The gut flora as a forgotten organ
TL;DR: The flora has a collective metabolic activity equal to a virtual organ within an organ, and the mechanisms underlying the conditioning influence of the bacteria on mucosal homeostasis and immune responses are beginning to be unravelled.
Abstract: The intestinal microflora is a positive health asset that crucially influences the normal structural and functional development of the mucosal immune system. Mucosal immune responses to resident intestinal microflora require precise control and an immunosensory capacity for distinguishing commensal from pathogenic bacteria. In genetically susceptible individuals, some components of the flora can become a liability and contribute to the pathogenesis of various intestinal disorders, including inflammatory bowel diseases. It follows that manipulation of the flora to enhance the beneficial components represents a promising therapeutic strategy. The flora has a collective metabolic activity equal to a virtual organ within an organ, and the mechanisms underlying the conditioning influence of the bacteria on mucosal homeostasis and immune responses are beginning to be unravelled. An improved understanding of this hidden organ will reveal secrets that are relevant to human health and to several infectious, inflammatory and neoplastic disease processes.
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TL;DR: Findings indicating that developmental aspects of the adaptive immune system are influenced by bacterial colonization of the gut are discussed, and the possibility that the mammalian immune system, which seems to be designed to control microorganisms, is in fact controlled by microorganisms is raised.
Abstract: Immunological dysregulation is the cause of many non-infectious human diseases such as autoimmunity, allergy and cancer. The gastrointestinal tract is the primary site of interaction between the host immune system and microorganisms, both symbiotic and pathogenic. In this Review we discuss findings indicating that developmental aspects of the adaptive immune system are influenced by bacterial colonization of the gut. We also highlight the molecular pathways that mediate host–symbiont interactions that regulate proper immune function. Finally, we present recent evidence to support that disturbances in the bacterial microbiota result in dysregulation of adaptive immune cells, and this may underlie disorders such as inflammatory bowel disease. This raises the possibility that the mammalian immune system, which seems to be designed to control microorganisms, is in fact controlled by microorganisms.
4,079 citations
TL;DR: The advances in modeling and analysis of gut microbiota will further the authors' knowledge of their role in health and disease, allowing customization of existing and future therapeutic and prophylactic modalities.
Abstract: Gut microbiota is an assortment of microorganisms inhabiting the length and width of the mammalian gastrointestinal tract. The composition of this microbial community is host specific, evolving throughout an individual's lifetime and susceptible to both exogenous and endogenous modifications. Recent renewed interest in the structure and function of this "organ" has illuminated its central position in health and disease. The microbiota is intimately involved in numerous aspects of normal host physiology, from nutritional status to behavior and stress response. Additionally, they can be a central or a contributing cause of many diseases, affecting both near and far organ systems. The overall balance in the composition of the gut microbial community, as well as the presence or absence of key species capable of effecting specific responses, is important in ensuring homeostasis or lack thereof at the intestinal mucosa and beyond. The mechanisms through which microbiota exerts its beneficial or detrimental influences remain largely undefined, but include elaboration of signaling molecules and recognition of bacterial epitopes by both intestinal epithelial and mucosal immune cells. The advances in modeling and analysis of gut microbiota will further our knowledge of their role in health and disease, allowing customization of existing and future therapeutic and prophylactic modalities.
3,077 citations
Cites background from "The gut flora as a forgotten organ"
...and profiles (220) and are impaired in the generation of...
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...The number of bacterial cells present in the mammalian gut shows a continuum that goes from 10(1) to 10(3) bacteria per gram of contents in the stomach and duodenum, progressing to 10(4) to 10(7) bacteria per gram in the jejunum and ileum and culminating in 10(11) to 10(12) cells per gram in the colon (220) (Fig....
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...The GF gut presents an increased enterochromaffin cell area (220), while the intestinal surface area is reduced (94)....
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TL;DR: The emerging concept of a microbiota–gut–brain axis suggests that modulation of the gut microbiota may be a tractable strategy for developing novel therapeutics for complex CNS disorders.
