The Gut Flora As A Forgotten Organ
The Gut Flora As A Forgotten Organ
The Gut Flora As A Forgotten Organ
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The intestinal microflora is a positive health asset that crucially sequence data has facilitated the development of molecular
influences the normal structural and functional development of probes for fluorescence in situ hybridization, DNA microarrays
the mucosal immune system. Mucosal immune responses to resi- and gene chips that can identify and enumerate specific species.
dent intestinal microflora require precise control and an These molecular approaches have been used to examine the indi-
immunosensory capacity for distinguishing commensal from viduality and stability of the flora over time and to detect shifts in
pathogenic bacteria. In genetically susceptible individuals, some its composition after weaning, exposure to antibiotics or dietary
components of the flora can become a liability and contribute to changes. Although the intestinal flora of an adult alters with
the pathogenesis of various intestinal disorders, including inflam- lifestyle, diet and age (Hopkins et al, 2001), the prevailing influence
matory bowel diseases. It follows that manipulation of the flora to of the host genotype over environmental factors on an individual’s
enhance the beneficial components represents a promising thera- microbial diversity has been shown in a comparative study of the
peutic strategy. The flora has a collective metabolic activity equal flora of adults with varying degrees of genetic relatedness
to a virtual organ within an organ, and the mechanisms underlying (Zoetendal et al, 2001).
the conditioning influence of the bacteria on mucosal homeostasis The structure and composition of the gut flora reflects natural
and immune responses are beginning to be unravelled. An selection at both the microbial and host levels, which promotes
improved understanding of this hidden organ will reveal secrets mutual cooperation within and functional stability of this complex
that are relevant to human health and to several infectious, ecosystem. Although bacteria predominate, archaea and eukarya
inflammatory and neoplastic disease processes. are also represented. Acid, bile and pancreatic secretions hinder
Keywords: commensal bacteria; homeostasis; intestinal epithelium the colonization of the stomach and proximal small intestine by
EMBO reports (2006) 7, 688–693. doi:10.1038/sj.embor.7400731 most bacteria. However, bacterial density increases in the distal
small intestine, and in the large intestine rises to an estimated
Introduction 1011–1012 bacteria per gram of colonic content, which contributes
Host–microbe interactions occur primarily along mucosal sur- to 60% of faecal mass (Fig 1A). In addition to variations in the com-
faces, and one of the largest interfaces is the human intestinal position of the flora along the axis of the gastrointestinal tract, sur-
mucosa. The intestine is adapted to bi-directional host–flora face-adherent and luminal microbial populations also differ
exchange and harbours a diverse bacterial community that is sep- (Eckburg et al, 2005), and the ratio of anaerobes to aerobes is lower
arated from the internal milieu by only a single layer of epithelial at the mucosal surfaces than in the lumen.
cells. Resident bacteria outnumber human somatic and germ cells The fetal gut is sterile but colonization begins immediately after
tenfold and represent a combined microbial genome well in birth and is influenced by the mode of delivery, the infant diet,
excess of the human genome (Shanahan, 2002). Collectively, the hygiene levels and medication (Gronlund et al, 1999). Enterobacteria
flora has a metabolic activity equal to a virtual organ within an and bifidobacteria represent early colonizers, although differences in
organ (Bocci, 1992). gut microflora composition and the incidence of infection occur
Most bacterial species cannot be cultured, but modern molecular between breast- and formula-fed infants (Mountzouris et al, 2002). It
methods, such as broad-range sequencing of 16S ribosomal RNA seems that these pioneering bacteria can modulate gene expression
from amplified bacterial nucleic acid extracted from faeces or in the host to create a suitable environment for themselves and can
biopsies, indicate evolutionary divergence that can be used to prevent growth of other bacteria introduced later to the ecosystem
identify and classify bacteria. The availability of bacterial (Xu & Gordon, 2003).
