MICROBIOTA INSIGHTS IN CLOSTRIDIUM DIFFICILE INFECTION AND INFLAMMATORY BOWEL DISEASE

Figures & data

Figure 1. Early history of concomitant CDI and IBD.

Table 1. Main changes detected in the gut microbiota of patients suffering from ulcerative colitis and Crohn´s disease. Bacteria for which a reduction in relative proportions has been detected.

Taxa depletion in the gut of patients with IBD
Phylum level	Class level	Order level	Family level	Genus level	Species level	IBD disease^Ψ	Type of sample^Ψ	Ref
Actinobacteria	-	-	-	-	-	CD, UC	Biopsy	45
	Actinobacteria	Actinomycetales	Actinomycetaceae	-	-	UC	Stools	46
		Bifidobacteriales	Bifidobacteriaceae	-	-	CD	Stools	47
				Bifidobacterium	-	CD	Biopsy Stools	38,40,46,48
		Coriobacteriales	Coriobacteriaceae	-	-	UC	Stools	46
Bacteroidetes	-	-	-	-	-	CD, UC	Biopsy Stools	49
	Bacteroidia	Bacteroidales	-	-	-	CD	Stools	47,50
			Bacteroidaceae	-	-	CD	Biopsy Stools	37,40
				Bacteroides	-	CD, UC	Biopsy	49
					B. fragilis	CD	Stools	51
					B. ovatus	UC	Biopsy	37
					B. thetaiotaomicron	CD, UC	Biopsy	52
					-	CD	Biopsy Stools	53-55
			Barnesiellaceae			CD, UC	Biopsy	37
			Odoribacteraceae			CD	Biopsy	37
				Odoribacter	-	CD, UC	Biopsy Stools	37,56
					O. splanchnus	CD	Biopsy Stools	38
			Porphyromonadaceae	-	.	CD, UC	Biopsy	37
				Parabacteroides	P. distasonis	CD	Stools	56
						CD, UC	Biopsy	49
					P. merdae	CD, UC	Biopsy	37
			Prevotellaceae	Prevotella	-	CD	Biopsy Stools	50,56
					P. copri	CD, UC	Stools	57
			Rikenellaceae	-	-	CD, UC	Biopsy Stools	37,49
				Alistipes	-	CD, UC	Biopsy Stools	52,56
					A. onderdonkii	CD, UC	Biopsy	37
					A. finegoldii	CD	Biopsy	37
					A. putredinis	CD	Biopsy	37
Firmicutes	-	-	-	-	-	CD, UC	Biopsy	45,49,58
	Bacilli	Lactobacillales	Lactobacillaceae	Lactobacillus	-	CD, UC	Biopsy	55
			Leuconostocaceae	-	-	UC	Biopsy	38
	Erysipelotrichia	Erysipelotrichales	Erysipelotrichaceae	-	-	CD	Biopsy Stools	38,46,47
	Clostridia	Clostridiales	-	-	-	CD, UC	Biopsy Stools	40,46–48,58
			Clostridiaceae	-	-	CD, UC	Stools Biopsy	38,39,46,59
				Clostridium	C. coccoides	CD	Stools	51,54
					C. colinum	UC	Stools	36
					C. nexile	CD, UC	Biopsy	52
					C. leptum	CD	Stools	51,54
				Butyricicoccus	B. pullicaecorum	UC	Stools	36
			Christensenellaceae	-	-	CD, UC	Biopsy Stools	46
			Dehalobacteriaceae	-	-	CD, UC	Stools	46
			Eubacteriaceae	Eubacterium	-	CD, UC	Biopsy Stools	55,56
					E. rectale	UC	Stools	60
			Lachnospiraceae	-	-	CD, UC	Biopsy Stools	38,40,46,49
				Blautia	-	CD	Biopsy	40
				Coprococcus	-	CD	Biopsy Stools	40,43,50,56
				Coprococcus	-	CD. UC	Biopsy	49
					C. catus	UC	Stools	36
				Dorea	D. formicigenerans	CD, UC	Stools	61
					-	CD	Biopsy Stools	40,56
				Roseburia	-	CD, UC	Biopsy Stools	36,38–40,45,46,50,56
					R. hominis	CD, UC	Biopsy Stools	61,62
			Mogibacteriaceae	-	-	CD, UC	Stools	46
			Peptococcaceae	-	-	CD	Stools	46
			Peptostreptococcaceae	-	-	CD	Stools	46
			Ruminococcaceae	-	-	CD, UC	Biopsy Stools	38,40,46,49
				Oscillospira	-	CD, UC	Stools	49
				Ruminococcus	-	CD	Stools	46,56
					R. obeum	CD, UC	Stools	61
				Faecalibacterium	-	CD	Biopsy Stools	38-40,46,48-50
					F. prausnitzi	CD, UC	Biopsy Stools	36,45,49,54,57,60,62-66
				Ruminococcus	-	CD	Biopsy	39,40
					R. gnavus	UC	Stools	36
			Veillonellaceae	Phascolarctobacterium	-	CD, UC	Biopsy Stools	36,38
Euryarchaeota	Methanobacteria	Methanobacteriales	Methanobacteriaceae	-	-	UC	Stools	46
Proteobacteria	Deltaproteobacteria	Desulfovibrionales	Desulfovibrionaceae	Desulfovibrio	D. simplex	CD	Biopsy	37
					D. vulgaris	CD	Biopsy	37
Ternericutes	Mollicutes	-	-	-	-	UC	Biopsy Stools	46
Verrucomicrobia	-	-	-	-	-	CD, UC	Stools	49
	Verrucomicrobiae	Verrucomicrobiales	Verrucomicrobiaceae	Akkermansia	A. muciniphila	CD, UC	Biopsy Stools	36,56,67

