Microbiome & Chronic Diseases

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Disease ⇒ Inflamatory bowel disease {40000180}

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Inflamatory bowel disease


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Gastroenterology, Rheumatology
Gut Inflammation


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Shared Reference Notes

  • [1.1
    - #Vitamin D receptor (VDR) regulates the biological actions of the active VitD (1α,25-dihydroxyvitamin D3), and is involved in the genetic, environmental, immune, and microbial aspects of IBD.
  • [1.2] [#Parkinson’s Disease
    - Patients with inflammatory bowel disease are more likely to develop Parkinson disease.
  • [1.3
    - Translocation of oral bacteria and yeasts to the lower GI tract may trigger inflammation in susceptible hosts, providing a mechanistic link to the development of IBD. - Conversely, dysbiosis of the oral microbiome may occur, possibly as a result of inflammatory responses and could represent a useful source of biomarkers of GI health.
  • [1.4
    - Some pro-inflammatory bacterial species are coated with a specific type of immune molecules called immunoglobulins A (IgA) which can be used as a proxy to identify microbes that stimulate immune responses - IgA coating of #Oscillospira was associated with a delay in time to surgery in IBD
  • [1.5
    - Gut metagenomic profiles of patients with inflammatory bowel disease (IBD) are highly correlated with fecal #Calprotectin levels, a biomarker for severity of inflammation in IBD.
  • [1.6
    - In IBD > reduced levels of #Christensenellaceae, #Odoribacter, #Mogibacteriaceae and #Gemmiger and increased abundance of #Peptostreptococcaceae.
  • [1.7] [#Akkermansia muciniphila
    - The genus Akkermansia belongs to the Verrucomicrobiaceae and is often associated with a healthy gut microbiome. Due to its low proportion in IBD and other metabolic diseases, anti-inflammatory properties are ascribed to this genus in IBD.
  • - #Dorea belongs to the Lachnospiraceae family, which was recently associated with IBD and which is also found in IBD patients with low short-chain fatty acid butyrate.
  • [1.8] [#Crohn’s disease
    - The blood–brain barrier allows the access of #Tryptophan. - In IBD, especially in CD patients, TRP metabolism increases; consequently, the amino acid levels are reduced with respect to normal healthy individuals, and these changes correlate with the gravity of the disease. - TRP undergoes two major metabolic host pathways, the #kynurenine (KYN) and #Serotonin (5-HT) biosynthetic pathways, and one microbial pathway to produce #Indole and its derivatives.
  • - Postbiotics, such as bile acids, short-chain fatty acids, and tryptophan metabolites in the development of IBD-associated gut and brain dysfunctions.
  • [1.9
    - A #Sugar-rich diet favors the increase of #Akkermansia muciniphila, a mucolytic bacterium. The mucus layer separates luminal bacteria from intestinal epithelium: A thinner mucus layer allows bacteria to come in contact with the epithelial cells, eliciting an inflammatory response.
  • [#High satureted fat diet] - Diet rich in high saturated fats promotes chronic inflammation. - One explanation is that the amino acid #Taurine, present in saturated fats, linked to #Bile Acids, seems to increase substrate availability for sulfur-reducing bacteria like #Bilophila wadsworthia, highly prevalent in the dysbiotic microbiota of IBD patients.
  • - There is mycobiome alterations in inflammatory bowel disease (IBD) patients experiencing a flare compared with a healthy or IBD patients in remission. - These alterations included an increased fungi/bacteria diversity ratio and an increased abundance of #Candida albicans, suggestive of fungal overgrowth during inflammation
  • - #Malassezia restricta, was identified in the majority of patients carrying the IBD risk allele CARD9, a molecule involved in fungal innate immunity.
  • [1.11] [#Escherichia coli
    - Patients with IBD typically have a far less diverse intestinal microbiota than healthy people, as well as an increase in pro-inflammatory bacteria like Enterobacteriaceae, especially E. coli and #Fusobacterium. - At the same time, bacteria that generate butyrate, an essential molecule for intestinal and immune health, are declining
  • [1.12
  • [1.13] [#Ultra-processed food intake
  • [1.14
    - Seven bacterial species correlated with expression levels of Th17 effector cytokines, IL-17A and IL-17F. - The seven associated species include #Ruminococcus gnavus, #Escherichia coli, #Lachnospiraceae bacterium, #Clostridium hathewayi, #Bacteroides faecis, #Bacteroides vulgatus, and #Akkermansia muciniphila. All of the species were positively associated with IL-17A/ IL-17F except #Akkermansia muciniphila, suggesting these species are proinflammatory, while #Akkermansia muciniphila is anti-inflammatory.
