising the human gastrointestinal tract are now recognized to contribute significantly to improved nutrient status and health of the host. These outcomes are achieved mainly through improved nutrient availability and nutrient capture in the human colon but also through enhanced immune functionality. Such positive effects on the immune system are though to confer protection against many human diseases including inflammatory bowel disease (IBD), atopic diseases and other
Hygiene hypothesis and the normal commensal microbiota
The hygiene hypothesis may be extended to encompass the protective effects of benign, non-infectious gut microbes. The basis of this assumption is that altered microbial diversity and functional activities of the luminal microbiota may be linked to the etiology of immune-mediated diseases. In children with allergic diseases, the fecal microbiota composition is markedly different from the norm. For example, the fecal microbiota of children with eczema is characterized by lower number of
Probiotic approaches to restore microbial balance and treat human diseases
Due to the potential beneficial effects of commensal bacteria on immune function, there is now considerable interest in using probiotics in clinical medicine for the treatment of a wide range of disorders including necrotizing enterocolitis in pre-term infants, atopic eczema, inflammatory bowel diseases and cancer (reviewed by [110], [111]). Some clinical trials suggest that probiotics exert either prophylactic or therapeutic benefit [112], [113] whereas others have shown that they have no
Summary
The functionally immature immune status of a newborn must be properly educated to deal with the challenges of autonomous life such as the development immune competence against pathogens, while ensuring that tolerance to common food antigens and commensal microbiota is maintained. Appropriate antigen exposure of the infant gut at the right time is crucial for the healthy development of gut-associated and systemic immune responses. This includes colonization of the gut by bacteria from the
Acknowledgements
The author's work was sponsored by the Scottish Executive Environment and Rural Affairs Department.
Reference (115)
- et al.
- et al.
Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis
Cell
(2004) Thematic review series: the immune system and atherogenesis. Bridging the innate and adaptive immune systems
J. Lipid Res.
(2005)The indigenous gastrointestinal microflora
Trends Microbiol.
(1996)- et al.
Mucosal flora in inflammatory bowel disease
Gastroenterology
(2002) - et al.
Mode of delivery and risk of allergic rhinitis and asthma
J. Allergy Clin. Immunol.
(2003) - et al.
Mode of delivery is associated with asthma and allergy occurrences in children
Ann. Epidemiol.
(2006) - et al.
Comparison of bacterial diversity along the human intestinal tract by direct cloning and sequencing of 16S rRNA genes
FEMS Microbiol. Ecol.
(2005) - et al.
How do we compare hundreds of bacterial genomes?
Curr. Opin. Microbiol.
(2006) - et al.
An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system
Cell
(2005)