Ψ Group of bacteria described in at least one form of IBD disease (ulcerative colitis or Crohn´s disease) and in at least one type of sample (biopsy or stools).

Table 2. Main changes detected in the gut microbiota of patients suffering from ulcerative colitis and Crohn´s disease. Bacteria for which an increase in relative proportions has been detected.

TAXA INCREASE IN THE GUT OF PATIENTS WITH IBD
Phylum level	Class level	Order level	Family level	Genus level	Species level	IBD disease^Ψ	Type of sample^Ψ	Ref
Actinobacteria	-	-	-	-	-	CD, UC	Biopsy	52
	Actinobacteria	Acidimicrobiales	Acidimicrobidae	-	-	CD, UC	Biopsy	52
		Actinomycetales	Actinomycetaceae	Actinomyces	A. oxydans	CD, UC	Biopsy	52
			Nocardioidaceae	Nocardioioides	-	CD, UC	Biopsy	52
		Bifidobacteriales	Bifidobacteriaceae	Bifidobacterium	–	CD	Biopsy	50
					B. adolescentis	CD	Stools	68
					B. breve	UC	Stools	61
Bacteroidetes	Bacteroidia	Bacteroidales	Bacteroidaceae	Bacteroides	-	CD, UC	Biopsy Stools	37,43,46,48,58,59,69
					B. distasonis	CD	Stools	51
			-	-	-	CD, UC	Stools	43,46
			Porphyromonadaceae	Porphyromonas	-	UC	Biopsy	43
				Parabacteroides	-	CD	Stools	46
					P. distasonis	CD	Stools	68
			Prevotellaceae	Prevotella	-	CD, UC	Biopsy Stools	43,51
					P. copri	CD, UC	Stools	68
			Rikenellaceae	-	-	UC	Stools	46
Firmicutes	Bacilli	-	-	-	-	CD, UC	Biopsy Stools	43,46,69
		Bacillales	Bacillaceae	Bacillus	B. licheniformis	CD, UC	Biopsy	52
		Lactobacillales	Aerococcaceae	-	-	CD	Stools	45
			Lactobacillae	-	-	UC	Stools	46
				Lactobacillus	-	CD, UC	Stools	40,49
			Enterococcaceae	-		UC	Stools	46
				Enterococcus	-	CD	Stools	40,56
			Streptococcaceae	Streptococcus	-	CD, UC	Biopsy Stools	40,49
		Staphylococcales	Gemellaceae			CD	Stools	47
				Gemella	G. moribillum	CD	Stools	40
	Clostridia	Clostridiales	Clostridiaceae	Clostridium	-	CD, UC	Biopsy Stools	38
					C. bolteae	CD	Biopsy Stools	62
					C. clostridioforme	CD	Stools	61
					C. hathewayi	CD	Biopsy Stools	62
					C. symbiosum	UC	Stools	61
					C. ramosum	UC	Stools	60
			Lachnospiraceae	-	-	CD	Biopsy	37,46
				Lachnobacterium	-	UC	Stools	46
				Blautia	-	UC	Biopsy	50
				Roseburia	-	CD, UC	Biopsy Stools	50,61
			Ruminococcaceae	-	-	CD	Biopsy	37
				Faecalibacterium	-	CD	Biopsy	50
				Ruminococcus	-	CD, UC	Stools	49
					R. gnavus	CD, UC	Biopsy Stools	43,50,61,62,67
					R. torques	CD, UC	Biopsy Stools	62,67
	Negativicutes	Selenomonadales	Acidaminocaccaceae	Acidaminococcus	-	CD, UC	Biopsy	45
		Vellionellales	Veillonellaceae	-	-	CD, UC	Biopsy Stools	40
				Veillonella	-	CD	Stools	56
					V. dispar	CD, UC	Biopsy	45
					V. parvula	CD	Stools	40
Fusobacteria	Fusobacteriia	Fusobacteriales	Fusobacteriaceae	-	-	CD	Biopsy Stools	40,47,69
				Fusobacterium	F. nucleatum	CD	Stools	40
Proteobacteria	-	-	-	-	-	CD, UC	Biopsy Stools	38,40,43,45,46,49,50,65,69
	Betaproteobacteria	Neisseriales	Neisseriaceae	-	-	CD	Stools	40
	Alphaproteobacteria	-	-		-	CD, UC	Biopsy	52
		Sphingomonadales	Sphingomonadaceae	Sphingomonas	-	CD, UC	Biopsy	52
				Novosphingobium	-	CD, UC	Biopsy	52
	Betaproteobacteria	Burkholderiales	-	-	-	CD, UC	Biopsy Stools	46
		Neisseriales	Neisseriaceae	-	-	CD	Biopsy Stools	40,47
	Gammaproteobacteria	-	-	-	-	CD, UC	Biopsy	52
		Enterobacteriales	Enterobacteriaceae	-	-	CD, UC	Biopsy Stools	9,37–40,45,46,49,68
				Citrobacter	-	CD	Biopsy	50
				Escherichia	-	CD	Biopsy Stools	38,50,56,61,62,69
					E. coli	UC	Stools	60
				Klebsiella	-	CD	Stools	56
				Shigella	-	CD	Biopsy Stools	38,69
		Pasteurellales	Pasteurellaceaea	-	-	CD	Stools	47
				Actinobacillus	-	CD	Biopsy	50
				Haemophilus	-	CD	Biopsy	40
		Pseudomonales	Pseudomonaceae	Pseudomonas	P. straminea	CD, UC	Biopsy	52

