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Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE
Yong Chan Lee |
Professor of Medicine Director, Gastrointestinal Research Laboratory Veterans Affairs Medical Center, Univ. California San Francisco San Francisco, USA |
Jong Pil Im | Seoul National University College of Medicine, Seoul, Korea |
Robert S. Bresalier | University of Texas M. D. Anderson Cancer Center, Houston, USA |
Steven H. Itzkowitz | Mount Sinai Medical Center, NY, USA |
All papers submitted to Gut and Liver are reviewed by the editorial team before being sent out for an external peer review to rule out papers that have low priority, insufficient originality, scientific flaws, or the absence of a message of importance to the readers of the Journal. A decision about these papers will usually be made within two or three weeks.
The remaining articles are usually sent to two reviewers. It would be very helpful if you could suggest a selection of reviewers and include their contact details. We may not always use the reviewers you recommend, but suggesting reviewers will make our reviewer database much richer; in the end, everyone will benefit. We reserve the right to return manuscripts in which no reviewers are suggested.
The final responsibility for the decision to accept or reject lies with the editors. In many cases, papers may be rejected despite favorable reviews because of editorial policy or a lack of space. The editor retains the right to determine publication priorities, the style of the paper, and to request, if necessary, that the material submitted be shortened for publication.
Sean M.P. Bennet*,†, Lena Öhman*,†, and Magnus Simrén*
Correspondence to: Magnus Simrén, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg 4135, Sweden Tel: +46-31-342-8068, Fax: +46-31-741-2917, E-mail: magnus.simren@medicine.gu.se
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Gut Liver 2015;9(3):318-331. https://doi.org/10.5009/gnl14344
Published online May 15, 2015, Published date May 30, 2015
Copyright © Gut and Liver.
Irritable bowel syndrome (IBS) is a multifactorial functional disorder with no clearly defined etiology or pathophysiology. Modern culture-independent techniques have improved the understanding of the gut microbiota’s composition and demonstrated that an altered gut microbiota profile might be found in at least some subgroups of IBS patients. Research on IBS from a microbial perspective is gaining momentum and advancing. This review will therefore highlight potential links between the gut microbiota and IBS by discussing the current knowledge of the gut microbiota; it will also illustrate bacterial-host interactions and how alterations to these interactions could exacerbate, induce or even help alleviate IBS.
Keywords: Irritable bowel syndrome, Microbiota, Immunity, Dysbiosis, Probiotics
Patients with functional bowel disorders (FBDs) have no clear structural or biochemical alterations on routine examinations, making diagnosis and treatment challenging. A number of FBDs affect the lower gastrointestinal (GI) tract with irritable bowel syndrome (IBS) being the most prevalent, affecting approximately 10% to 20% of the population in the Western world.1–3 IBS is characterized by abdominal discomfort or pain associated with disturbed bowel habits,4 but also other GI symptoms such as distension and bloating, with patients often reporting more stress and anxiety than the general population.5 Recent data supports the notion that there is a link between bacterial composition and gut wellbeing, therefore this review article will focus on gut microbiota in relation to IBS.
Regarded by some as a neglected organ,6 the GI microbiota comprises around 400 species and greatly outnumbers the cell count of all other established organs combined.7,8 Commensal bacteria are seen to be necessary in healthy digestion, with roles such as producing enzymes and metabolites which help the body absorb otherwise unavailable essential nutrients and vitamins.9,10 Presence of bacteria is also important for normal development and function of the intestinal immune system which must be both tolerant to food antigens and commensal bacteria, but also able to mount a response to pathogens.11,12 Commensal bacteria also contribute to the maintenance of gut homeostasis by the secretion of bacteriocins,13 proteins that are able to inhibit bacterial toxins,14 and the pH lowering short-chain fatty acids15–17 which withhold an aggressive defence against colonization by noncommensal intruders. Finally, by outcompeting for resources and filling distinct colonization niches,18 commensal microbiota are able to block pathogenic organisms from gaining an all-important foothold in the intestinal microbiota ecosystem.