Abstract: Recent years have witnessed the rise of the gut microbiota as a major topic of research interest in biology. Studies are revealing how variations and changes in the composition of the gut microbiota influence normal physiology and contribute to diseases ranging from inflammation to obesity. Accumulating data now indicate that the gut microbiota also communicates with the CNS — possibly through neural, endocrine and immune pathways — and thereby influences brain function and behaviour. Studies in germ-free animals and in animals exposed to pathogenic bacterial infections, probiotic bacteria or antibiotic drugs suggest a role for the gut microbiota in the regulation of anxiety, mood, cognition and pain. Thus, the emerging concept of a microbiota-gut-brain axis suggests that modulation of the gut microbiota may be a tractable strategy for developing novel therapeutics for complex CNS disorders.
3,058 citations
TL;DR: It is suggested that a holistic approach to studying the microbiota that goes beyond characterization of community composition and encompasses dynamic interactions between all components of the microbiota and host tissue over time will be crucial for building predictive models for diagnosis and treatment of diseases linked to imbalances in the microbiota.
2,832 citations
Cites background from "The gut flora as a forgotten organ"
...It appears that both the innate and adaptive immune systems have evolved to require microbial interactions during their development (Chow et al., 2010; O’Hara and Shanahan, 2006)....
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...When TLRs are not present or are mutated, the gut and mucosal immune systems do not form normally (O’Hara and Shanahan, 2006)....
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...The microbiota plays a major role in health and disease in humans; indeed, it is sometimes referred to as our ‘‘forgotten organ’’ (O’Hara and Shanahan, 2006)....
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...The commensal bacteria appear to be important in suppressing inflammatory response and promoting immunological tolerance, and this interaction also occurs through TLRs (O’Hara and Shanahan, 2006; Round et al., 2011)....
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...Toll-like receptors (TLRs) are one of the several proteins that the host uses to recognize such antigens....
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TL;DR: The gut microbiota has a beneficial role during normal homeostasis, modulating the host's immune system as well as influencing host development and physiology, including organ development and morphogenesis, and host metabolism.
Abstract: Establishing and maintaining beneficial interactions between the host and its associated microbiota are key requirements for host health. Although the gut microbiota has previously been studied in the context of inflammatory diseases, it has recently become clear that this microbial community has a beneficial role during normal homeostasis, modulating the host's immune system as well as influencing host development and physiology, including organ development and morphogenesis, and host metabolism. The underlying molecular mechanisms of host-microorganism interactions remain largely unknown, but recent studies have begun to identify the key signalling pathways of the cross-species homeostatic regulation between the gut microbiota and its host.
2,585 citations
References
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TL;DR: A majority of the bacterial sequences corresponded to uncultivated species and novel microorganisms, and significant intersubject variability and differences between stool and mucosa community composition were discovered.
Abstract: The human endogenous intestinal microflora is an essential “organ” in providing nourishment, regulating epithelial development, and instructing innate immunity; yet, surprisingly, basic features remain poorly described. We examined 13,355 prokaryotic ribosomal RNA gene sequences from multiple colonic mucosal sites and feces of healthy subjects to improve our understanding of gut microbial diversity. A majority of the bacterial sequences corresponded to uncultivated species and novel microorganisms. We discovered significant intersubject variability and differences between stool and mucosa community composition. Characterization of this immensely diverse ecosystem is the first step in elucidating its role in health and disease.
7,049 citations
"The gut flora as a forgotten organ" refers background in this paper
...In addition to variations in the composition of the flora along the axis of the gastrointestinal tract, surface-adherent and luminal microbial populations also differ (Eckburg et al, 2005), and the ratio of anaerobes to aerobes is lower at the mucosal surfaces than in the lumen....
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TL;DR: Analysis of the microbiota of genetically obese ob/ob mice, lean ob/+ and wild-type siblings, and their ob/+ mothers, all fed the same polysaccharide-rich diet, indicates that obesity affects the diversity of the gut microbiota and suggests that intentional manipulation of community structure may be useful for regulating energy balance in obese individuals.