Ψ Group of bacteria described in at least one form of IBD disease (ulcerative colitis or Crohn´s disease) and in at least one type of sample (biopsy or stools).

Figure 2. Changes in the gut microbiota communities of IBD patients.

Table 3. Group of bacteria modifications associated with CDI and IBD. Main characteristics and role in disease and fecal microbiota transplant treatment.

Bacteria group at genus level	Taxonomy	Main characteristics and role in the intestinal metabolic activity◊	Gut ecosystem modifications observed	Fecal microbiota transplant treatment
				Expected changes after taxa restoration	Main microbiota communities identified in bacteriotherapy studies for gut restoration (∇)
Alistipes	Bacteroidetes Bacteroidia Bacteroidales Rikenellaceae	Gram-stain negative Straight or slightly curved rods Non-spore forming Non-motile Obligately anaerobic Produce succinic acid (major glucose metabolic end product) and acetic acid (minor) Produce indole and digest gelatin Bile tolerant	Depletion in children with both CDI and IBD^Citation100	– Stable engraftment and restoration of the structure of the gut microbiota. Cessation of CD-related changes and resolution of other gastrointestinal symptoms (in combination with genera Bacteroides and Parabacteroides)^Citation104	Alistipes and Blautia (positively correlated with colonic melatonin receptor expression) (AM)^Citation114
Blautia	Firmicutes Clostridia Clostridiales Lachnospiraceae	Gram-stain-positive, non-motile coccoid or oval-shaped short rods Obligate anaerobe Growth is stimulated by fermentable carbohydrates. End products after fermentation include acetate, ethanol, lactate, butyrate, and succinate - Some species also produce bile salt hydrolase (B. obeum)	Depletion in adult patients with both CDI and IBD^Citation76	- Increase of butyrate production (negative correlation with the presence of C. difficile)^Citation81 - Restitution of microbiota bile salt hydrolases (restoration of gut bile metabolism)^Citation87	Blautia Bacteroides and Ruminococcus (in detriment of Enterococcus, Escherichia, Shigella) (CDI)^Citation81 Blautia producta, Escherichia coli, Clostridium bifermentans (to antagonize C. difficile and restore Bacteroides levels) (CDI)^Citation82 Blautia and Ruminococcaceae (associated to colonization resistance) (CDI)^Citation83 Blautia hansenii (protective against infection) (CDI)^Citation83 Blautia, Coprococcus, Faecalibacterium (restoration after FMT) (CDI)^Citation84 Blautia and Blautia producta (Taxa used in bacteriotherapy studies) (CDI)^Citation85 Blautia and Alistipes (positively correlated with colonic melatonin receptor expression)^Citation114 Blautia, Dorea, Roseburia, Oscillobacter (CDI)^Citation115
Dorea	Firmicutes Clostridia Clostridiales Lachnospiraceae	Gram-stain-positive rods, non-spore forming, non-motile. Obligately anaerobic and chemo-organotrophic. Major end products of glucose metabolism include ethanol, formate, acetate, H2, and CO2	Depletion in adult patients with both CDI and IBD^Citation76	- Recovery of short fatty acid production and therefore the metabolic activity of the microbial community (related with CDI remission)^Citation115	Dorea (CDI)^Citation85 Dorea, Blautia Roseburia, Oscillobacter (CDI)^Citation115
