Bacteria and the large intestine - Love Your Gut
Humans and bacteria coexist in different types of symbiotic relationships. aspects of the relationship between humans and bacteria are considered. inside the mouth, nose, throat, and intestines of humans and animals. The difference between the mucosa-associated bacterial communities in the colon and the In recent years, researchers studying the human gut microbiota have .. of the symbiotic relationship between the host and the intestinal microbiota. In these mutualistic relationships, the hosts gain carbon and energy, and their microbes are provided with a rich buffet of glycans and a protected anoxic.
This wide arsenal of toleragenic and inflammatory mediators is necessary as the decision to cooperate or defect is under continuous deliberation by both parties, where the costs of maintaining such an alliance are assessed. During incidences of disease, which inflate the costs of cooperation such that individual host or microbial fitness is threatened, a pause is placed on the partnership while various mediators host and microbial collaborate to reestablish intestinal homeostasis. This back and forth between tolerance and immunity, cooperation and defection, implies mechanisms of plasticity within the host and microbial response are necessary for protection from disease as well as maintenance of the cooperative system over time Edwards, ; Ulvestad, ; van Baalen, Accordingly, mathematical models of host—microbial interactions demonstrate that conditions where players are allowed to alter their actions, in response to one another, promote the evolution of commensalism, as compared to conditions where actions are fixed Taylor et al.
Applying this concept to the host, plasticity in immune development can be viewed as a mechanism of negotiating alliance between the host and the microbiota, in conditions of steady state and disease, allowing for the maintenance of a mutualism over time that is critical to both parties. Several recent reports have shown the ability of various T cell sub-populations to redifferentiate into cells that differ in cytokine expression and functional profile.
This conversion of Th2 cells, which required antigen presentation and IL cytokine stimulation, into Th1Th2 hybrid cells allowed for viral clearance and prevented viral-mediated immunopathology. These two examples demonstrate the ability of effector T cells to alter their expression profile, possibly to tailor a specific response to a particular microbial agent. In addition to T effector cells, T regulatory cells have been recently shown to adopt a proinflammatory profile, implicating the need to establish an immunogenic response to an agent once tolerated.
These exFoxp3 cells adopted an activated memory phenotype CD44hi as well as the expression of proinflammatory cytokines that were environment-specific. The study additionally demonstrated an increased ratio of exFoxp3 to Foxp3 positive cells during states of inflammatory disease.
To explore the functional properties of these cells, BDC2. Additional evidence of regulatory T cell plasticity was shown by Murai et al. Additional analysis confirmed that a greater proportion of the transferred regulatory cells into IL deficient hosts lost Foxp3 expression, compared to cells transferred into IL competent mice.
Loss of Foxp3 expression was dependent on the presence of inflammation, as transfer of Tregs alone without T effector cells into IL deficient hosts did not lead to loss of Foxp3 expression. In these two examples, it is shown how T regulatory cells can, under regulated conditions, lose their toleragenic profile, presumably to contribute to immune eradication of an infectious agent.
Although it still remains to be shown that proinflammatory T cells can be redifferentiated into cells that promote tolerance, the overall ability of T cells to be reprogrammed into cells with different function has been established. And while it is currently speculation, one could appreciate the value of this flexible immune response to the continuously changing microbial environment in the gut which is regulated by immune cells able to switch promoting tolerance to developing an immunogenic response.
Immune plasticity in response to the microbiota While direct evidence is currently lacking, it can be inferred that the changes in the immune profile and function of certain T cell populations are in part driven by alterations in the microbiota. The microbiota has been shown to directly modulate both innate and adaptive immune responses.
The immune subsets that are influenced by certain microbes may require continuous stimulation to maintain profile and function. Therefore, loss or alteration of particular microbial communities could then potentially result in a change in immune profile and function among certain immune populations. Mucosal Th17 cells represent one immune subset that may require continuous stimulation by certain microbial species to maintain its cytokine profile.
Multiple studies have shown that Th17 cells are largely absent in the small intestine of germ-free mice Atarashi et al. The adoption of an IL profile by mucosal T cells was shown to be in part dependent on intestinal colonization with SFB, a commensal microbe that tightly adheres to the small intestinal epithelium Ivanov et al.
Mice that are normally colonized, but lack SFB also showed reduced Th17 cells in the small intestine, similar to germ-free animals. However, upon colonization with SFB, these mice developed Th17 cells similar to that of control animals.