  • [1.15
  • [1.16
    - #Anti-TNF therapy shifted the diversity of fecal microbiota in patients with IBD
  • [1.17
  • [1.18
  • [1.19
  • [1.21
    - #Lactoferrin > potent anti-inflammatory and immunomodulatory substrate > prevention and treatment of IBD through regulating intestine mucosal immune response.
  • [1.22] [#Clostridium difficile infection, #Irritable bowel syndrome
    - Combining human variables and gut microbiota achieved the best performances in predicting IBD, IBS, CDI, and unhealthy status, indicating independent associations between gut microbiota and these diseases.
  • [1.23] [#Colorectal cancer, #Crohn’s disease] [#Common consumer products
    - #Triclosan (TCS), an antimicrobial agent found in thousands of consumer products > exacerbates #Colitis and #Colitis-associated colorectal tumorigenesis in animal models. - intestinal commensal microbes > microbial β-glucuronidase (GUS) enzymes > mediate metabolic activation of #Triclosan in the colon > gut toxicology.
  • [1.24] [#Crohn’s disease, #Ulcerative Colitis] [#Western-style diet
    - Two commonly used emulsifiers, #Carboxymethylcellulose and #Polysorbate-80 > induce inflammation and metabolic changes, mediated by gut microbes.
  • - #Exclusive Enteral Nutrition > reduce microbial diversity > lower SCFA concentrations (including #Butyrate) & reduce #Faecalibacterium prausnitzii, which is usually considered beneficial in IBD. - Responders to EEN showed lower bacterial richness than nonresponders. - EEN > showed a decrease in Shannon diversity with EEN, but this returned to pretreatment levels two months after EEN was stopped, as did decreases in Bifidobacterium, Ruminococcus, and Faecalibacterium. - It is hypothesized that some of these decreases in specific taxa and diversity are simply due to the lack of fibre in EEN.
  • [1.25
  • [1.26
  • [1.27
  • [1.28] [#Salmonella typhimurium
    - adherent-invasive #Escherichia coli (AIEC), and Salmonella enterica serovar Typhimurium > induce inflammation (through elevated T helper (TH) 1 and TH17 immune responses) in IBD animal model > fibrosis development. - in patients with #Crohn’s disease, AIEC strains > ileal mucosa > trigger the initiation or perpetuation of the inflammatory disease.
  • [1.29] [#Chronic fatigue syndrome, #Multiple Sclerosis
    - MC/CFS > a reduction of #Faecalibacterium was also found in IBD patients with fatigue (compared to IBD patients without fatigue), , #Cancer-related fatigue (compared to #Cancer patients with low fatigue) and other autoimmune diseases such as MS and #Diabetes Type 1 .
  • [#Bacteroides thetaiotaomicron
  • [1.31
    - Bile acid > gut-residing bacteria produce metabolite #3-oxolithocholic acid (3-oxoLCA) > inhibits TH17 (inhibitory) cell differentiation. - Secondary bile acid #Lithocholic acid > gut bacteria > 3-oxoLCA as well as the abundant gut metabolite #Isolithocholic acid (isoLCA). - IsoLCA suppressed TH17 differentiation by inhibiting RORγt (retinoic acid receptor-related orphan nuclear receptor γt), a key TH17 cell-promoting transcription factor. - Levels of both 3-oxoLCA and isoLCA and the 3α-hydroxysteroid dehydrogenase (3α-HSDH) genes required for their biosynthesis were significantly reduced in patients with inflammatory bowel diseases (IBD). - levels of these #Bile Acids were inversely correlated with expression of TH17 cell-associated genes. - bacterially produced TH17 cell-inhibitory #Bile Acids may reduce the risk of autoimmune and inflammatory disorders such as IBD
  • [1.32
    - the colonic mucosa of patients with inflammatory bowel disease > rich genetic diversity of opportunistic #Candida albicans strains. - Among these human-gut-derived isolates, strains with high immune-cell-damaging capacity (HD strains) reflect the disease features of individual patients with #Ulcerative Colitis and aggravated intestinal inflammation in vivo through IL-1β-dependent mechanisms. - Niche-specific inflammatory immunity and interleukin-17A-producing T helper cell (TH17 cell) antifungal responses by HD strains in the gut were dependent on the C. albicans-secreted peptide toxin #Candidalysin during the transition from a benign commensal to a pathobiont state.