Clostridium	Firmicutes Clostridia Clostridiales Clostridiaceae	Usually Gram-stain-positive rods. Motile or non-motile (when motile, cells usually are peritrichous) The majority of species form oval or spherical endospores that usually distend the end.	Increase in the gut of patients with CDI and IBD^Citation76 (although altered patterns of Clostridium group are not always the same in CDI and IBD patients separately)	- Restore the phylogenetic richness of the gut (restoration of Firmicutes/Bacteroidetes ratio)^Citation115 - Increase of butyrate production (negative correlation with the presence of C. difficile)^Citation81	Clostridium bifermentans, Clostridium innocuum, Clostridium ramosum, Clostridium cocleatum^Citation85 Blautia producta, Escherichia coli, Clostridium bifermentans (to antagonize C. difficile and restore Bacteroides levels) (CDI)^Citation82
Enterococcus	Firmicutes Bacilli Lactobacillales Enterococcaceae	Gram-stain-positive rods, non-spore forming. Some strains motile by scanty flagella Cells are ovoid Facultative anaerobic Carboxyphilic (C02 dependant)	Increase in the gut of patients with both CDI and IBD^Citation76 (although altered patterns of Enterococcus group are not always the same in CDI and IBD patients studied separately)	- Reduction of lactic acid-producing bacteria and their metabolites - Restitution of the intestinal homeostasis	Enterococcus faecalis (CDI)^Citation85
Faecalibacterium	Firmicutes Clostridia Clostridiales Ruminococcaceae	Usually Gram-stain-negative Rod-shaped cells Non-motile Non-sporulating Butyrate production Metabolize pectin, uronic acids, and N-acetyl glucosamine	Depletion in children with both CDI and IBD^Citation100	- Increase methionine biosynthesis to improve intestinal antioxidant capacity^105 - Increase the anti-inflammatory response in the gut^Citation49	Faecalibacterium prausnitzii and Bacteroides ovatus (CDI)^Citation115 Faecalibacterium, Blautia, Coprococcus (CDI)^Citation84
Roseburia	Firmicutes Clostridia Clostridiales Lachnospiraceae	Gram-stain-negative to variable stain reaction Rod-shaped cells Non-sporulating Motile (37ºC) by flagella Chemo-organotrophic Strictly anaerobic Use of carbohydrates as a carbon and energy source Produces H2, CO2 and large amounts of butyrate after fermentation of glucose and acetate May produce lactate, formate, and ethanol	Depletion in children with both CDI and IBD^Citation100	- Increase methionine biosynthesis to improve intestinal antioxidant capacity^105 - Increase of butyrate production (negative correlation with dysbiosis in UC)^Citation74	Roseburia, Oscillobacter, Blautia, Dorea (CDI)^Citation115
Ruminococcus gnavus	Firmicutes Clostridia Clostridiales Ruminococcaceae	Gram-stain positive cell wall structure (but many stain Gram-negative) Cells are coccoid, in pairs and chains Only few motile (flagella) Chemo-organotrophic Strictly anaerobic Growth is stimulated by fermentable carbohydrates and the end products include acetate, formate, ethanol, lactate, and succinate Mucin degradation	Increase of Ruminococcus gnavus in adult patients with both CDI and IBD^Citation76 Depletion (genus level) in children with both CDI and IBD^Citation100	- Reduction of digestive endogenous mucin substrate to prevent other bacteria proliferation and to allow host bacteria to multiply^Citation67	Ruminococcus, Blautia, Bacteroides (in detriment of Enterococcus, Escherichia, Shigella) (CDI)^Citation81 Ruminococcaceae, Blautia (associated to colonization resistance) (CDI)^Citation83

◊ According to Bergey´s Manual of Systematics of Archea and Bacteria.