Additionally, short-term antibiotic treatment that depleted the microbiota resulted in a loss of intestinal Th17 cells, supporting the concept that certain immune cells require continuous stimulation by particular microbes to maintain their functional profile Ivanov et al.
The change in the Th17 population following intestinal colonization with SFB or antibiotic-mediated reduction of the microbiota indicates plasticity in T cell response to changes in the microbiota. In another example, Polysaccharide A PSAa capsular polysaccharide expressed by commensal organism Bacteroides fragilis has been shown to modulate both the mucosal and systemic immune system.
Even short-term oral exposure to purified PSA is able to promote the toleragenic T cell profile, resulting in protection from autoinflammatory intestinal disease. Additionally, one could speculate once the threat of systemic infection by B.
The ability of antigen-specific T cells to switch between pro- and anti-inflammatory subtypes is one possible example as to how the mucosal immune system is able to effectively shuffle between the inflammatory and toleragenic immune responses necessary to maintain intestinal homeostasis. Additionally, the microbiota may in part contribute to directing T cells to adopt the immune profile necessary for maintaining homeostasis.
One could then speculate that loss of either the host or microbial components necessary to switch between inflammation and tolerance could enhance susceptibility to immune disorders such as IBD. Bacterial induction of proinflammatory responses Studies from germ-free animals have provided a great deal of insight on the biological repercussions of bacterial colonization Falk et al. These studies of gnotobiology, which involve known colonization of selective microorganisms, have revealed that the microbiota plays a key role in the postnatal development of intestinal immune structures, such as gut-associated lymphoid tissues GALT and isolated lymphoid follicles ILF Bouskra et al.
Furthermore, the gut microbiota has been shown to affect the development of the adaptive immune response by actively inducing proinflammatory responses. Th17 cells play an important role in eliminating extracellular pathogens. Th17 cells produce the cytokines ILA, ILF, and IL, which subsequently trigger inflammatory signaling cascades and can lead to the recruitment of innate immune responder cells Korn et al.
Although Th17 cells are essential for immunity, they have been implicated in many autoimmune diseases, including IBD, arthritis, psoriasis, and experimental autoimmune encephalomyelitis EAE highlighting the importance of T cell effector regulation.
During steady state, Th17 cells are most abundant in gut-associated immune tissues. Interestingly, Th17 cells accumulate only in the presence of the intestinal commensal microbiota and are virtually absent in germ-free animals Atarashi et al. Treatment of conventionally colonized animals with selective antibiotics greatly diminished the amount of intestinal Th17 cells Ivanov et al.
Conversely, upon colonization with a conventional microbiota, germ-free animals acquired intestinal Th17 cells. The composition of the microbiota appears to be important as germ-free animals colonized with a defined cocktail of bacteria Altered Schaedler Flora still lacked Th17 cells in the small intestine Ivanov et al. Thus, the induction of intestinal Th17 cells is dependent on specific bacterial taxa as opposed to the general presence of bacteria.
The precise molecular signaling mechanisms that commensal bacteria employ to induce these Th17 responses still remain to be discovered. Compared to conventional animals, germ-free mice had greatly reduced concentrations of luminal ATP, and correspondingly, fewer Th17 cells in the lamina propria. Administration of ATP to germ-free animals led to a significant increase in intestinal Th17 cells.
Recent studies by two independent laboratories have identified a unique population of the intestinal microbiota, SFB, that is capable of inducing intestinal Th17 cells and recapitulating the maturation of T cell responses induced by the complete conventional mouse microbiota Gaboriau-Routhiau et al. SFB colonization of the murine small intestine of germ-free animals was sufficient to induce lamina propria Th17 cells, which were marked by the production of IL and IL cytokines Ivanov et al.
Colonization with SFB also correlated with an increase in expression of genes associated with antimicrobial defenses. More importantly, animals colonized with only SFB showed enhanced resistance to infection with the intestinal pathogen Citrobacter rodentium, suggesting a functional role for SFB-induced immune responses in mucosal protection.
In mice, Th17 immune responses have been shown to mediate protective roles in infections with extracellular and intracellular enteric pathogens such as C. Thus, bacteria-induced Th17 responses may provide a mechanism for increased intestinal resistance against pathogens. Commensal bacteria play a critical role in modulating other responses of the adaptive and innate immune system as well.
Colonization of germ-free animals with the human intestinal commensal B. Furthermore, the commensal microbiota has been shown to drive the expansion of Th1 cells as well in the colonic lamina propria Niess et al.