Abstract: We have analyzed 5,088 bacterial 16S rRNA gene sequences from the distal intestinal (cecal) microbiota of genetically obese ob/ob mice, lean ob/+ and wild-type siblings, and their ob/+ mothers, all fed the same polysaccharide-rich diet. Although the majority of mouse gut species are unique, the mouse and human microbiota(s) are similar at the division (superkingdom) level, with Firmicutes and Bacteroidetes dominating. Microbial-community composition is inherited from mothers. However, compared with lean mice and regardless of kinship, ob/ob animals have a 50% reduction in the abundance of Bacteroidetes and a proportional increase in Firmicutes. These changes, which are division-wide, indicate that, in this model, obesity affects the diversity of the gut microbiota and suggest that intentional manipulation of community structure may be useful for regulating energy balance in obese individuals.
5,365 citations
"The gut flora as a forgotten organ" refers background in this paper
...Moreover, the microflora itself is a substantial consumer of energy, and increasing adiposity has been shown to mediate changes in the diversity of the gut flora (Ley et al, 2005)....
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TL;DR: In this article, the authors found that conventionalization of adult germ-free C57BL/6 mice with a normal microbiota harvested from the distal intestine (cecum) of conventionally raised animals produces a 60% increase in body fat content and insulin resistance within 14 days despite reduced food intake.
Abstract: New therapeutic targets for noncognitive reductions in energy intake, absorption, or storage are crucial given the worldwide epidemic of obesity. The gut microbial community (microbiota) is essential for processing dietary polysaccharides. We found that conventionalization of adult germ-free (GF) C57BL/6 mice with a normal microbiota harvested from the distal intestine (cecum) of conventionally raised animals produces a 60% increase in body fat content and insulin resistance within 14 days despite reduced food intake. Studies of GF and conventionalized mice revealed that the microbiota promotes absorption of monosaccharides from the gut lumen, with resulting induction of de novo hepatic lipogenesis. Fasting-induced adipocyte factor (Fiaf), a member of the angiopoietin-like family of proteins, is selectively suppressed in the intestinal epithelium of normal mice by conventionalization. Analysis of GF and conventionalized, normal and Fiaf knockout mice established that Fiaf is a circulating lipoprotein lipase inhibitor and that its suppression is essential for the microbiota-induced deposition of triglycerides in adipocytes. Studies of Rag1-/- animals indicate that these host responses do not require mature lymphocytes. Our findings suggest that the gut microbiota is an important environmental factor that affects energy harvest from the diet and energy storage in the host. Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. AY 667702--AY 668946).
5,221 citations
TL;DR: It is shown that commensal bacteria are recognized by TLRs under normal steady-state conditions, and this interaction plays a crucial role in the maintenance of intestinal epithelial homeostasis and protection from injury.
3,972 citations
"The gut flora as a forgotten organ" refers background in this paper
...Moreover, ligands from commensal bacteria and commensal-derived symbiosis factors influence the normal development and function of the mucosal immune system (Mazmanian et al, 2005; Rakoff-Nahoum et al, 2004)....
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...Decreased enterocyte proliferation and levels of cytoprotective factors have been observed in TLR-defective mice, and TLR signals mediated by commensal bacteria or their ligands are essential for intestinal barrier function and repair of the gut (Fukata et al, 2005; Rakoff-Nahoum et al, 2004)....
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TL;DR: During colonization of animals with the ubiquitous gut microorganism Bacteroides fragilis, a bacterial polysaccharide (PSA) directs the cellular and physical maturation of the developing immune system.
2,520 citations
"The gut flora as a forgotten organ" refers background in this paper
...Moreover, ligands from commensal bacteria and commensal-derived symbiosis factors influence the normal development and function of the mucosal immune system (Mazmanian et al, 2005; Rakoff-Nahoum et al, 2004)....
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