  • [1.33
  • [1.34
    - patients with #Depression were two times as likely to develop IBD. - 30% of inflammatory bowel disease (IBD) patients develop #Depression.
  • [1.35
    - Inflammatory Bowel Disease > increased Primary #Bile Acids
  • [#Short Chain Fatty Acid] - inflammatory bowel disease (IBD), SCFAs have been shown to alleviate inflammatory phenotypes by regulating IL-10 production by T cells in both humans and the mouse model.
  • [1.36
    - studies have demonstrated striking differences between luminal and mucosal samples within the colon itself, specifically regarding mucosa-associated bacteria such as #Bifidobacterium, #Lactobacillus, and #Akkermansia. - the microbial community composition is different between ileal luminal samples from colonic and fecal samples, as well along the length of the colon itself.
  • [1.37] [#Bacteriophage
    - #Klebsiella pneumoniae (Kp) strains are associated with IBD severity across geography. - A Kp-targeting five-phage combination suppresses intestinal inflammation in IBD models
  • [1.38] [#Systemic anti-microbiota IgG
    - a modified high-throughput, culture-independent approach to quantify systemic IgG against gut commensal bacteria in human serum samples without the need for paired stool samples. - Using this approach, we highlight several commensal bacterial species that elicit elevated IgG responses in patients with inflammatory bowel disease (IBD) including taxa within the clades #Collinsella, #Bifidobacterium, #Lachnospiraceae, and #Ruminococcaceae.
  • [1.39] [#Bile Acids, #Primary bile acids, #Secondary bile acids
    - Reduced BA deconjugation is associated with inflammatory bowel diseases (IBD) including #Ulcerative Colitis (UC) and #Crohn’s disease (CD), as well as #Irritable bowel syndrome (IBS).
  • - IBD Patient > Leukemia inhibitory factor receptor (LIF-R) concentrations were inversely associated with severe #Fatigue
  • - Ninety-two (92) different inflammation-related proteins were measured in plasma of 350 patients with clinically quiescent IBD.
  • [1.41] [#Indole-3-acetic acid
    - IBD patients have reduced fecal concentrations of the AhR agonist IAA.
  • [#Indole-3-propionic acid] - The metabolite IPA regulates the intestinal barrier function in mice by activating the pregnane X receptor (PXR) or AhR. - Trp metabolite IPA in the serum from patients with active colitis is also selectively diminished.
  • [#kynurenine, #Tryptophan] - patients with inflammatory bowel diseases (IBD) have lower levels of Trp in both their serum and feces than healthy subjects. - active IBD > increased Kyn or Kyn/Trp ratios in IBD patients, indicating the promoted Trp metabolism along the Kyn pathway.
  • [1.42] [#Sutterella wadsworthensis
    - Sutterella, a Gram-negative genus from Proteobacteria, has been associated with various diseases including #Autism and inflammatory bowel disease (IBD)
  • [1.43] [#Colorectal cancer
    - Morganella morganii is enriched in the gut microbiota of both IBD and CRC patients. - Morganella morganii-derived small-molecule genotoxins—termed the #Indolimines—that elicited DNA damage in cell-based and cell-free assays. - In a mouse model of colon cancer, M. morganii exacerbated tumor burden, but a mutant form of the bacteria unable to produce indolimine did not.
  • [1.44
    - 65% of individuals with IBD exhibited elevated psychological distress and 21% exhibited symptoms of #Depression.
  • [1.45] [#Antibiotic Therapy
    - Antibiotic exposure was associated with an increased risk of IBD as compared with no antibiotic exposure for all age groups, although was greatest among individuals aged 40–60 years and ≥60 years, with similar results seen for both ulcerative colitis and Crohn’s disease. - The highest risk of developing IBD was seen 1–2 years after antibiotic exposure, and after use of antibiotic classes often prescribed to treat gastrointestinal pathogens. - Nitrofurantoin was the only class of antibiotics not found to be associated with the development of IBD across all age groups. - The classes with the highest risk were the nitroimidazoles and fluroquinolones.