Addition of microbial DNA was sufficient to restore immune responses in these animals. TLR-dependent stimulation of host dendritic cells by gut bacteria has also been shown to play a key role in both innate and adaptive immunity to Toxoplasma gondii Benson et al. Taken together, these studies suggest that intestinal commensal bacteria may function as molecular adjuvants for mounting immune responses toward infectious microorganisms.
Furthermore, signaling through TLRs by commensal bacteria seems to be critical for maintaining intestinal epithelial homeostasis and protection from intestinal injury Rakoff-Nahoum et al. Thus, host communication with commensal bacteria plays a crucial role in priming and expanding basal levels of innate and adaptive immune activation.
Imbalances in host—microbial interactions Interactions between the mammalian host and the intestinal microbiota require a delicate balance that must be actively maintained by both host and microbe to achieve a healthy steady state Pamer, ; Round and Mazmanian, ; Sansonetti, Regulatory mechanisms exist to control bacterial colonization of the gut, while simultaneously preventing the immune system from reacting against innocuous microbial antigens.
As MAMPs are found ubiquitously on both pathogenic and commensal bacteria, it is crucial for the immune system to account for these important subtleties.
When this equilibrium is disrupted, inflammation can ensue potentially leading to disease. The mammalian gut has evolved numerous physical and molecular mechanisms for maintaining homeostasis with commensal organisms.
The intestinal surface constitutes an area of approximately m2 that is continuously exposed to mucosal and luminal microbes Artis, A single layer of IECs serves as an essential barrier between luminal contents and underlying host tissues. Tight junctions formed between IECs prevent bacteria from penetrating tissues. A rich glycocalyx layer of mucus and other glycoproteins further hinder bacterial attachment and invasion to host cells. Paneth cells and enterocytes in the gut secrete antimicrobial peptides, such as defensins, cathelicidins, and angiogenins which generally function by forming pores in bacterial cell walls.
These molecules are released in a concentration gradient manner that can modulate the spatial colonization of gut bacteria. While some classes of antimicrobial peptides are constitutively expressed, others are regulated by bacterial signaling through PRRs.
Peristalsis of the intestinal tract, rapid turnover of IECs, and secretion of IgA serve to confine the majority of the microbiota to the luminal compartment as well.How Bacteria Rule Over Your Body – The Microbiome
It has also been suggested that commensal organisms of the microbiota may preferably colonize the lumen of the intestine instead of the mucosal layer to maintain a safe distance from host tissues, whereas enteric pathogens may overstep these boundaries Hooper, Spatial localization of PRRs, such as toll-like receptors TLRs and NOD proteins, in the gut help prevent inadvertent activation of the innate immune system by the microbiota.
In the small intestine of mice, expression of TLR4 and possibly NOD receptors may occur primarily in the bottom of intestinal crypts, allowing innate immune activation only when bacteria have breached host borders Hornef et al. Furthermore, commensal bacteria may actively employ mechanisms to maintain equilibrium with host cells.
Modulating expression of immunodominant epitopes may be one method used by symbiotic bacteria to avoid immune recognition and to stably colonize the gut Comstock and Coyne, ; Krinos et al.
Genomic sequencing of several human gut-associated Bacteroides species has shown the presence of many genetic loci for the purpose of generating diversity in the polysaccharide coat Cerdeno-Tarraga et al.
Studies of Helicobacter hepaticus, a Gram-negative murine bacterium, have provided insight on host immune responses that lead to disease. In some cases, animals with genetic deficiencies may select for a pathogenic microbiota that can elicit inflammation in the host and even cause disease when transferred to other animals Garrett et al. Initial work had identified T-bet as mainly functioning in the development of Th1 cells; however, T-bet has recently been implicated in directing proinflammatory roles in the innate immune system as well.
Intestinal disease in these animals progressively worsens into colonic dysplasia and rectal adenocarcinoma, implicating a strong role for T-bet in maintaining proper host—commensal relationships Garrett et al. Antibiotic treatment of animals cured intestinal inflammation indicating the role of the microbiota in driving disease.
Antimicrobial peptides appear to also be important in regulating the composition of the microbiota.
Evolution of Symbiotic Bacteria in the Distal Human Intestine
Dysregulation of antimicrobial peptides in Drosophila melanogaster gut led to host mortality, caused by the outgrowth of a pathogenic microbiota dominated primarily by a single gut microbe Ryu et al. In addition, signaling through IECs plays a critical role in gut homeo-stasis and intestinal inflammation.