1
Lessons from a life without intestinal microflora
Alimentary Pharmabiotic Centre, University College Cork, National University of Ireland,
Cork, Ireland
Enteric bacteria form a natural defence barrier and exert numerous
2Department of Medicine, University College Cork, National University of Ireland, Cork, protective, structural and metabolic effects on the epithelium
Ireland (Fig 1B). Their influence on intestinal physiology has been shown in
+Corresponding author. Tel: + 353 21 4901226; Fax: + 353 21 4345300;
comparative studies of germ-free and colonized animals. Germ-free
E-mail: [email protected]
animals are more susceptible to infection and have reduced vascu-
Submitted 23 February 2006; accepted 24 April 2006 larity, digestive enzyme activity, muscle wall thickness, cytokine
B
Protective functions Structural functions Metabolic functions
Pathogen displacement Barrier fortification Control IEC differentiation Ferment non-digestible
and proliferation dietary residue and endo-
Nutrient competition Induction of IgA
genous epithelial-derived
Metabolize dietary
Receptor competition Apical tightening of mucus
carcinogens
tight junctions
Production of anti-microbial Ion absorption
Synthesize vitamins
factors e.g., bacteriocins, Immune system
e.g., biotin, folate Salvage of energy
lactic acids development
Fig 1 | Functions of the intestinal flora. (A) Bacteria density increases in the jejunum/ileum from the stomach and duodenum, and in the large intestine, colon-
residing bacteria achieve the highest cell densities recorded for any ecosystem. The most common anaerobic and aerobic genera are listed. (B) Commensal bacteria
exert a miscellany of protective, structural and metabolic effects on the intestinal mucosa.
production ands serum immunoglobulin levels, smaller Peyer’s intestinal epithelial cell differentiation and proliferation, and
patches and fewer intraepithelial lymphocytes, but increased entero- mediate other metabolic effects (Fig 1B; Shanahan, 2002).
chromaffin cell area (Shanahan, 2002). However, reconstitution of Together, this complex metabolic activity recovers valuable energy
germ-free mice with an intestinal microflora is sufficient to restore and absorbable substrates for the host, and provides energy and
the mucosal immune system (Umesaki et al, 1995). Indeed, colo- nutrients for bacterial growth and proliferation. Colonization
nization of germ-free mice with a single species, Bacteroides increases the uptake of glucose in the intestine and, compared
thetaiotaomicron, affects the expression of various host genes that with colonized mice, germ-free mice require a greater caloric
influence nutrient uptake, metabolism, angiogenesis, mucosal barrier intake to sustain a normal body weight (Backhed et al, 2004). This
function and the development of the enteric nervous system (Xu & implicates gut bacteria as modulators of fat deposition in the host.
Gordon, 2003). Moreover, ligands from commensal bacteria and
commensal-derived symbiosis factors influence the normal devel- Host–flora communication at the mucosal surface
opment and function of the mucosal immune system (Mazmanian Host defence requires an accurate interpretation of the micro-
et al, 2005; Rakoff-Nahoum et al, 2004). Commensal bacteria pro- environment to distinguish commensal organisms from episodic
foundly influence the development of humoral components of the pathogens and a precise regulation of subsequent responses. The
gut mucosal immune system (Weinstein & Cebra, 1991) and also epithelium provides the first sensory line of defence and active sam-
modulate the fine-tuning of T-cell repertoires and T-helper (Th)-cell pling of resident bacteria, pathogens and other antigens is mediated
type 1 or type 2 cytokine profiles (Cebra, 1999; Shanahan, 2002). Thus, by three main types of immunosensory cell (Fig 2). First, surface
it is possible that the composition of the colonizing flora influences enterocytes serve as afferent sensors of danger within the luminal
individual variations in immunity. microenvironment by secreting chemokines and cytokines that
The intestinal microbiome has a metabolic activity that is both alert and direct innate and adaptive immune responses to the
adaptable and renewable (Bocci, 1992). Through the production of infected site (Shanahan, 2005). Second, M cells that overlie lym-
short-chain fatty acids, resident bacteria positively influence phoid follicles sample the environment and transport luminal
β-defensin
IgA Mucus
Commensal flora
M cell
Intestinal
epithelial PRR
cells
Dendrite
Cytokines
Dendritic cells Chemokines
PRR
Antigen
presenting
cells
Th1/Th2 effector T cells
Fig 2 | Immunosensory detection of intestinal bacteria. Surface enterocytes secrete many immune mediators in response to antigens, including antibacterial
peptides, immunoglobulin A (IgA) and chemokines. Specialized epithelial cells, termed M cells, transport and deliver antigens to antigen-presenting cells, which
subsequently process antigens and present them to naïve T cells. Antigen-presenting dendritic cells (DCs) also survey and sample the mucosal microenvironment.