∇ Specific studies addressing the efficacy of different bacterial species in the restoration of the gut microbiota after inflammation and/or infection.

CDI: Clostridium difficile infection.

AM: animal model.

Altomare A, Putignani L, Del Chierico F, Cocca S, Angeletti S, Ciccozzi M, Tripiciano C, Dalla Piccola B, Cicala M, Guarino MPL, et al. Gut mucosal-associated microbiota better discloses inflammatory bowel disease differential patterns than faecal microbiota. Dig Liver Dis. 2019;51(5):648–656. doi:10.1016/j.dld.2018.11.021. PMID: 30573380.

 PubMedGoogle Scholar

Imhann F, Vich Vila A, Bonder MJ, Fu J, Gevers D, Visschedijk MC, Spekhorst LM, Alberts R, Franke L, van Dullemen HM, et al. Interplay of host genetics and gut microbiota underlaying the onset and clinical presentation of inflammatory bowel disease. Gut. 2018;67(1):108–119. doi:10.1136/gutjnl-2016-312135. PMID: 27802154.

 PubMed Web of Science ®Google Scholar

Shaw KA, Bertha M, Hofmekler T, Chopra P, Vatanen T, Srivatsa A, Prince J, Kumar A, Sauer C, Zwick ME. Dysbiosis, inflammation, and response to treatment: a longitudinal study of pediatric subjects with newly diagnosed inflammatory bowel disease. Genome Med. 2016;8(1):75. doi:10.1186/s13073-016-0331-y. PMID: 27412252.

 PubMedGoogle Scholar

Morgan XC, Tickle TL, Sokol H, Gevers D, Devaney KL, Ward DV, Reyes JA, Shah SA, LeLeiko N, Snapper SB, et al. Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol. 2012;13(9):R79. doi:10.1186/gb-2012-13-9-r79. PMID: 23013615.

 PubMed Web of Science ®Google Scholar

Gevers D, Kugathasan S, Denson LA, Vázquez-Baeza Y, Van Treuren W, Ren B, Schwager E, Knights D, Song SJ, Yassour M, et al. The treatment-naïve microbioma in new-onset Crohn´s disease. Cell Host Microbe. 2014;15(3):382–392. doi:10.1016/j.chom.2014.02.005. PMID: 24629344.

 PubMed Web of Science ®Google Scholar

Andoh A, Kuzuoka H, Tsujikawa T, Nakamura S, Hirai F, Suzuki Y, Matsui T, Fujiyama Y, Matsumoto T. Multicenter analysis of fecal microbiota profiles in Japanese patients with Crohn´s disease. J Gastroenterol. 2012;47(12):1298–1307. doi:10.007/s00535-012-0605-0. PMID:22576027.

 PubMed Web of Science ®Google Scholar

Lo Presti A, Zorzi F, Del Chierico F, Altomare A, Cocca S, Avola A, De Biasio F, Russo A, Cella E, Reddel S, et al. Fecal and mucosa microbiota profiling in irritable bowel syndrome and inflammatory bowel disease. Front Microbiol. 2019;10:1655. doi:10.3389/fmicb.2019.01655. PMID: 31379797.

 PubMed Web of Science ®Google Scholar

Nishino K, Nishida A, Inoue R, Kawada Y, Ohno M, Skai S, Inatomi O, Bamba S, Sugimoto M, Kawahara M, et al. Analysis of endoscopic brush samples identified mucosa-associated dysbiosis in inflammatory bowel disease. J Gastroenterol. 2018;53(1):95–106. doi:10.1007/s00535-017-1384-4. PMID: 28852861.

 PubMed Web of Science ®Google Scholar

Alipour M, Zaidi D, Valcheva R, Jovel J, Martinez I, Sergi C, Walter J, Mason AL, Wong GK, Dieleman LA, et al. Mucosal barrier depletion and loss of bacterial diversity are primary abnormalities in paediatric ulcerative colitis. J Crohns Colitis. 2016;10(4):462–471. doi:10.1093/ecco-jcc/jiv223. PMID: 26660940.