Generally, the intestinal microbiota composition of healthy individuals is relatively stable; however, changes in the microbiota community may lead to a permanent imbalance known as dysbiosis.19 Several factors, such as antibiotics, diet (including specific probiotic and prebiotic consumption), the host immune system and acidic milieu have been seen to affect the microbiota composition of the gut (Fig. 1). Disturbances to the gut microbiota ecosystem resulting in dysbiosis can lead to maladies of the GI tract20,21 with current research suggesting dysbiosis to have potential significance in IBS, but also other conditions such as obesity,22,23 diabetes,24,25 metabolic syndrome,26 cardiovascular disease,27 and IBD.28
In a healthy individual the small intestine contains a much lower density of bacteria than the large intestine. IBS has been suggested to be associated with small intestinal bacterial overgrowth (SIBO), defined as a bacterial density (colonic bacteria) of ≥105 colony-forming units (cfu) per mL of intestinal fluid,29 measured by the “gold standard” jejunal culture method.30,31 SIBO is, however, often diagnosed through culture-independent techniques such as glucose hydrogen and lactulose hydrogen breath tests.32–36 There has been much deliberation over these studies and the findings due to the validity of the techniques used.21,37,38 A meta-analysis study by Ford
Postinfectious IBS (PI-IBS) is likely the strongest evidence in the case of microbiota being important for the development of IBS, and may present after a bout of gastroenteritis caused by viral, parasitic or bacterial infections. Enteric pathogens such as
An episode of gastroenteritis will cause an inflammatory response of the gut, and may potentially lead to an intestinal dysbiosis. For example,
The interplay of intestinal microbes and host immunity being widely acknowledged in promoting a normally functioning immune system7,12 is strengthened with studies suggesting that an altered gut microbiota composition may lead to an altered immune activity,52 potentially leading to low-grade inflammation in IBS.53–55 The putatively increased immune activity in IBS patients56 may be due to exogenous or endogenous triggers; however, the immune activity pattern of IBS is far from being fully understood and likely involves both the innate and adaptive immunity.
Having a fundamental role in the innate immune system, mast cells are on the front line barrier between the host and the external environment. Numerous studies have reported an increase in number, level of activation and area occupied by mast cells in the intestinal mucosa of IBS patients when compared with healthy controls57–67 although other studies are not in agreement.68–71 These discrepancies potentially arise through methodological inconsistencies such as from which intestinal region the biopsy was taken from and the techniques used for detection and counting of the cells. Considering how intertwined the gut microbiota and immune system are72 and the reports of increase in mast cell numbers in IBS, it could be reasoned that a shift in gut microbiota composition could mediate an immune response leading to a subsequent mast cell increase, potentially contributing to visceral hypersensitivity.70 However, there is still no evidence supporting an association between an altered microbiota composition and levels of mast cells in IBS, so this putative link remains to be determined.
Another aspect of innate immunity is the phagocytic macrophages. Currently, the number of macrophages is still under discussion with reports of increased47,73 and decreased68 levels of this cell population seen in IBS. Potentially, for a subgroup of IBS patients, it could be proposed that the immune system may be compromised and therefore less capable to respond to pathogenic microorganisms. This theory is supported by the report of decreased levels of secreted chemoattractants such as CXCL-9 and MCP-1,74 known to recruit dendritic cells and other immune cells. However, data on the expression of intestinal chemoattractants is also under discussion as an elevation of MCP-1 has also been reported in IBS.75 Moreover, increased levels of proinflammatory serum cytokines such as interleukin (IL)-6, IL-8, and tumour necrosis factor α, tend to be found in IBS patients,61,75–79 once again evoking the idea of discord in the gut microbiota subsequently provoking an immune response to tackle any pathogenically caused disturbances.
Widely expressed by many cells, including but not limited to epithelial cells and macrophages are Toll-like receptors (TLRs). TLRs are utilized in the recognition of danger signals such as structures found on bacteria and viruses. Studies showing altered TLR expression in IBS patients compared to healthy controls80 with specific increases in TLR2, TLR4, and TLR581–83 and decreases in TLR7 and TLR8,81 present the notion that IBS is linked to an altered activation of the immune system in response to microorganisms of the gut. Also, defensins such as human β-defensin 2, antimicrobial peptides secreted by colon epithelial cells in response to proinflammatory cytokines or pathogenic microorganisms, have been shown to be increased in IBS patients.84
Following the hypothesis of a low-grade immune activation occurring in IBS, the T cells of the adaptive immune system have been suggested to have an increased presence in IBS patients47,59,85–87 and subgroups such as PI-IBS;88 however, a contradictory study by Braak
Still, the evidence linking an increased immune activity and altered gut microbiota composition in IBS is limited93 and further research is therefore required.
There is no clear consensus on the benefit of antibiotics to treat symptoms in IBS; however, several studies show that antibiotics alter the composition of the gut microbiota in a potentially deleterious way.94–97 The reported disruptive effect of antibiotics can diminish protective commensal bacteria populations, making it more likely for expansion of pathogenic species to occur,98,99 which may lead to dysbiosis and potentially even cause symptoms of IBS.100–103 However, nonabsorbable antibiotics such as neomycin104 and rifaximin105–107 have been seen to have beneficial effects, providing partial alleviation of IBS in general and bloating in particular. Findings showing reduction in IBS symptoms through the use of antibiotics further support the influence microbiota has on gut wellbeing and how the restoration of intestinal microbial normobiosis may help some patients with IBS.