In mice deficient in the single immunoglobulin IL-1 receptor-related molecule SIGIRRwhich acts as a negative regulator for Toll-IL-1R signaling, increases in cell proliferation and inflammatory responses that were commensal-dependent were observed Xiao et al. Altogether, these studies highlight the profound implications genetic disorders can have on host—commensal mutualisms.
IBD results in a wide range of clinical outcomes in affected individuals. The disease is, generally, thought to be mediated by an overt T cell inflammatory response that is perpetuated by stimulation from microbial antigens. Current animal models of IBD suggest that pathogenesis is driven by a variety of interacting factors, including host genetic and immune status, the gut microbiota, and environmental triggers Packey and Sartor, Commensal bacteria of the microbiota have been strongly implemented in the initiation and progression of IBD.
Host–Bacterial Symbiosis in Health and Disease
Patients with IBD show higher serological and T cell responses to enteric microbial antigens and respond favorably to antibiotic treatment Macpherson et al. In models of experimental colitis, inflammation generally does not ensue when animals are placed under germ-free conditions.
Despite the important contribution of the microbiota in IBD, only one bacterial species has been identified as being strongly correlated with disease. IBD may be caused in part by overall changes in the development or composition of the intestinal microbiota, known as dysbiosis Kinross et al. Currently, it remains unknown whether dysbiosis of the gut microbiota is a result of IBD or the cause of inflammation. Clinical data show that in IBD patients with underlying genetic mutations, inflammation is directed toward specific commensal organisms of the microbiota, such as Clostridium and Enterococcus species which are ubiquitously found in the mammalian gut.
Thus, symbiotic microbes which are, generally, perceived as innocuous by hosts become sources of inflammatory antigen. Culture-independent rRNA sequence analysis of intestinal tissue samples from patients with and without IBD revealed a striking difference between the microbiota of healthy and IBD patients.
Temporal stability and diversity of the gut microbiota composition in IBD patients were revealed to be significantly decreased compared to non-IBD controls Scanlan et al. Interestingly, the microbiotas of IBD patients were marked by a reduction in commensal bacteria, particular in members of the phyla Firmicutes and Bacteroidetes, and exhibited a concomitant increase in Proteobacteria and Actinobacteria Frank et al. A reduction in Clostridia species and Bacteroides species in IBD patients may have profound effects on intestinal health, as these species produce butyrate and other short-chain fatty acids SCFAs that are important in enhancing epithelial barrier integrity and modulating intestinal immune system responses.
Human and Bacteria Mutualism by Kelly Lee on Prezi
The concept of dysbiosis is also supported by animal models of obesity Turnbaugh et al. In these studies, transferring the microbiota from obese mice to nonobese mice led to an increase in mean body fat of recipient animals, suggesting that disturbances in the microbiota can directly affect physiological health.
With the development of large-scale metagenomic sequencing technologies, future studies will uncover the precise role the microbiota play during initiation and progression of IBD Turnbaugh et al. Gnotobiotic studies of germ-free animals will be instrumental in identifying functional effects of colonization with specific species.
In addition, genetic factors in the host can contribute to susceptibility to disease. Mutations in other innate immune proteins that respond to microbial antigens have further been identified—TLR1, 2, 4, and 6; ATG16L1, which is involved in the autophagosome pathway; and NCF4, which mediates bactericidal activities in phagocytes Franchimont et al. Intestinal homeostasis requires proper bacterial recognition and elimination of organisms that invade host tissues.
Defects in these critical processes can lead to increased microbial antigen exposure and subsequent chronic inflammation.
Variations in genes related to T cell immunity have also been implicated. ILR variants associated with increased susceptibility correlated strongly with higher serum levels of IL, suggesting a role for Th17 cell function Schmechel et al. In an experimental model of colitis, treatment of animals with monoclonal antibody against ILp19 alleviated inflammation and induced apoptosis of Th17 cells, highlighting the importance of these findings Elson et al.
Although the majority of the commensal community exhibits beneficial relationships with the host, some members of the community have the potential to trigger pathogenic inflammatory responses under certain conditions.
Since certain components of the commensals still possess pathogenic activity, the question becomes how the symbiotic relationships between commensals and their hosts are maintained during steady state without eliciting harmful inflammation that may result in tissue damage. In early sections, we discussed various host mechanisms that contribute to the host—microbial homeostasis.