 PubMed Web of Science ®Google Scholar

Manichanh C, Rigottier-Gois L, Bonnaud E, Gloux K, Pelletier L, Frangeul L, Nalin R, Jarrin C, Chardon P, Marteau P, et al. Reduced diversity of faecal microbiota in Crohn´s disease revealed by a metagenomic approach. Gut. 2006;55(2):205–211. doi:10.1136/gut.2005.073817. PMID: 16188921.

 PubMed Web of Science ®Google Scholar

Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel disease. Proc Natl Acad Sci USA. 2007;104(34):13780–13785. doi:10.1073/pnas.0706625104. PMID: 17699621.

 PubMed Web of Science ®Google Scholar

Pryde SE, Duncan SH, Hold GL, Stewart CS, Flint HJ. The microbiology of butyrate formation in the human colon. FEMS Microbiol Lett. 2002;217(2):133–139. doi:10.1111/J.1574-6968.2002.tb11467.x. PMID: 12480096.

 PubMed Web of Science ®Google Scholar

Ott SJ, Musfeldt M, Wenderoth DF, Hampe J, Brant O, Fölsch UR, Timmis KN, Schreiber S. Reduction in diversity of the colonic mucosa associated bacterial microflora in patients with active inflammatory bowel disease. Gut. 2004;53(5):685–693. doi:10.101136/gut2003.025403. PMID: 15082587.

 PubMed Web of Science ®Google Scholar

Lewis DJ, Chen EZ, Baldassson RN, Otley AR, Griffiths AN, Lee D, Bithinger K, Bailey A, Friedman ES, Hoffmann C, et al. Inflammation, antibiotics, and diet as environmental stressors of the gut microbiome in pediatric Crohn´s disease. Cell Host Microbe. 2015;18(4):489–500. doi:10.1016/j.chom.2015.09.008. PMID:26468751.

 PubMed Web of Science ®Google Scholar

Halfvarson J, Brislawn CJ, Lamendella R, Vazquez-Baeza Y, Walters WA, Bramer LM, D´Amato M, Bonfiglio F, McDonald D, Gonzalez A, et al. Dynamics of the human gut microbiome in inflammatory bowel disease. Nat Microbiol. 2017;2:17004. doi:10.1038/nmicrobiol.2017.4. PMID: 28191884.

 PubMed Web of Science ®Google Scholar

Rojas-Feria M, Romero-García T, Fernández Caballero-Rico JA, Pastor Ramírez H, Avilés-Recio M, Castro-Fernández M, Chueca Porcuna N, Romero-Gómez M, García F, Grande L, et al. Modulation of faecal metagenome in Crohn´s disease: role of microRNAs as biomarkers. World J Gastroenterol. 2018;24(46):5223–5233. doi:10.3748/wjg.v24.i46.5223. PMID: 30581271.

 PubMed Web of Science ®Google Scholar

Baumgart M, Dogan B, Rishniw M, Weitzman G, Bosworth B, Yantiss R, Orsi RH, Wiedmann M, McDonough P, Kim SG, et al. Culture independent analysis of ileal mucosa reveals a selective increase in invasive Escherichia coli of novel phylogeny relative to depletion of Clostridiales in Crohn´s disease involving the ileum. Isme J. 2007;1(5):403–418. doi:10.1038/ismej.2007.52. PMID: 18043660.

 PubMed Web of Science ®Google Scholar

Andoh A, Imaeda H, Aomatsu T, Inatomi O, Bamba S, Sasaki M, Saito Y, Tsujikama T, Fujiyama Y. Comparison of the fecal microbiota profiles between ulcerative colitis and Crohn´s disease using terminal restriction fragment length polymorphism analysis. J Gastroenterol. 2011;46(4):479–486. doi:10.1007/s00535-010-0368-4. PMID: 21253779.

 PubMed Web of Science ®Google Scholar

Rajca S, Grondin V, Louis E, Venier-Massoville G, Grimaud JC, Bouhnik Y, Laharie D, Dupas JL, Pillant H, Picon L, et al. Alterations in the intestinal microbiome (dysbiosis) as a predictor of relapse after infliximab withdrawal in Crohn´s disease. Inflamm Bowel Dis. 2014;20(6):978–986. doi:10.1097/MIB.0000000000000036. PMID: 24788220.