  • [1.46
    - The common skin resident fungus #Malassezia restricta, is also linked to the presence of an IBD-associated polymorphism in the gene for CARD9, a signaling adaptor important for anti-fungal defense. - M. restricta elicits innate inflammatory responses largely through CARD9 and is recognized by #Crohn’s disease patient anti-fungal antibodies. This yeast elicits strong inflammatory cytokine production from innate cells harboring the IBD-linked polymorphism in CARD9 and exacerbates colitis via CARD9 in mouse models of disease.
  • [1.47] [#Short Chain Fatty Acid
    The first signs of aggravation of IBD are : - a loss of the main anti-inflammatory Short-Chain Fatty Acids (SCFAs) #Roseburia, #Eubacterium, #Subdoligranumum, #Ruminococcus - an increase in pro-inflammatory pathogens #Proteus, #Finegoldia - an increase of other minor SCFA producers such as #Ezakiella, #Anaerococcus, #Megasphaera, #Anaeroglobus, #Fenollaria. - Further aggravation of clinical signs is significantly linked to the subsequent loss of these minor SCFAs species and to an increase in other proinflammatory Proteobacteria such as Klebsiella, Pseudomonas, Salmonella, Acinetobacter, Hafnia and proinflammatory Firmicutes such as Staphylococcus, Enterococcus, Streptococcus.
  • [1.48
    - #Psyllium, a fiber derived from Plantago seeds, can inhibit #inflammation that leads to #Colitis in mice by increasing serum #Bile Acids and activating the farnesoid X receptor (FXR). - This is exciting since it suggests that pharmacologic FXR activation might be an interesting target for the management of inflammation found in IBD.
  • [1.49] [#Bipolar disorder, #Irritable bowel syndrome
    - IBS , #Celiac Disease and IBD have been associated with an increment in the risk of developing BD.
  • - #Secondary bile acids escape hepatic recirculation, which reportedly, in turn, decreases #Cholesterol absorption and enhances its fecal excretion via modulation of farnesoid X receptor (FXR) signalling. - Microbial modulation of bile acid profiles has been linked to inflammatory bowel disease (IBD), with related FXR modifications as an underlying mechanism of gut barrier destabilisation
  • [1.51
    - IBD is associated with higher fecal levels of aromatic amino acid metabolites‒markers of protein fermentation. - Patients with IBD have increased fecal levels of long-chain fatty acids and PUFAs, suggesting an upstream impairment in dietary fat absorption by an inflamed ileal epithelium.
  • - The ratio between fecal #Lactosyl-N-palmitoyl-sphingosine and #L-urobilin discriminated IBD and non-IBD samples, with the #Sphingolipid occurring at higher relative abundance in stool from IBD patients.
  • - Bile acid and ceramide metabolites were more abundant in stool from patients with IBD, concomitant with a loss of bacteria genomically predicted to metabolize #Primary bile acids. - Bile-resistant pathobionts were increased in dysbiotic stool from IBD patients
  • [1.52] [#Colorectal cancer
    - #Gemella enriches in the intestinal mucosa of IBD and CRC
  • [#Colorectal cancer] [#Peptostreptococcus stomatis] - Regarding IBD and CRC, P. stomatis is among the oral-derived biomarker panel of CRC either
  • [#Klebsiella pneumoniae] - saliva K. #Pneumonia of IBD patients rapidly establishes colonization in mice’s intestines, triggering a strong inflammatory response
  • [#Ulcerative Colitis] - In terms of IBD, #Prevotella is a potential alternative biomarker for UC, tightly matched with feces and other oral areas
  • [#Clostridioides difficile, #Fusobacterium nucleatum] - F. nucleatum coexists with #Clostridium through adhesin RadD, encouraging the intestinal mucus layer’s bacterial biofilm formation in IBD patients. This symbiotic relationship accelerates the extracellular polysaccharides-producing process and chemotaxis level of C. difficile
  • [1.53] [#Irritable bowel syndrome] [#β-defensin 2
    - Inflammatory proteins such as human β-defensin 2, a bactericide, have been identified as a useful fecal biomarker in IBS and IBD
  • [#Lactic acid] - Patients with IBD have lower fecal levels of #Acetate, #Propionate and #Butyrate, and higher levels of lactic and #Pyruvic acids than healthy individuals
  • - #Acetate and #Propionate activate cell surface receptor GPR43 to induce neutrophil chemotaxis. - GPR43 is anti-lipolysis and implicated in IBD.