Such mechanisms include the secretion of a thick mucus layer by goblet cells in the intestine, the production of antimicrobial peptides and IgA by Paneth cells and B cells, respectively, all of which restrict the microbiota from directly contacting host tissues and prevent the penetration of commensals across the epithelial barrier which may further induce host inflammatory responses.
However, immunological ignorance of the microbiota is just one side of the story. The constant interaction between commensals and the epithelium is inevitable because stable colonization of the microbiota requires close contact of bacteria with mucosal surfaces.
Moreover, PRRs, such as TLRs and NOD family proteins, are expressed on epithelial cells to specifically monitor the microbial components in the environment and are ready to trigger downstream inflammatory responses once bound with MAMPs.
Therefore, there must exist other mechanisms to dampen the constant inflammation that the microbiota may induce in healthy hosts. In recent years, an increasing amount of evidence has suggested that commensals actually have evolved different ways to actively suppress inflammation, not only during steady state, but also during pathogenic states.
Downregulation of innate immunity PRRs, such as TLRs, play essential roles in innate immunity in response to microbial agents. They are surface or intracellular signaling receptors that are able to recognize microbe-specific molecules and trigger intracellular signaling cascades, which eventually lead to the activation of several transcription factors e. However, the molecular mechanism by which this occurs remains to be found.
An in vitro study by Neish et al. Furthermore, a prevalent commensal bacterium of the human intestinal microbiota, B. The authors discovered that the mechanism underlying this anti-inflammatory activity involved B. It is worth noting that some pathogens have also evolved a similar mechanism to escape attack from the proinflammatory response. However, this does not appear to be the case as colonization by beneficial bacteria does not result in immunodeficiency.
Thus, the immune-suppression mechanism of commensals must differ from that of pathogens in that it must keep basal inflammation at a low level while also allowing the host immune system to retain its ability to elicit strong proinflammatory responses against pathogens.
More importantly, it may bring up new targets for treating inflammatory diseases. Therefore, the optimization of primer selection can help to decrease such errors, although it requires complete knowledge of the microorganisms present in the sample, and their relative abundances. The first thing to do in a marker gene amplicon analysis is to remove sequencing errors; a lot of sequencing platforms are very reliable, but most of the apparent sequence diversity is still due to errors during the sequencing process.
To reduce this phenomenon a first approach is to cluster sequences into Operational taxonomic unit OTUs: Another approach is Oligotypingwhich includes position-specific information from 16s rRNA sequencing to detect small nucleotide variations and from discriminating between closely related distinct taxa.
These methods give as an output a table of DNA sequences and counts of the different sequences per sample rather than OTU. Other popular analysis packages provide support for taxonomic classification using exact matches to reference databases and should provide greater specificity, but poor sensitivity. Unclassified microorganism should be further checked for organelle sequences.
Phylogenetic comparative methods PCS are based on the comparison of multiple traits among microorganisms; the principle is: Ancestral state reconstruction is used in microbiome studies to impute trait values for taxa whose traits are unknown. Phylogenetic variables are chosen by researchers according to the type of study: All this methods are negatively affected by horizontal gene trasmission HGTsince it can generate errors and lead to the correlation of distant species.
There are different ways to reduce the negative impact of HGT: Skin and vaginal sites showed smaller diversity than the mouth and gut, these showing the greatest richness. The bacterial makeup for a given site on a body varies from person to person, not only in type, but also in abundance. Bacteria of the same species found throughout the mouth are of multiple subtypes, preferring to inhabit distinctly different locations in the mouth. Even the enterotypes in the human gut, previously thought to be well understood, are from a broad spectrum of communities with blurred taxon boundaries.
Firmicutes and Bacteroidetes dominate but there are also ProteobacteriaVerrumicrobiaActinobacteriaFusobacteria and Cyanobacteria.
If this is not removed by brushing, it hardens into calculus also called tartar. The same bacteria also secrete acids that dissolve tooth enamelcausing tooth decay. The vaginal microflora consist mostly of various lactobacillus species. It was long thought that the most common of these species was Lactobacillus acidophilusbut it has later been shown that L.
Other lactobacilli found in the vagina are L. Disturbance of the vaginal flora can lead to infections such as bacterial vaginosis or candidiasis "yeast infection". Archaea[ edit ] Archaea are present in the human gut, but, in contrast to the enormous variety of bacteria in this organ, the numbers of archaeal species are much more limited.