 PubMed Web of Science ®Google Scholar

Bajer L, Kuerka M, Kostovcik M, Macinga P, Dvorak J, Stehlikova Z, Brezina J, Wohl P, Spicak J, Drastich P. Distinct gut microbiota profiles in patients with primary sclerosing cholangitis and ulcerative colitis. World J Gastroenterol. 2017;23(25):4548–4558. doi:10.3748/wjg.v23.i25.4548. PMID: 28740343.

 PubMed Web of Science ®Google Scholar

Knoll RL, Forslund K, Kultima JR, Meyer CU, Kullmer U, Sunagawa S, Bork P, Gehring S. Gut microbiota differs between children with inflammatory bowel disease and healthy siblings in taxonomic and functional composition: a metagenomic analysis. Am J Physiol Gastrointest Liver Physiol. 2017;312(4):G327–G339. doi:10.1152/ajpgi.00293.2016. PMID: 28039159.

 PubMed Web of Science ®Google Scholar

Kabeerdoss J, Jayakanthan P, Pugazhendhi S, Ramakrishna SB. Alterations of mucosal microbiota in the colon of patients with inflammatory bowel disease revealed by real time polymerase chain reaction amplification of 16S ribosomal ribonucleic acid. Indian J Med Res. 2015;142(1):23–32. doi:10.4103/0971-5916.162091. PMID: 26261163.

 PubMedGoogle Scholar

Franzosa EA, Sirota-Madi A, Avila-Pacheco J, Fornelos N, Haiser HJ, Reinker S, Vatanen T, Hall AB, Mallick H, Mclver LJ, et al. Gut microbiome structure and metabolic activity in inflammatory bowel disease. Natural Microbiol. 2019;4(2):293–305. doi:10.1038/s41564-018-0306-5. PMID: 30531976.

 PubMed Web of Science ®Google Scholar

Lloyd-Price J, Arze C, Ananthakrishnan AN, Schirmer M, Avila-Pacheco J, Poon TW, Andrews E, Ajami NJ, Bonham KS, Brisawn CJ, et al. Multi-omics of the gut microbial ecosystem in inflammatory bowel disease. Nature. 2019;569(7758):655–662. doi:10.1038/s41586-019-1237-9. PMID: 31142855.

 PubMed Web of Science ®Google Scholar

Swidsinski A, Loening-Baucke V, Vaneechoutte M, Doerffel Y. Active Crohn´s disease and ulcerative colitis can be specifically diagnosis and monitored based on the biostructure of fecal flora. Inflamm Bowel Dis. 2008;14(2):147–161. doi:10.101002/ibd.20330. PMID: 18050295.

 PubMed Web of Science ®Google Scholar

Png CW, Lindén SK, Gilshenan KS, Zoetendal EG, McSweeney CS, Sly LI, McGuckin MA, Florin TH. Mucolytic bacteria wit increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria. Am J Gastroenterol. 2010;105(11):2420–2428. doi:10.1038/ajg.2010.281. PMID: 20648002.

 PubMed Web of Science ®Google Scholar

Jacobs JP, Goudarzi M, Singh N, Tong M, McHardy IH, Rvegger P, Asadourian M, Moon B, Ayson A, Borneman Y, et al. A disease-associated microbial and metabolomics state in relatives of pediatric inflammatory bowel disease patients. Cell Mol Gastroenterol Hepatol. 2016;2(6):750–766. doi:10.1016/j.jcmgh.2016.06.004. PMID: 281747747.

 PubMed Web of Science ®Google Scholar

Forbes JD, Van Domselaar G, Bernstein CN. Microbiome survey of the inflamed and non-inflamed gut at different compartments within the gastrointestinal tract of inflammatory bowel disease patients. Inflamm Bowel Dis. 2016;22(4):817–825. doi:10.1097/MIB.0000000000000684. PMID: 26937623.

 PubMed Web of Science ®Google Scholar

Vaster-Andersen MK, Mirsepasi-Lauridsen HC, Prosberg MV, Mortensen CO, Träger C, Skovsen K, Thorkilgaard T, Nojgaard C, Vind I, Krogfelt KA, et al. Increased abundance of proteobacteria in aggressive Crohn´s disease seven years after diagnosis. Sci Rep. 2019;9(1):13473. doi:10.1038/s41598-019-49833-3. PMID: 31530835.

 PubMedGoogle Scholar

Rao K, Higgins P. Epidemiology, diagnosis and management of Clostridium difficile infection in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2016;22:1744–1754. doi:10.1097/MIB.0000000000000793. PMID: 27120571.