The act of directly altering gut microbiota composition through the use of probiotics such as
If probiotics are like adding seeds of beneficial bacteria to the gut, prebiotics are the equivalent of fertilizers which affect only the favorable species already colonising the bowels. Commonly used and tested prebiotics are nondigestible oligosaccharides such as fructo-oligosaccharides and galacto-oligosaccharides. Currently, there have not been many randomized controlled trials regarding IBS and prebiotics. Supporting the link between microbiota composition and gut wellbeing, studies on prebiotic use and subsequent mitigation of IBS symptoms tend to show a similar beneficial effect as the use of probiotic strains such as
The composition of the gut microbiota has been shown to be responsive and adaptable to the diet of the host organism.127–131 Since anything not absorbed by the host becomes a source of nutrients for the microbial community residing in the colon, differences have been seen in gut microbiota in favor of those species able to best adapt to and metabolise the primary nutrients like fat, protein, or carbohydrates present in the diet.132 This adaptability thus denotes the types and levels of metabolites produced, e.g., butyrate128 or methane133 and consequent promotion of gut health or IBS symptoms, respectively. Although there is no recommended IBS diet, a reduction in FODMAPs might subdue symptoms associated with IBS.134–137
In conclusion, the findings with regards to therapeutic methods for IBS, e.g., antibiotics, probiotics and prebiotics and restoration of the gut microbiota, adds to the rationale behind the suggested correlation of altered gut microbiota and IBS33,51,81,107,111,123,128,137 whereby treatment of the dysbiosis may help a subgroup of patients.
With increasing numbers of studies focusing on investigating the gut microbiota profile, data suggests that there is an altered diversity of gut microbiota in patients with IBS.138–140 Several studies suggest that fecal microbiota is altered in IBS, and present differences in microbiota composition between healthy controls and IBS patients as well as within the subgroups of IBS patients.141–146 Although the aforementioned endeavours141–146 are interesting and a definite step towards a better understanding of IBS from a microbiological point of view, it must be taken into consideration that the results are usually based on relatively small sample populations. Considering that IBS is a multifactorial disorder with many putative causes and broad symptom presentation, a conjecture could be made that results derived from these studies might not represent the IBS patient population as a whole, but rather a subgroup of patients. Also, microbiota can vary quite extensively even between healthy individuals, making a general inference on the microbiota composition of IBS, let alone of the subgroups, a difficult one.
The most easily obtainable material when sampling GI microbiota is fecal matter. For this reason it is used prevalently in gut microbiota research, as well as the less easily obtainable mucosal biopsies. Taken from various locations of the small and large intestine, biopsies can provide a more site specific view of the mucosa adherent microbes inhabiting the gut.
Today, over 50 bacterial phyla have been defined147 with only 29 of these possible to culture.148 Ten of the known phyla have been discovered in the human gut149 with the majority of species attributed to one of the two largest phyla colonizing the human gut, Firmicutes and Bacteroidetes. Notably, since the advent and prominent use of culture-independent methods such as 16S sequencing in the last decade, numerous studies have focused on determining the gut microbiota in IBS patients. Table 1 gives a brief overview of the current findings on gut microbiota composition in patients with IBS in comparison to healthy controls with a more detailed review presented below.
The most predominant phylum found in the gut microbiota of healthy individuals,150,151 the gram positive Firmicutes, consist of a number of genera which include the commonly known probiotic,
Conversely, there might be a positive correlation between some potentially pathogenic species within the phylum of Firmicutes, such as
Within the Clostridia class, conflicting results have been reported with both an observed increase163 and decrease142,155,164 in IBS patients. Specifically,
Unlike
At this time, there is no clear consensus on the significance of alterations of Firmicutes in all IBS patients, although evidence suggests that Firmicutes, specifically the family Lachnospiraceae, are increased significantly enough in IBS-D as to make it discernible from other IBS subgroups.143 Nevertheless, although no consensus has been agreed upon, a weak tendency for a reduction in the beneficial bacteria of the gut, countered with an increase in pathogenic species is seen in IBS patients. This dysbiosis may potentially have influence on gut function whereby a degradation of the mucus layer by
The second most abundant phylum in the human gut, gram negative Bacteroidetes are found to have a varying higher52,142,163 or lower143,145,161,178 presence and diversity in the gut microbiota of patients with IBS. Furthermore, increases in
The Bacteroidetes phylum harbours species with either beneficial or nonbeneficial traits, as shown in the comprehensive review by Wexler.179 The abundance of beneficial or nonbeneficial Bacteroidetes species may therefore be important to IBS, under the assumption that more nonbeneficial species might correlate with an increase in symptoms or severity, such as visceral pain.