Pattern recognition receptors (PRRs) expressed by DCs and enterocytes mediate the detection of bacterial antigens, and DCs modulate immune responsiveness or
tolerance by promoting either effector or regulatory T cells.
antigens to subadjacent dendritic cells and other antigen-presenting Many PRR ligands are expressed by commensal bacteria, yet the
cells. Third, intestinal dendritic cells themselves have a pivotal healthy gut does not evoke inflammatory responses to these bacteria.
immunosensory role and can directly sample gut contents by either Conversely, some commensal bacteria exert protective effects by
entering or extending dendrites between surface enterocytes with- attenuating pro-inflammatory responses induced by various
out disrupting tight junctions (Rescigno et al, 2001). Dendritic cells enteropathogenic bacteria (Kelly et al, 2004; Ma et al, 2004; O’Hara
can ingest and retain live commensal bacteria and travel to the et al, 2006). The host and bacterial mechanisms that underpin these
mesenteric lymph node where immune responses to commensal effects are being explored.
bacteria are induced locally (Macpherson & Uhr, 2004). Thus, act-
ing as a gatekeeper, the mesenteric lymph node prevents access of Host systems that contribute to homeostasis. In the healthy gut, TLR
commensal bacteria to the internal milieu. expression profiles contribute to homeostasis. Normal enterocytes
The ability of immunosensory cells to discriminate pathogenic express low levels of TLR2, TLR4 and the co-receptor MD-2, and lack
from commensal bacteria is mediated, in part, by two major host membrane-bound CD14, which is a co-receptor for lipopolysaccha-
pattern recognition receptor (PRR) systems—the family of Toll-like ride (Abreu et al, 2001; Otte et al, 2004). There have been conflicting
receptors (TLRs) and the nucleotide-binding oligomerization reports relating to the restricted expression of certain TLRs in the gut
domain/caspase recruitment domain isoforms (NOD/CARD; Cario, (Kelly et al, 2005). In particular, expression of TLR5 in vitro seems to
2005). These PRRs have a fundamental role in immune-cell activa- be basolateral (Gewirtz et al, 2001), but TLR5 is expressed on both
tion in response to specific microbial-associated molecular patterns. the apical and basolateral poles in vivo. This illustrates that intestinal
For example, TLR2 is activated by peptidoglycan and lipotechoic epithelial cell lines might express different levels, or have a different
acids, TLR4 by lipopolysaccharide, TLR5 by flagellin, and NOD1/ cellular distribution, of TLRs compared with normal gut mucosa. In
CARD4 and NOD2/CARD15 function as intracellular receptors of gastric epithelial cells, TLR5 can redistribute to a predominantly
peptidoglycan subunits. basolateral localization in response to Helicobacter pylori infection
TLRs and NOD proteins are expressed by surface enterocytes and (Cario & Podolsky, 2000; Schmausser et al, 2004), suggesting that
dendritic cells (Abreu et al, 2005), and in the gut PRRs seem to be under certain conditions TLR5 redistributes to the basolateral mem-
crucial for bacterial–host communication. Decreased enterocyte brane where it is ideally positioned to detect translocated flagellin. In
proliferation and levels of cytoprotective factors have been observed addition, intestinal enterocytes constitutively or inducibly express
in TLR-defective mice, and TLR signals mediated by commensal bac- high levels of the TLR inhibitor Toll-interacting protein (Tollip; Otte
teria or their ligands are essential for intestinal barrier function and et al, 2004). Tollip expression correlates directly with the luminal
repair of the gut (Fukata et al, 2005; Rakoff-Nahoum et al, 2004). bacterial load in vivo and is highest in healthy colonic mucosa.