Role of regenerating islet-derived proteins in inflammatory bowel disease

Table 1 Reported REG expressions in inflammatory bowel disease patients

Ref.	REGs	Samples (size)	Relevant findings
Lawrance et al[38], 2001	REG1α/1β/3α	CD (6) UC (6) control (6)	Increased intestinal REG1α/1β/3α in IBD detected by microarray
Shinozaki et al[39], 2001	REG1α	CD (9) UC (21) control (5 non-IBD, 6 normal)	Increased intestinal REG1α in IBD detected by RT-PCR and ISH
Desjeux et al[40], 2002	REG3α	CD (124) normal control (54)	Increased serum REG3α in active CD detected by ELISA
Dieckgraefe et al[41], 2002	REG1α/1β/3γ	CD (3) UC (5) control (4)	Increased intestinal REG1α/1β/3γ in IBD detected by microarray and IHC
Ogawa et al[12], 2003	REG3α	CD (20) UC (23) control (18)	Increased intestinal REG3α in IBD detected by ISH and Northern blot
Kämäräinen et al[42], 2003	REG4	CD (N/A) UC (N/A)	By ISH and IHC, REG4 constitutively expressed in neuroendocrine cells, and upregulated in inflamed epithelial cells
Gironella et al[43], 2005	REG3α	IBD (171) control (14 non-IBD, 29 normal)	Increased serum REG3α correlated with IBD severity detected by ELISA. Higher REG3α in CD than UC. REG3α localized to colonic Paneth cells
Wu et al[44], 2007	REG1β/REG3α	CD (9) UC (5) control (4)	Increased intestinal REG1β in CD and REG3α in CD and UC detected by microarray
Nanakin et al[45], 2007	REG4	UC (22) normal control (5)	Increased intestinal REG4 in UC detected by RT-PCR, ISH and IHC
Sekikawa et al[46], 2010	REG1α	UC (60) control (10)	Increased intestinal REG1α in UC detected by RT-PCR and IHC
Tanaka et al[47], 2011	REG1α	UC (31) control (5)	Increased intestinal REG1α in UC detected by IHC
Granlund et al[14], 2011	REG1α/1β/3α/4	CD/control (12/21) UC/control (32/34)	Increased intestinal REG1α/1β/3α/4 in IBD detected by microarray. Different cellular localizations of REG1α and REG4 detected by IHC
van Beelen Granlund et al[48], 2013	REG1α/1β/3α/4	CD (N/A) UC (N/A)	By ISH, REG1α/1β/3α localized to Paneth cells in the crypt base, REG4 localized to enteroendocrine cells towards the luminal face
Planell et al[49], 2013	REG1α/4	Microarray: UC (15 active/8 remissive), Non-IBD (13); RT-PCR: UC (8 active/12 remissive), non-IBD (10)	Comparably increased intestinal REG4 in active and remissive UC, and significantly increased REG1α in active UC but not in remissive UC, detected by microarray and RT-PCR
Marafini et al[50], 2014	REG3α	CD (72) UC (22)	Infliximab treatment decreased the high serum REG3α in CD and UC
Nunes et al[51], 2014	REG3α	CD (66) UC (74)	Increased serum REG3α serum in active CD but not UC detected by ELISA
Tsuchida et al[52], 2017	REG1α/1β/3α/4	CD (49) UC (39) control (44)	Increased intestinal REG1α/1β/4 in CD, and REG4 in UC detected by RT-PCR

IHC: Immunohistochemistry; ISH: In situ hybridization; RT-PCR: Reverse transcription-polymerase chain reaction; ELISA: Enzyme-linked immunosorbent assay. N/A: Not available.

Table 2 Effects of genetically modified REG/Reg genes on the composition of intestinal bacterial microbiota in mice

Class	Order	Family	Genera
Actinobacteria	Bifidobacteriales	Bifidobacteriaceae	Bifidobacterium ↑2
	Coriobacteriales	Coriobacteriaceae ↓1↓3
	Eggerthellales	Eggerthellaceae	Enterorhabdus ↓3
Alphaproteobacteria	Caulobacterales	Caulobacteraceae	Brevundimonas ↓3
	Rhizobiales	Bartonellaceae	Bartonella ↑3
Bacilli	Bacillales	Bacillaceae	Oceanobacillus ↑3
		Staphylococcaceae	Staphylococcus ↓2
			Lactococcus ↑3
		N/A	Gemella ↑3
	Lactobacillales ↑3	Lactobacillaceae −1	Lactobacillus ↓2↑3−4↓5
		Enterococcaceae	Enterococcus ↑2↑3
		Aerococcaceae	Facklamia ↓3
		Carnobacteriaceae	Carnobacterium ↑3
Bacteroidia	Bacteroidales ↑1↑3↓5	Prevotellaceae ↓1↑3	Prevotella ↓1↑2↑3
		Rikenellaceae −1
		Porphyromonadaceae ↓1↓5	Parabacteroides ↓1↑3↑5
			Barnesiella ↓1
		Bacteroidaceae ↓1	Bacteroides ↓1−2−3−4↑5
Betaproteobacteria	Burkholderiales	Sutterellaceae ↓1	Parasutterella ↑1↓3
Clostridia ↑1	Clostridiales ↓5	Lachnospiraceae ↑1↑3−5	Roseburia ↑3
		Ruminococcaceae −2↑3−5	Faecalibacterium ↑3
		Clostridiaceae	Clostridium ↑2↑3(XI Cluster) ↓5(XIVa Cluster) ↑5
			Candidatus Arthromitus ↑3
			Candidatus Savagella ↑4
		Eubacteriaceae	Eubacterium (rectale) ↑4
		Oscillospiraceae	Oscillibacter ↑1
		Peptococcaceae ↑3
Delta Proteobacteria	Desulfovibrionales ↑1	Desulfovibrionaceae −5	Lawsonia −5
			Desulfovibrio −5
Epsilonproteobacteria	Campylobacterales	Helicobacteraceae	Helicobacter ↑2↑3
Erysipelotrichia	Erysipelotrichales	Erysipelotrichaceae ↑3↑5	Turicibacter ↑3
			Allobaculum −3↓5
Gammaproteobacteria	Enterobacterales	Enterobacteriaceae ↑3	Escherichia ↓2
			Enterobacter ↓1
		Morganellaceae	Proteus ↓2
	Pseudomonadales	Moraxellaceae	Psychrobacter ↑3
			Acinetobacter ↑3
	Xanthomonadales	Xanthomonadaceae	Stenotrophomonas ↑3
Negativicutes	Acidaminococcales	Acidaminococcaceae	Phascolarctobacterium ↑3
	Veillonellales	Veillonellaceae ↑3
Verrucomicrobiae	Verrucomicrobiales	Akkermansiaceae	Akkermansia ↓1↑3↑5
		Verrucomicrobiaceae ↓1

Increased (↑), decreased (↓) and unaltered (−) intestinal bacterial proportions are indicated in:

¹hepatocyte specific REG3α transgenic mice[79].

²intestinal cell specific Reg4 knockout mice[16].

³intestinal cell specific REG3γ transgenic mice[80].

⁴the intestinal mucosa of Reg3γ knockout mice[31].

⁵the intestinal mucosa of Reg3β knockout mice[35].