 PubMed Web of Science ®Google Scholar

Hellmann J, Andersen H, Fei L, Linn A, Bezold R, Lake K, Jackson K, Meyer D, Dirksing K, Bonkowski E, et al. Microbial shifts and shorter time to bowel resection surgery associated with C. difficile in pediatric Crohn´s disease. Inflamm Bowel Dis. 2019;14. PMID 31725875. doi:10.1093/ibd/izz263.

 Google Scholar

Hamilton MJ, Weingarden AR, Unno T, Khoruts A, Sadowsky MJ. High-throughput DNA sequence analysis reveals stable engraftment of gut microbiota following transplantation of previously frozen fecal bacteria. Gut Microbes. 2013;4(2):125–135. doi:10.4161/gmic.23571. PMID: 23333862.

 PubMed Web of Science ®Google Scholar

Wang B, Zhang L, Zhu SW, Zhang JD, Duan LP. Short chain fatty acids contribute to gut microbiota-induced promotion of colonic melatonin receptor expression. J Biol Regul Homeost Agents. 2019;33(3):763–771. PMID:31204469.

 PubMed Web of Science ®Google Scholar

Sokol H, Jegou S, McQuitty C, Straub M, Leducq V, Landman C, Kirchgesner J, Le Gall G, Bourrier A, Nion-Larmurier I, et al. Specificities in the intestinal microbiota in patients with inflammatory bowel disease and Clostridium difficile infection. Gut Microbes. 2018;9(1):55–60. doi:10.1080/19490976.2017.1361092. PMID: 28786749.

 PubMed Web of Science ®Google Scholar

Kellingray L, Le Gall G, Defernez M, Beales ILP, Franslem-Elumogo N, Narbad A. Microbial taxonomic and metabolic alterations during faecal microbiota transplantation to treat Clostridium difficile infection. J Infect. 2018;77(2):107–118. doi:10.1016/j.jinf.2018.04.012. PMID: 29746938.

 PubMed Web of Science ®Google Scholar

Thoma C. Bile salt involved in the effectiveness of FMT for Clostridium difficile infection. Nat Rev Gastroenterol Hepatol. 2019;16(4):198. doi:10.1038/s41575-019-0128-8. PMID: 30837698.

 Google Scholar

Collins J, Auchtung JM. Control of Clostridium difficile infection by defined microbial communities. Microbiol Spectr. 2017;5(5). doi:10.1128/microbiolspec.BAD-0009-2016. PMID: 28936948.

 Web of Science ®Google Scholar

Hudson LE, Anderson SE, Corbett AH, Lamb TJ. Gleaning insights from fecal microbiota transplantation and probiotic studies for the rational design of combination microbial therapies. Clin Microbiol Rev. 2017;30(1):191–231. doi:10.1128/CMR.00049-16. PMID: 27856521.

 PubMed Web of Science ®Google Scholar

Shankar V, Hamilton MJ, Khoruts A, Kilburn A, Unno T, Paliy O, Sadowsky MJ. Species and genus level resolution analysis of gut microbiota in Clostridium difficile patients following fecal microbiota transplantation. Microbiome. 2014;2:13. doi:10.1186/2049-2618-2-13. PMID: 24855561.

 PubMed Web of Science ®Google Scholar

Amrane S, Hocquart M, Afouda P, Kuete E, Pham TPT, Dione N, Ngom II, Valles C, Banchar D, Raoult D, et al. Metagenomic and culturomic analysis of gut microbiota dysbiosis during Clostridium difficile infection. Sci Rep. 2019;9:12807. doi:10.1038/s41598-019-49189-8. PMID 31488869.

 PubMed Web of Science ®Google Scholar

Ling Z, Liu X, Jia X, Cheng Y, Luo Y, Yuan L, Wang Y, Zhao C, Guo S, Li L, et al. Impacts of infection with different toxigenic Clostridium difficile strains on feacal microbiota. Sci Rep. 2014;4:7485. doi:10.1038/srep07485. PMID: 25501371.

 PubMed Web of Science ®Google Scholar

Machiels K, Joossens M, Sabino J, De Preter V, Arijs I, Eeckhaut V, Ballet V, Claes K, Van Immerseel F, K V, et al. A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut. 2014;63(8):1275–1283. doi:10.1136/gutjnl-2013-304833. PMID: 24021287.

 PubMed Web of Science ®Google Scholar