  • [#Ruminococcus gnavus] - R. gnavus, a prevalent gut microbe that proliferates in IBD, has been found to secrete a unique L-rhamnose oligosaccharide that induces tumor necrosis factor alpha (TNFα), a major pro-inflammatory cytokine.
  • - transient blooms of pro-inflammatory #Ruminococcus have been associated with active flare-ups in IBD.
  • [1.54] [#Anti-TNF therapy
    - Dietary #Palmitoleic acid (POA) repaired gut mucosal barriers, reduced inflammatory cell infiltrations and expressions of TNF-α and #IL-6, and improved efficacy of anti-TNF-α therapy in both acute and chronic IBD mouse models.
  • [1.55] [#Akkermansia muciniphila] [#Antibiotic Therapy
    - Conditions like inflammatory bowel disease (IBD), #Salmonella typhimurium infection or post-antibiotic reconstitution may not benefit from #Akkermansia supplementation. - using #Akkermansia in patients with endocrine and gynecological disorders—such as #Polycystic ovary syndrome (PCOS) or #Endometriosis—that have a higher risk of developing IBD, should be critically evaluated. - the gut microbiota of patients suffering from #Parkinson’s Disease or #Multiple Sclerosis exhibits a characteristic signature of #Akkermansia municiphila abundance.
  • [1.56] [#Crohn’s disease
    - CD-HPA microbiota from colonized mice was characterized by a decrease in known beneficial #Bacteria such as #Akkermansia muciniphila, #Alistipes putredinis, and #Ruminococcus bromii, previously shown to be reduced in IBD patients.
  • [#Crohn’s disease] [#Escherichia coli, #Hungatella hathewayi] - H. hathewayi transcript as belonging to the TIGR02037 family, which includes both K04771 and K04772 . - Proteases from these families are found in pathogens, such as Enteropathogenic E. coli (EPEC) and #Helicobacter pylori, where they have been described as virulence factors, shown to degrade E-cadherin,Citation46 and hypothesized to cleave PAR2.
  • - #Hungatella hathewayi to be increased compositionally and transcriptionally in IBD patients, suggesting high metabolic activity of the species during inflammation. - protease K04772 of H. hathewayi is actively transcribed in samples from CD-HPA colonized mice compared with CD-LPA colonized mice.
  • [1.57
    - The #Clostridium XlVa cluster and #Ruminococcaceae are also reduced in those with inflammatory bowel disease (IBD) compared to those without disease, which agrees with their protective role in the gut inflammation and an anti-inflammatory effect of #Aspirin on the gut microbiome.
  • [#Ruminococcus gnavus] - Ruminococcocus gnavus, was shown to be increased in IBD, which could explain an increased abundance of the Ruminococcocus genus in the #Aspirin vs placebo arm observed in our study.
  • [1.58
    - 80% of the IBD cohort were diagnosed with #Anxiety two or more years before the IBD diagnosis
  • [1.59
    - HLA-B27 spondyloarthropathies (SpA) > #Ankylosing spondylitis, #Reactive arthritis, #Psoriatic Arthritis, #Juvenile idiopathic arthritis, inflammatory bowel disease, #Acute anterior uveitis, and undifferentiated SpA > segmented filamentous bacteria (SFB) have been illustrated to be a common culprit in initiating an arthritogenic reaction. - The Th17 response, induced in the mesenteric lymph nodes by dendritic cells, in such patients specifically targets SFB, resulting in a breach in the mucosal barrier. - This is thought to result from cross-reactivity between HLA-B27 and pathogenic surface antigens. - Other enteric gram-negative pathogens, which mimic HLA-B27, associated with SpA and uveitis include #Shigella, #Chlamydia and #Yersinia
  • - #Veillonella parvula, an asaccharolytic, anaerobic, oral microbe that derives energy from organic acids, increases in abundance in the intestine of patients with inflammatory bowel disease.
