Intestinal epithelial barrier and neuromuscular compartment in health and disease

Table 1 Summary of current human and experimental data on molecular, morphological and functional changes in intestinal epithelial barrier and neuromuscular compartment in digestive disorders

Digestive disorder	Morphofunctional changes in intestinal epithelial barrier	Morphofunctional changes in enteric neuromuscular compartment	Notes	Ref.
Human investigations
IBD	Altered composition of mucus layer	↓ Myenteric neurons (b)	(a) UC ↓ claudin-1 and -4; CD ↓ claudin-3, -5 and -8	[5,16-19,23-26,29-36]
	Abnormal glycosylation of mucins	↑ SP release (c)	(b) Another study reported an increment of the enteric neuron number
	↑ Paracellular and transcellular permeability	↑ NK-1 and NK-2 receptors
	↑ Claudin-2 and claudin-18 (a)	Altered morphology of ICC	(c) Other authors reported a significant reduction of both AChE activity and ACh release in IBD patients suffering from moderate-severe disease, as compared with healthy controls or IBD patients with low disease severity
	↓ Occludin and ZO-1	Functional alterations of EGCs
IBS	↑ Mucus secretion	↓ Thickness of muscle layer	(d) Positive correlation between increased intestinal permeability and visceral pain	[51,54-63]
	↑ Paracellular permeability (d)	↑ Entero-endocrine cell activity
	↓ Occludin and ZO-1	↑ SP release (f)
	Altered expression of claudins (e)	Altered circulating levels of 5-HT	(e) IBS-D: ↓ claudin-1 and claudin-4, resulting in diarrhea; IBS-C: ↑ claudin-1, claudin-3 and claudin-4, resulting in constipation
		Altered number and morphology of ICC	(f) Positive correlation between increased SP release and pain scores
		↑ EGC density
Intestinal infections	Altered composition of mucus layer	↓ Circulating levels of 5-HT		[72,74,75,76,78,79]
	↓ Goblet cell number	↑ SP release
	↑ Paracellular permeability altered TJs
	↑ Epithelial apoptosis
Diverticulosis and diverticulitis	↑ Mucosal folds	Altered smooth muscle cells	(g) A more recent study did not observe alterations of ENS	[77,80-83]
	Mucosal ulcerations	Altered serotonergic system
	Crypt distortion	↑ Tachykinergic contractile activity
		↓ Cholinergic pathway activity
		↓ ICC number
		↓ EGC density (g)
Experimental models
IBD	Altered composition of mucus layer	↓ Myenteric neurons		[37-50]
	↓ Goblet cell number	Altered morphology of ICC
	↑ Paracellular and transcellular permeability	↓ EGC density
	↑ Claudin-1 and claudin-2
	↓ Occludin and ZO-1
IBS	↑ Mucus secretion	↓ Thickness of muscle layer	(h) Positive correlation between increased intestinal permeability and visceral pain	[63,65-68,70]
	↑ Paracellular permeability (h)	Altered number of ICC
	↓ Occludin and ZO-1	↑ SP release
		↓ Circulating levels of 5-HT
		↑ EGC density
Intestinal infections	↑ MUC1 expression	↑ SP release		[84-87]
	↓ MUC2 expression
	↑ Paracellular permeability
	Altered TJs

↑: Increase; ↓: Decrease; 5-HT: Serotonin; Ach: Acetylcholine; AChE: Acetylcholinesterase; CD: Crohn’s disease; EGCs: Enteric glial cells; ENS: Enteric nervous system; IBD: Inflammatory bowel disease; IBS: Irritable bowel syndrome; IBS-C: IBS with constipation; IBS-D: IBS with diarrhea; ICC: Interstitial cells of Cajal; MUC: Mucin; NK: Neurokinin; SP: Substance P; TJ: Tight junction; UC: Ulcerative colitis; ZO-1: Zonulin-1.