Another of the main phyla of the human gut microbiota, the gram positive Actinobacteria includes the probiotic containing genera such as
Increases of Proteobacteria165 in IBS, notably IBS-D,143 of the specific family Enterobacteriaceae155,158,161,173 which encompasses many gram negative pathogenic species, including other coliform bacteria157 such as
Since being found in both healthy controls159 and IBS patients43 there is no consensus on altered abundance of known, potentially pathogenic, genera such as
Increased levels of the not so well documented
The methane generating archaea Methanogens convert hydrogen produced in the gut into methane. This gas was previously thought to be inert,182 but has now been shown to reduce gut transit.133,183 An increase of Methanogens in IBS, especially in those suffering of constipation predominant IBS, could possibly explain the slow gut transit in these patients and why methane is being found at increased volumes in IBS-C patients.184–186 Also,
A temporal decreased stability of gut microbiota leading to a state of flux and dysbiosis may provide an explanation for the characteristic symptoms of certain IBS subgroups. The gut microbiota has the potential to affect and also be affected by the physiology of the gut, thus there is bidirectional communication. There are many factors which can potentially alter the normal gut microbiota composition. The use of antibiotics to treat infection is likely to have the side effect of depleting commensal bacterial, thus unintentionally allowing for later pathogenic infiltration of the gut. The consumption of probiotics and prebiotics, however, serve to increase beneficial bacteria of the gut. These beneficial bacteria employ various mechanisms, such as pH regulation, which alters their surroundings as to hinder the growth of noncommensals. The immune system works constantly in order to keep microbial homeostasis. Through this maintenance, alterations to the gut microbiota community occur by removing potentially pathogenic species. Additionally, diet can shape the composition of the gut microbiota through the shift in bacterial species which occurs when a gradual or radical change occurs in the food consumed by the host (Fig. 1). As levels of bacterial species fluctuate to adapt to these changes the shift may eventually favor certain species whereby a subsequent population expansion would likely occur. For example, an expansion of Methanogens in IBS could be linked to symptoms of IBS-C.185 A few studies have investigated gut microbiota stability through DNA157 and RNA analysis,164 showing that IBS patients have an instability of the gut microbiota composition over time as compared to healthy controls.157 Importantly, it must be acknowledged that the temporal fluctuation in at least some IBS patients, and healthy individuals for that matter, may be partially attributed to the administration of antibiotics.157
Several studies have demonstrated that IBS patients may have a diminished diversity of the gut microbiota composition,139,155,178,188 although, when focusing on specific groups such as Bacteroidetes and Lactobacillus, a broader diversity has been observed in IBS.52 In the gut microbiota ecosystem, much like in any other ecosystem, diversity and species richness is required for the system to flourish, where by all niches are filled and kept in check by neighboring beneficial or competing species. However, further studies with larger cohorts and potentially longer time periods are required in order to further investigate gut microbiota composition, instability and diversity in IBS.
Patients with IBS suffer from symptoms such as pain, constipation, diarrhea, abdominal distension, bloating and even psychiatric problems. The extent to which the gut microbiota influences these symptoms is not fully understood, especially not mechanistically. Interestingly, negative correlation between beneficial species of the gut and IBS symptoms have been demonstrated163 with Rajilić-Stojanović
Over the past decade the importance of gut microbiota in IBS has drawn increasing attention. Growing evidence suggest that at least subgroups of IBS patients have an altered gut microbiota composition or dysbiosis. Presented as an altered balance in beneficial or pathogenic bacterial species, dysbiosis is thought to have a bigger impact on gut wellbeing in IBS patients than previously thought, affecting such processes as intestinal barrier function and immune system regulation (Fig. 2). Therefore the use of therapeutic methods which interact with the microbiota continue to be an interesting option to both increase efficacy in hampering the growth of unwanted species whilst promoting beneficial bacteria in IBS. Improved understanding of the microbiota in respect to IBS may guide future therapeutic strategies with focus on the modulation of gut microbiota composition.
