Role of Intestinal Microbiota in Ulcerative Colitis
Role of Intestinal Microbiota in Ulcerative Colitis Role of Intestinal Microbiota in Ulcerative Colitis
Abstract Background Detailed knowledge about the composition of the intestinal microbiota may be critical to unravel the pathogenesis of ulcerative colitis (UC), a human chronic inflammatory bowel disease, since the intestinal microbes is thought to influence some of the key mechanisms that are involved in the inflammatory process of the gut mucosa. The aim of this study was to investigate the fecal microbiota in patients either with UC in remission, or with active disease, and in healthy controls. The composition of Gram‐negative bacteria and Gram‐positive bacteria respectively was examined, as antigenic structures of Gram‐negative bacteria such as lipopolysaccharides have been related to the inflammatory responses and pathogenesis of inflammatory bowel disease. Results Dice cluster analysis and principal component analysis of fecal microbiota profiles obtained by Denaturing Gradient Gel Electrophoresis and quantitative PCR, respectively, revealed that the composition of fecal bacteria from UC patients differed from the healthy control group, and that this difference should be ascribed to Gram‐negative bacteria, in particular members of the Bacteroidetes phylum, including the genera Bacteroides and Prevotella. The analysis did not show any clear grouping of the UC patients in remission with some samples resemble those of patients in relapse, while others resemble those of the healthy controls. Lactobacillus spp., Akkermansia muciniphila and Bifidobacterium bifidum were underrepresented in UC patients with clinically active disease compared to the healthy control group. Conclusions In line with previous communications, we have shown that the microbiota in UC patients differ from that in healthy controls. However, this is to our knowledge the first study to show a specific correlation of the composition of the Gram‐negative population to this disease, and an underrepresentation of Lactobacillus spp., Akkermansia muciniphila and Bifidobacterium bifidum in UC patients. Additionally, the fact that some samples from patients in remission resembled those from healthy controls, while others resembled those from patients with active disease, 2
indicates that a change in the microbiota from ‘healthy’ to ‘unhealthy’ occurs during the remission period. Background Ulcerative colitis (UC) is an idiopathic inflammatory bowel disease (IBD) which is characterized by chronic inflammation of the colonic mucosa. UC is usually associated with recurrent attacks and complete remission of symptoms in the interim. The classical symptoms of patients in relapse are diarrhea with passage of blood or mucus, or both, occasional abdominal cramping and pain as well as systemic symptoms such as fever and weight loss in severe cases [2,13]. The aetiology of inflammatory bowel disease remains an enigma, and no known infectious agent has yet been demonstrated [30,44]. However, the intestinal microbiota seems to be involved in triggering inflammation, as observed in several animal models, where colitis could not be induced in the absence of a microbiota [45]. Hence, the intestinal microbes may influence some of the key mechanisms that are involved in the inflammatory processes of the gut mucosa [20,44]. Lipopolysaccharides (LPS) released by Gram‐ negative bacteria are able to trigger an inflammatory response through the nuclear factor κB (NF‐κB) pathway leading to over‐expression of pro‐ inflammatory cytokines [42]. However, certain Gram‐positive bacteria, particularly bifidobacteria and lactobacilli, have been shown to have a beneficial therapeutic effect in inflammatory bowel disease [23,54]. Additionally, in vitro studies show that strains of lactobacilli and bifidobacteria do not possess any intrinsic pro‐inflammatory characteristics but exert anti‐inflammatory actions such as inhibition of NF‐κB activation and IL‐8 secretion [16,42]. Both Gram‐negative and Gram‐ positive bacteria may therefore be involved in the pathogenesis of inflammatory bowel disease. A recent study, including a large metagenomic sequencing approach, has shown that the fecal microbiota differs between subjects with UC and healthy controls [41]. However, only very few investigations [51,52] have so far examined if there are differences between the fecal microbiota from UC patients in relapse and in remission by quantitative methods. The aim of our study was therefore to compare fecal microbiota derived from healthy controls, patients with UC in remission, and patients with active disease. Additionally, we wanted to investigate if the composition of Gram‐negative bacteria and Gram‐positive bacteria differed 3
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Abstract<br />
Background<br />
Detailed knowledge about the composition <strong>of</strong> the <strong>in</strong>test<strong>in</strong>al microbiota may be critical to unravel<br />
the pathogenesis <strong>of</strong> ulcerative colitis (UC), a human chronic <strong>in</strong>flammatory bowel disease, s<strong>in</strong>ce the<br />
<strong>in</strong>test<strong>in</strong>al microbes is thought to <strong>in</strong>fluence some <strong>of</strong> the key mechanisms that are <strong>in</strong>volved <strong>in</strong> the<br />
<strong>in</strong>flammatory process <strong>of</strong> the gut mucosa. The aim <strong>of</strong> this study was to <strong>in</strong>vestigate the fecal<br />
microbiota <strong>in</strong> patients either with UC <strong>in</strong> remission, or with active disease, and <strong>in</strong> healthy controls.<br />
The composition <strong>of</strong> Gram‐negative bacteria and Gram‐positive bacteria respectively was<br />
exam<strong>in</strong>ed, as antigenic structures <strong>of</strong> Gram‐negative bacteria such as lipopolysaccharides have<br />
been related to the <strong>in</strong>flammatory responses and pathogenesis <strong>of</strong> <strong>in</strong>flammatory bowel disease.<br />
Results<br />
Dice cluster analysis and pr<strong>in</strong>cipal component analysis <strong>of</strong> fecal microbiota pr<strong>of</strong>iles obta<strong>in</strong>ed by<br />
Denatur<strong>in</strong>g Gradient Gel Electrophoresis and quantitative PCR, respectively, revealed that the<br />
composition <strong>of</strong> fecal bacteria from UC patients differed from the healthy control group, and that<br />
this difference should be ascribed to Gram‐negative bacteria, <strong>in</strong> particular members <strong>of</strong> the<br />
Bacteroidetes phylum, <strong>in</strong>clud<strong>in</strong>g the genera Bacteroides and Prevotella. The analysis did not show<br />
any clear group<strong>in</strong>g <strong>of</strong> the UC patients <strong>in</strong> remission with some samples resemble those <strong>of</strong> patients<br />
<strong>in</strong> relapse, while others resemble those <strong>of</strong> the healthy controls. Lactobacillus spp., Akkermansia<br />
muc<strong>in</strong>iphila and Bifidobacterium bifidum were underrepresented <strong>in</strong> UC patients with cl<strong>in</strong>ically<br />
active disease compared to the healthy control group.<br />
Conclusions<br />
In l<strong>in</strong>e with previous communications, we have shown that the microbiota <strong>in</strong> UC patients differ<br />
from that <strong>in</strong> healthy controls. However, this is to our knowledge the first study to show a specific<br />
correlation <strong>of</strong> the composition <strong>of</strong> the Gram‐negative population to this disease, and an<br />
underrepresentation <strong>of</strong> Lactobacillus spp., Akkermansia muc<strong>in</strong>iphila and Bifidobacterium bifidum<br />
<strong>in</strong> UC patients. Additionally, the fact that some samples from patients <strong>in</strong> remission resembled<br />
those from healthy controls, while others resembled those from patients with active disease,<br />
2
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