Table 2 Summary of current human and experimental data on molecular, morphological and functional changes in intestinal epithelial barrier and neuromuscular compartment in metabolic disorders

Metabolic disorder	Morphofunctional changes in intestinal epithelial barrier	Morphofunctional changes in enteric neuromuscular compartment	Ref.
Human investigations
Obesity	↑ Circulating LPS	NA	[6]
	↓ Occludin and tri-cellulin immunopositivity
	↑ ZO-1
Diabetes	↑ Intestinal permeability (urinary excretion of lactulose)	NA	[6]
Experimental models
HFD-induced obese mice	↓ ZO-1, occludin and claudins	↓ Nitrergic and VIPergic neurons Altered smooth muscle cell excitability	[89-91,93,94,96,97]
	↑ Circulating LPS	↓ Enteric inhibitory neurotransmission
		↑ Enteric excitatory tachykininergic neurotransmission
		↑ SP immunopositivity
		↑ A2B adenosine receptor expression
Lep ob/ob mice	↑ Intestinal permeability	NA	[92]
	Alterations of villi/crypt length
	↓ TJs and mucus-related genes
Ob/ob mice	↑ Paracellular permeability	↓ Intestinal motor activity	[95]
	Altered TJs	↓ ACh receptors
		Delayed intestinal transit rate

↑: Increase; ↓: Decrease; A_2B: Adenosine 2B receptor; Ach: Acetylcholine; HFD: High-fat diet; Lep: Leptin; LPS: Lipopolysaccharide; NA: Not available; Ob/ob: Obese mice; SP: Substance P; TJ: Tight junction; ZO-1: Zonulin-1.

Table 3 Summary of current human and experimental data on molecular, morphological and functional changes in intestinal epithelial barrier and neuromuscular compartment in central nervous system disorders

Central nervous system disorder	Morphofunctional changes in intestinal epithelial barrier	Morphofunctional changes in enteric neuromuscular compartment	Ref.
Human investigations
PD	↑ Intestinal permeability	↑ EGC density	[7,98-100]
	↓ Occludin and ZO-1 expression	α-syn accumulation in myenteric neurons
AD	NA	↑ Aβ, AβPP and p-Tau immunoreactivity in colonic myenteric and submucosal neurons	[102]
MS	↑ Intestinal permeability (urinary mannitol concentration)	ENS fiber disgregation	[8,101]
		EGC activation
ASD	Altered intestinal permeability	NA	[9]
Experimental models
Rotenone-induced central dopaminergic neurodegeneration	↑ Intestinal permeability	α-syn accumulation in myenteric neurons	[7,104]
		Delayed bowel transit
LPS-induced central dopaminergic neurodegeneration	↑ intestinal permeability (lactulose/mannitol ratio and sucralose levels)	α-syn accumulation in myenteric neurons	[7,104]
		Delayed bowel transit
6-OHDA-induced nigrostriatal neurodegeneration	NA	Impairment of colonic cholinergic and tachykininergic motor activity	[105-106]
Tg A53T mice (genetic model of PD)	NA	Impairment of colonic cholinergic motor activity	[107]
		α-syn accumulation in myenteric and submucosal neurons
APP/PS1 mouse (genetic model of AD)	NA	↑ Aβ protein precursor, Aβ	[4]
		Protein and p-Tau
		↓ nNOS and ChAT
		EGC activation
Tg CRND8 mice (genetic models of AD)	NA	↑ Aβ protein precursor in myenteric neurons	[4]
		Enteric glial activation (GFAP, nestin)
		Enteric neuronal loss
		Smooth muscle cell atrophy
EAE (animal model of MS)	Abnormal intestinal permeability (plasma Na-F and FITC levels)	Crypt depth and thickness of submucosal and muscular layers	[4]
	↓ ZO-1 expression	Enteric glial activation
		Neuronal loss
		Abnormal GI motility
G93A mice (genetic model of ALS)	↑ Circulating LPS	NA	[4,103]
	↓ ZO-1 and E-cadherin expression
	↑ Paneth cells number

↑: Increase; ↓: Decrease; 6-OHDA: 6-hydroxydopamine; α-syn: α-synuclein; Aβ: Amyloid β; AβPP: β-amyloid protein precursor; AD: Alzheimer’s disease; ALS: Amyotrophic lateral sclerosis; ASD: Autism spectrum disorder; ChAT: Choline acetyltransferase; EGC: Enteric glial cell; ENS: Enteric nervous system; FITC: Fluorescein isothiocyanate; GFAP: Glial fibrillary acidic protein; GI: Gastrointestinal; LPS: Lipopolysaccharide; nNOS: Neuronal nitric oxide synthase; MS: Multiple sclerosis; NA: Not available; PD: Parkinson’s disease; p-Tau: Phosphorylated Tau; ZO-1: Zonulin.