Overview of Papers Studying the Microbiota of the Gut with Regards to Irritable Bowel Syndrome
Phyla | Genus | IBS against healthy |
---|---|---|
Firmicutes | → Tana (2010)154; Carroll (2010)153; Carroll (2011)139 ↓ Balsari (1982)152; Kassinen (2007)141 ↔ Si (2004)158; Malinen (2005)159; Kerckhoffs (2009)160; Rajilić-Stojanović (2011)161 | |
→ Kassinen (2007)141; Rajilić-Stojanović (2011)161 | ||
→ Saulnier (2011)165; Rajilić-Stojanović (2011)161; Kassinen (2007)141 | ||
→ Kassinen (2007)141; Rajilić-Stojanović (2011)161; Jalanka-Tuovinen (2014)142 | ||
↔ Rajilić-Stojanović (2011)161 | ||
↔ Lopez-Siles (2014)175 | ||
Actinobacteria | → Kassinen (2007)141 ↔ Balsari (1982)152; Si (2004)158; Kerckhoffs (2009)160; Rajilić-Stojanović (2011)161; Malinen (2005)159; Duboc (2012)173 | |
Bacteroidetes | → Jalanka-Tuovinen (2014)142 ↓ Compared to IBD Swidsinski (2005)190 | |
Proteobacteria | → Rajilić-Stojanović (2011)161; Duboc (2012)173; Si (2004)158 | |
↓ Malinen (2005)159 | ||
Verrucomicrobia | → Saulnier (2011)165 ↔ Rajilić-Stojanović (2011)161 | |
Euryarchaeota | ↓ Rajilić-Stojanović (2011)161; Jalanka-Tuovinen (2014)142; Rana (2009)187 |
Gut and Liver 2015; 9(3): 318-331
Published online May 30, 2015 https://doi.org/10.5009/gnl14344
Copyright © Gut and Liver.
Sean M.P. Bennet*,†, Lena Öhman*,†, and Magnus Simrén*
*Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, †Department of Microbiology and Immunology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Correspondence to: Magnus Simrén, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg 4135, Sweden Tel: +46-31-342-8068, Fax: +46-31-741-2917, E-mail: magnus.simren@medicine.gu.se
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Irritable bowel syndrome (IBS) is a multifactorial functional disorder with no clearly defined etiology or pathophysiology. Modern culture-independent techniques have improved the understanding of the gut microbiota’s composition and demonstrated that an altered gut microbiota profile might be found in at least some subgroups of IBS patients. Research on IBS from a microbial perspective is gaining momentum and advancing. This review will therefore highlight potential links between the gut microbiota and IBS by discussing the current knowledge of the gut microbiota; it will also illustrate bacterial-host interactions and how alterations to these interactions could exacerbate, induce or even help alleviate IBS.
Keywords: Irritable bowel syndrome, Microbiota, Immunity, Dysbiosis, Probiotics
Patients with functional bowel disorders (FBDs) have no clear structural or biochemical alterations on routine examinations, making diagnosis and treatment challenging. A number of FBDs affect the lower gastrointestinal (GI) tract with irritable bowel syndrome (IBS) being the most prevalent, affecting approximately 10% to 20% of the population in the Western world.1–3 IBS is characterized by abdominal discomfort or pain associated with disturbed bowel habits,4 but also other GI symptoms such as distension and bloating, with patients often reporting more stress and anxiety than the general population.5 Recent data supports the notion that there is a link between bacterial composition and gut wellbeing, therefore this review article will focus on gut microbiota in relation to IBS.
Regarded by some as a neglected organ,6 the GI microbiota comprises around 400 species and greatly outnumbers the cell count of all other established organs combined.7,8 Commensal bacteria are seen to be necessary in healthy digestion, with roles such as producing enzymes and metabolites which help the body absorb otherwise unavailable essential nutrients and vitamins.9,10 Presence of bacteria is also important for normal development and function of the intestinal immune system which must be both tolerant to food antigens and commensal bacteria, but also able to mount a response to pathogens.11,12 Commensal bacteria also contribute to the maintenance of gut homeostasis by the secretion of bacteriocins,13 proteins that are able to inhibit bacterial toxins,14 and the pH lowering short-chain fatty acids15–17 which withhold an aggressive defence against colonization by noncommensal intruders. Finally, by outcompeting for resources and filling distinct colonization niches,18 commensal microbiota are able to block pathogenic organisms from gaining an all-important foothold in the intestinal microbiota ecosystem.
Generally, the intestinal microbiota composition of healthy individuals is relatively stable; however, changes in the microbiota community may lead to a permanent imbalance known as dysbiosis.19 Several factors, such as antibiotics, diet (including specific probiotic and prebiotic consumption), the host immune system and acidic milieu have been seen to affect the microbiota composition of the gut (Fig. 1). Disturbances to the gut microbiota ecosystem resulting in dysbiosis can lead to maladies of the GI tract20,21 with current research suggesting dysbiosis to have potential significance in IBS, but also other conditions such as obesity,22,23 diabetes,24,25 metabolic syndrome,26 cardiovascular disease,27 and IBD.28
In a healthy individual the small intestine contains a much lower density of bacteria than the large intestine. IBS has been suggested to be associated with small intestinal bacterial overgrowth (SIBO), defined as a bacterial density (colonic bacteria) of ≥105 colony-forming units (cfu) per mL of intestinal fluid,29 measured by the “gold standard” jejunal culture method.30,31 SIBO is, however, often diagnosed through culture-independent techniques such as glucose hydrogen and lactulose hydrogen breath tests.32–36 There has been much deliberation over these studies and the findings due to the validity of the techniques used.21,37,38 A meta-analysis study by Ford
Postinfectious IBS (PI-IBS) is likely the strongest evidence in the case of microbiota being important for the development of IBS, and may present after a bout of gastroenteritis caused by viral, parasitic or bacterial infections. Enteric pathogens such as
An episode of gastroenteritis will cause an inflammatory response of the gut, and may potentially lead to an intestinal dysbiosis. For example,
The interplay of intestinal microbes and host immunity being widely acknowledged in promoting a normally functioning immune system7,12 is strengthened with studies suggesting that an altered gut microbiota composition may lead to an altered immune activity,52 potentially leading to low-grade inflammation in IBS.53–55 The putatively increased immune activity in IBS patients56 may be due to exogenous or endogenous triggers; however, the immune activity pattern of IBS is far from being fully understood and likely involves both the innate and adaptive immunity.
