Contribution of ghrelin to functional gastrointestinal disorders’ pathogenesis

Table 1 Comparison of physiological actions of acyl- and des-acyl ghrelin

Parameter	Acyl-ghrelin	Des-acyl ghrelin	Ref.
Appetite1	Increase	Decrease	[87]
Metabolism1	Positive energy balance	Negative energy balance	[87]
Adipogenesis	Increase	Increase	[88]
Cardiomyocyte and endothelial cell death	Inhibition	Inhibition	[20]
Papillary muscle contractility	Negative inotropy	Negative inotropy	[89]
Blood pressure	Decrease	Decrease	[90]
Insulin release1	Decrease	Increase	[91]
Insulin sensitivity1	Decrease	Increase	[92]
Muscle wasting	Decrease	Decrease	[93]
Gastric emptying1	Increase	Decrease	[94]
Gastric motility1	Increase	Decrease	[95]

¹Opposing actions.

Table 2 Ghrelin genetics and expression in functional dyspepsia patients compared to controls

Ref.	Participants	Parameters	FD patients compared to Controls	P value
Shindo et al[57]	PDS (n = 76)/Controls ( n = 20)	Acyl-ghrelin, plasma levels	Lower	< 0.05a
Shinomiya et al[54]	FD (n = 18)/Controls (n = 18)	Acyl-ghrelin, plasma levels	Higher	> 0.05
		Des-acyl ghrelin, plasma levels	Lower	> 0.05
Nishizawa et al[49]	FD (n = 47)/Controls (n = 17)	Total ghrelin, plasma levels	Higher	< 0.05a
		Acyl-ghrelin, plasma levels	Higher	< 0.05a
Lanzini et al[48]	FD (n = 39)/Controls ( n = 53)	Total ghrelin, plasma levels	Higher	< 0.01a
Takamori et al[51]	FD (n = 16)/Controls (n = 19)	Des-acyl ghrelin, fasting state, plasma levels	Lower	0.0019a
		Acyl-ghrelin, fasting state, plasma levels	Lower	0.4191
		Des-acyl ghrelin to acyl-ghrelin ratio, fasting state, plasma levels	Lower	0.0154a
Lee et al[50]	FD (n = 42)/Controls (n = 14)	Total ghrelin, fasting state, plasma levels	Lower	< 0.05a
Choi et al[56]	FD (n = 39)/Controls (n = 38)	Male patients, acyl-ghrelin, plasma levels	Lower	0.017a
	FD (n = 65)/Controls (n = 49)	Female patients, acyl-ghrelin, plasma levels	Lower	0.348
Lee et al[65]	FD (n = 167)/Controls (n = 434)	rs42451, A allele	More frequent (PDS subgroup)	< 0.05a
		rs42451, AA genotype	More frequent (PDS subgroup)	< 0.05a

^aStatistical significance. PDS: Postprandial distress syndrome; FD: Functional dyspepsia.

Table 3 GHRL genetic polymorphisms and associations with laboratory/clinical parameters related to functional dyspepsia

Ref.	Participants	Genotype	Phenotype	P value
Ando et al[62]	Healthy (n = 264)	Leu72Met, AA+CA compared to CC	Higher acyl-ghrelin plasma levels	0.015a
		3056T C, CC+TC compared to TT	Higher acyl-ghrelin plasma levels	0.021a
Futagami et al[63]	FD (n = 74)/PDS (n = 51)/EPS (n = 23)/Controls	3056TC, TC+CC compared to TT	Higher acyl-ghrelin plasma levels	0.025a
		Leu72Met, CA+AA compared to CC	Higher acyl-ghrelin plasma levels	0.347
Yamawaki et al[64]	FD (n = 74)	Leu72Met, GG compared to GT+TT	Early phase of gastric emptying, 10 minutes after meal	0.038a
	FD (n = 74)	Leu72Met, GT+TT compared to GG	Higher SRQ-D scores (GT+TT compared to GG genotype)	0.0097a
	Controls (n = 64)	Leu72Met, GG compared to GT+TT	Early phase of gastric emptying, 10 minutes after meal	> 0.05

^aStatistical significance. FD: Functional dyspepsia; PDS: Postprandial distress syndrome; SRQ-D: Self-rating Questionnaire for Depression Score (an index of depression severity).

Table 4 Ghrelin genetics and expression in irritable bowel syndrome patients compared to controls

Ref.	Participants	Parameters	IBS patients compared to Controls	P value
Salhy et al[77]	IBS-C (n = 19)/Controls (n = 10)	Ghrelin cell density in gastric mucosa	Higher	< 0.0001a
	IBS-D (n = 18)/Controls (n = 10)	Ghrelin cell density in gastric mucosa	Lower	< 0.0001a
Şahin-Eryılmaz et al[79]	IBS-C (n = 30)/Controls (n = 30)	Ghrelin staining, antral mucosal glands	Higher	0.038a
	IBS-D (n = 30)/Controls (n = 30)	Plasma ghrelin levels	Higher	0.001a
Sjölund et al[78]	IBS (n = 9)/Controls (n = 9)	Acyl-ghrelin and motilin plasma levels covariation	Covariation present in IBS patients only	< 0.02a
		Des-acyl ghrelin and motilin plasma levels covariation	Covariation present in IBS patients only	< 0.04a
		Total ghrelin and motilin plasma levels covariation	Covariation present in IBS patients only	< 0.004a
Lee et al[65]	IBS (n = 60)/Controls (n = 434)	rs3755777, G allele	Less frequent (IBS-D subgroup)	< 0.05a
		rs3755777, GG+CG genotypes	Less frequent (IBS-D subgroup)	< 0.05a
Russo et al[36]	IBS-D (n = 28)/Controls (n = 19)	Leu72Met, T allele	Less frequent	0.027a
		Leu72Met, GT genotype	Less frequent	0.041a
Videlock et al[81]	IBS (n = 20)/Controls (n = 10)	GHRLOS lncRNA levels	Down-regulated, IBS	< 0.05a
			Down-regulated, IBS-D	< 0.05a

^aStatistical significance. IBS-C: Irritable bowel syndrome, constipation predominant; IBS-D: Irritable bowel syndrome, diarrhea predominant; GHRLOS: Ghrelin opposite strand transcript; lncRNA: Long non-coding RNA.