  • [1.61] [#Short Chain Fatty Acid
    - the genus #Allobaculum of the phylum Firmicutes was increased in the 5-ASA group compared with the NT group. Because #Allobaculum produces short-chain fatty acids (SCFAs)
  • [1.62] [#Crohn’s disease, #Ulcerative Colitis
    - The incidence of IBD was significantly higher in patients with #Migraine, CD and UC than in those without #Migraine. - After 5 years of follow-up, those with #Migraine showed curves implying cumulative incidences of IBD with a steep increase, especially for CD.
  • [1.63] [#Crohn’s disease, #Ulcerative Colitis] [#Escherichia coli
    - Most UC, and to a lesser extent CD patients develop peri-nuclear anti-neutrophil cytoplasmic antibodies (pANCA). - These antibodies cross-react with the E. coli membrane porin C (#OmpC) protein, suggesting a possible role for B cell autoreactivity and gut microbial antigenic cross-reactivity in the pathogenesis of IBD
  • - IBD has been associated with autoantibody responses against Glycoprotein 2 (GP2), a receptor for bacterial adhesin FimH that is upregulated in the gut epithelium of patients. - high levels of anti-GP2 IgA antibodies have been described in pediatric IBD patients
  • - An increased prevalence of autoantibodies against FAM84A, a neuronal sensory protein expressed in the gastrointestinal tract, has also been associated with IBD
  • [#Faecalibacterium prausnitzii] - Decreased abundance on #Firmicutes bacteria belonging to the #Ruminococcaceae spp., #Lachnospiraceae spp, F. prausnitzii and #Roseburia spp. families is a signature of microbial dysbiosis in IBD.
  • [1.64
  • [1.65] [#Proton pump inhibitors
    - regular use of PPIs consistently showed a significantly positive association with IBD, #Crohn’s disease, and #Ulcerative Colitis risk - Direct comparison with H2 receptor antagonist, a less potent acid suppressor, showed that PPI use was also associated with higher IBD risk
  • [1.66
    - Abnormally high levels of #Succinate have been linked to inflammatory diseases like IBD and #Obesity. - This is likely due to #Succinate’s ability to stimulate pro-inflammatory immune cells.
  • [1.67
    - increased risk of developing IBD in patients with #Celiac Disease as compared to the general population
  • [1.68
    - administration of #Succinate to mice (mutants with chronic inflammatory arthritis and IBD) and to anti-CD3E-treated mice reduces intestinal inflammation and modulates the immune response in a tuft cell-dependent manner
  • [1.69
    - infections with parasites like #Strongyloides stercoralis and #Blastocystis have been shown to mimic the symptoms of IBD, highlighting the intricate relationship between parasites and the pathogenesis of these diseases.
  • - #Ruminococcus gnavus, which is a mucin-degrading group, in inflammatory bowel disease and in altered lipid metabolism related to #Non-alcoholic fatty liver disease (NAFLD) and #Obesity
  • [1.71] [#Escherichia coli
    - #Colectomy > there was a significant increase in the expansion of E.coli in individuals who underwent surgery and, in particular, samples from IBD patients who underwent #Colectomy had the highest abundance of E.coli. - At 6 months, endoscopic recurrence was associated with elevated #Proteus genera and at 18 months with reduced #Faecalibacterium, #Desulfovibrio and #Bilophila abundance. At 18 months severe endoscopic recurrence was associated with increase in #Proteobacteria.
  • [1.72
    - Among #Adult participants, the scientists found that those with #Atopic Dermatitis had a 34% increased risk of IBD, a 36% higher risk of #Crohn’s disease, and a 32% increased risk of #Ulcerative Colitis.
  • [#Crohn’s disease, #Ulcerative Colitis] - #Children with #Atopic Dermatitis had a 44% increased risk of IBD and a 74% increased risk of CD, which increased with worsening AD; however, they did not have increased risk of UC except for those with severe AD.
  • [1.73
    - Ruminococcus torques and Ruminococcus gnavus, two prominent species in IBD19, were also differentially abundant in dysbiotic CD and UC, respectively as well as showing differences in abundance, including Clostridium hathewayi, Clostridium bolteae, and R. gnavus. All had significantly increased expression during dysbiosis, and thus their roles in IBD may be more pronounced than suggested solely by their differences in genomic abundance. - The reduction in butyrate in particular is consistent with the previously observed depletion of butyrate producers such as F. prausnitzii and R. hominis.

References Notes

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Common References