Having a fundamental role in the innate immune system, mast cells are on the front line barrier between the host and the external environment. Numerous studies have reported an increase in number, level of activation and area occupied by mast cells in the intestinal mucosa of IBS patients when compared with healthy controls57–67 although other studies are not in agreement.68–71 These discrepancies potentially arise through methodological inconsistencies such as from which intestinal region the biopsy was taken from and the techniques used for detection and counting of the cells. Considering how intertwined the gut microbiota and immune system are72 and the reports of increase in mast cell numbers in IBS, it could be reasoned that a shift in gut microbiota composition could mediate an immune response leading to a subsequent mast cell increase, potentially contributing to visceral hypersensitivity.70 However, there is still no evidence supporting an association between an altered microbiota composition and levels of mast cells in IBS, so this putative link remains to be determined.
Another aspect of innate immunity is the phagocytic macrophages. Currently, the number of macrophages is still under discussion with reports of increased47,73 and decreased68 levels of this cell population seen in IBS. Potentially, for a subgroup of IBS patients, it could be proposed that the immune system may be compromised and therefore less capable to respond to pathogenic microorganisms. This theory is supported by the report of decreased levels of secreted chemoattractants such as CXCL-9 and MCP-1,74 known to recruit dendritic cells and other immune cells. However, data on the expression of intestinal chemoattractants is also under discussion as an elevation of MCP-1 has also been reported in IBS.75 Moreover, increased levels of proinflammatory serum cytokines such as interleukin (IL)-6, IL-8, and tumour necrosis factor α, tend to be found in IBS patients,61,75–79 once again evoking the idea of discord in the gut microbiota subsequently provoking an immune response to tackle any pathogenically caused disturbances.
Widely expressed by many cells, including but not limited to epithelial cells and macrophages are Toll-like receptors (TLRs). TLRs are utilized in the recognition of danger signals such as structures found on bacteria and viruses. Studies showing altered TLR expression in IBS patients compared to healthy controls80 with specific increases in TLR2, TLR4, and TLR581–83 and decreases in TLR7 and TLR8,81 present the notion that IBS is linked to an altered activation of the immune system in response to microorganisms of the gut. Also, defensins such as human β-defensin 2, antimicrobial peptides secreted by colon epithelial cells in response to proinflammatory cytokines or pathogenic microorganisms, have been shown to be increased in IBS patients.84
Following the hypothesis of a low-grade immune activation occurring in IBS, the T cells of the adaptive immune system have been suggested to have an increased presence in IBS patients47,59,85–87 and subgroups such as PI-IBS;88 however, a contradictory study by Braak
Still, the evidence linking an increased immune activity and altered gut microbiota composition in IBS is limited93 and further research is therefore required.
There is no clear consensus on the benefit of antibiotics to treat symptoms in IBS; however, several studies show that antibiotics alter the composition of the gut microbiota in a potentially deleterious way.94–97 The reported disruptive effect of antibiotics can diminish protective commensal bacteria populations, making it more likely for expansion of pathogenic species to occur,98,99 which may lead to dysbiosis and potentially even cause symptoms of IBS.100–103 However, nonabsorbable antibiotics such as neomycin104 and rifaximin105–107 have been seen to have beneficial effects, providing partial alleviation of IBS in general and bloating in particular. Findings showing reduction in IBS symptoms through the use of antibiotics further support the influence microbiota has on gut wellbeing and how the restoration of intestinal microbial normobiosis may help some patients with IBS.
The act of directly altering gut microbiota composition through the use of probiotics such as
If probiotics are like adding seeds of beneficial bacteria to the gut, prebiotics are the equivalent of fertilizers which affect only the favorable species already colonising the bowels. Commonly used and tested prebiotics are nondigestible oligosaccharides such as fructo-oligosaccharides and galacto-oligosaccharides. Currently, there have not been many randomized controlled trials regarding IBS and prebiotics. Supporting the link between microbiota composition and gut wellbeing, studies on prebiotic use and subsequent mitigation of IBS symptoms tend to show a similar beneficial effect as the use of probiotic strains such as
The composition of the gut microbiota has been shown to be responsive and adaptable to the diet of the host organism.127–131 Since anything not absorbed by the host becomes a source of nutrients for the microbial community residing in the colon, differences have been seen in gut microbiota in favor of those species able to best adapt to and metabolise the primary nutrients like fat, protein, or carbohydrates present in the diet.132 This adaptability thus denotes the types and levels of metabolites produced, e.g., butyrate128 or methane133 and consequent promotion of gut health or IBS symptoms, respectively. Although there is no recommended IBS diet, a reduction in FODMAPs might subdue symptoms associated with IBS.134–137
In conclusion, the findings with regards to therapeutic methods for IBS, e.g., antibiotics, probiotics and prebiotics and restoration of the gut microbiota, adds to the rationale behind the suggested correlation of altered gut microbiota and IBS33,51,81,107,111,123,128,137 whereby treatment of the dysbiosis may help a subgroup of patients.
With increasing numbers of studies focusing on investigating the gut microbiota profile, data suggests that there is an altered diversity of gut microbiota in patients with IBS.138–140 Several studies suggest that fecal microbiota is altered in IBS, and present differences in microbiota composition between healthy controls and IBS patients as well as within the subgroups of IBS patients.141–146 Although the aforementioned endeavours141–146 are interesting and a definite step towards a better understanding of IBS from a microbiological point of view, it must be taken into consideration that the results are usually based on relatively small sample populations. Considering that IBS is a multifactorial disorder with many putative causes and broad symptom presentation, a conjecture could be made that results derived from these studies might not represent the IBS patient population as a whole, but rather a subgroup of patients. Also, microbiota can vary quite extensively even between healthy individuals, making a general inference on the microbiota composition of IBS, let alone of the subgroups, a difficult one.
The most easily obtainable material when sampling GI microbiota is fecal matter. For this reason it is used prevalently in gut microbiota research, as well as the less easily obtainable mucosal biopsies. Taken from various locations of the small and large intestine, biopsies can provide a more site specific view of the mucosa adherent microbes inhabiting the gut.
Today, over 50 bacterial phyla have been defined147 with only 29 of these possible to culture.148 Ten of the known phyla have been discovered in the human gut149 with the majority of species attributed to one of the two largest phyla colonizing the human gut, Firmicutes and Bacteroidetes. Notably, since the advent and prominent use of culture-independent methods such as 16S sequencing in the last decade, numerous studies have focused on determining the gut microbiota in IBS patients. Table 1 gives a brief overview of the current findings on gut microbiota composition in patients with IBS in comparison to healthy controls with a more detailed review presented below.
The most predominant phylum found in the gut microbiota of healthy individuals,150,151 the gram positive Firmicutes, consist of a number of genera which include the commonly known probiotic,
Conversely, there might be a positive correlation between some potentially pathogenic species within the phylum of Firmicutes, such as
Within the Clostridia class, conflicting results have been reported with both an observed increase163 and decrease142,155,164 in IBS patients. Specifically,
Unlike
At this time, there is no clear consensus on the significance of alterations of Firmicutes in all IBS patients, although evidence suggests that Firmicutes, specifically the family Lachnospiraceae, are increased significantly enough in IBS-D as to make it discernible from other IBS subgroups.143 Nevertheless, although no consensus has been agreed upon, a weak tendency for a reduction in the beneficial bacteria of the gut, countered with an increase in pathogenic species is seen in IBS patients. This dysbiosis may potentially have influence on gut function whereby a degradation of the mucus layer by
The second most abundant phylum in the human gut, gram negative Bacteroidetes are found to have a varying higher52,142,163 or lower143,145,161,178 presence and diversity in the gut microbiota of patients with IBS. Furthermore, increases in
The Bacteroidetes phylum harbours species with either beneficial or nonbeneficial traits, as shown in the comprehensive review by Wexler.179 The abundance of beneficial or nonbeneficial Bacteroidetes species may therefore be important to IBS, under the assumption that more nonbeneficial species might correlate with an increase in symptoms or severity, such as visceral pain.
Another of the main phyla of the human gut microbiota, the gram positive Actinobacteria includes the probiotic containing genera such as
Increases of Proteobacteria165 in IBS, notably IBS-D,143 of the specific family Enterobacteriaceae155,158,161,173 which encompasses many gram negative pathogenic species, including other coliform bacteria157 such as
Since being found in both healthy controls159 and IBS patients43 there is no consensus on altered abundance of known, potentially pathogenic, genera such as
Increased levels of the not so well documented
The methane generating archaea Methanogens convert hydrogen produced in the gut into methane. This gas was previously thought to be inert,182 but has now been shown to reduce gut transit.133,183 An increase of Methanogens in IBS, especially in those suffering of constipation predominant IBS, could possibly explain the slow gut transit in these patients and why methane is being found at increased volumes in IBS-C patients.184–186 Also,
A temporal decreased stability of gut microbiota leading to a state of flux and dysbiosis may provide an explanation for the characteristic symptoms of certain IBS subgroups. The gut microbiota has the potential to affect and also be affected by the physiology of the gut, thus there is bidirectional communication. There are many factors which can potentially alter the normal gut microbiota composition. The use of antibiotics to treat infection is likely to have the side effect of depleting commensal bacterial, thus unintentionally allowing for later pathogenic infiltration of the gut. The consumption of probiotics and prebiotics, however, serve to increase beneficial bacteria of the gut. These beneficial bacteria employ various mechanisms, such as pH regulation, which alters their surroundings as to hinder the growth of noncommensals. The immune system works constantly in order to keep microbial homeostasis. Through this maintenance, alterations to the gut microbiota community occur by removing potentially pathogenic species. Additionally, diet can shape the composition of the gut microbiota through the shift in bacterial species which occurs when a gradual or radical change occurs in the food consumed by the host (Fig. 1). As levels of bacterial species fluctuate to adapt to these changes the shift may eventually favor certain species whereby a subsequent population expansion would likely occur. For example, an expansion of Methanogens in IBS could be linked to symptoms of IBS-C.185 A few studies have investigated gut microbiota stability through DNA157 and RNA analysis,164 showing that IBS patients have an instability of the gut microbiota composition over time as compared to healthy controls.157 Importantly, it must be acknowledged that the temporal fluctuation in at least some IBS patients, and healthy individuals for that matter, may be partially attributed to the administration of antibiotics.157
Several studies have demonstrated that IBS patients may have a diminished diversity of the gut microbiota composition,139,155,178,188 although, when focusing on specific groups such as Bacteroidetes and Lactobacillus, a broader diversity has been observed in IBS.52 In the gut microbiota ecosystem, much like in any other ecosystem, diversity and species richness is required for the system to flourish, where by all niches are filled and kept in check by neighboring beneficial or competing species. However, further studies with larger cohorts and potentially longer time periods are required in order to further investigate gut microbiota composition, instability and diversity in IBS.
Patients with IBS suffer from symptoms such as pain, constipation, diarrhea, abdominal distension, bloating and even psychiatric problems. The extent to which the gut microbiota influences these symptoms is not fully understood, especially not mechanistically. Interestingly, negative correlation between beneficial species of the gut and IBS symptoms have been demonstrated163 with Rajilić-Stojanović
Over the past decade the importance of gut microbiota in IBS has drawn increasing attention. Growing evidence suggest that at least subgroups of IBS patients have an altered gut microbiota composition or dysbiosis. Presented as an altered balance in beneficial or pathogenic bacterial species, dysbiosis is thought to have a bigger impact on gut wellbeing in IBS patients than previously thought, affecting such processes as intestinal barrier function and immune system regulation (Fig. 2). Therefore the use of therapeutic methods which interact with the microbiota continue to be an interesting option to both increase efficacy in hampering the growth of unwanted species whilst promoting beneficial bacteria in IBS. Improved understanding of the microbiota in respect to IBS may guide future therapeutic strategies with focus on the modulation of gut microbiota composition.
Table 1 Overview of Papers Studying the Microbiota of the Gut with Regards to Irritable Bowel Syndrome
Phyla | Genus | IBS against healthy |
---|---|---|
Firmicutes | → Tana (2010)154; Carroll (2010)153; Carroll (2011)139 | |
→ Kassinen (2007)141; Rajilić-Stojanović (2011)161 | ||
→ Saulnier (2011)165; Rajilić-Stojanović (2011)161; Kassinen (2007)141 | ||
→ Kassinen (2007)141; Rajilić-Stojanović (2011)161; Jalanka-Tuovinen (2014)142 | ||
↔ Rajilić-Stojanović (2011)161 | ||
↔ Lopez-Siles (2014)175 | ||
Actinobacteria | → Kassinen (2007)141 | |
Bacteroidetes | → Jalanka-Tuovinen (2014)142 | |
Proteobacteria | → Rajilić-Stojanović (2011)161; Duboc (2012)173; Si (2004)158 | |
↓ Malinen (2005)159 | ||
Verrucomicrobia | → Saulnier (2011)165 | |
Euryarchaeota | ↓ Rajilić-Stojanović (2011)161; Jalanka-Tuovinen (2014)142; Rana (2009)187 |