What does irritable bowel syndrome share with non-alcoholic fatty liver disease?

Table 1 Principal findings on inflammatory cytokines in non-alcoholic fatty liver disease in humans, and in in vitro and animal models

Principal findings
TNF-α
In vitro: FFA induce TNF-α gene expression[60]. KC and hepatocytes from NAFLD produce ↑ TNF-α and ↑ lipid peroxidation and accumulation[59,61]. TNF-α induces hepatocyte apoptosis[59]
Animal: TNF-α regulates KC apoptosis[58]. Hepatic, portal blood and intestinal TNF-α is ↑[52,53,61]
Human: Circulating levels are ↑ in NAFLD and NASH[57,68]. Contrasting data on simple FL[55,62]. They correlate with activity and progression of NAFLD[64] but do not differentiate mild to severe NASH[60]. NASH subjects have also ↑PBMCs TNF-α, IL-6 and IL-8 production[68]. TNF-α mRNA expression is ↑ in liver and fat of NASH compared with NAFLD[57], but there are contrasting data[55,238] TNF-α polymorphism is most frequent in NAFLD and correlates also with IR[56]
IL-6
In vitro: FFA induces IL-6 expression in hepatic cell cultures[72] and enhances Th17 response[49]
Animal: IL-6, TNF-α, IL-8 production is ↑ in liver and muscle of NAFLD mice[64]. Possible hepatoprotective role[70,71]
Human: ↑ IL-6 blood levels and other inflammatory and cytonecrosis indexes in NAFLD and NASH subjects compared to controls and obese[57,68,69]. IL-6 is an index of NASH activity and progression[72]. Normal levels of IL-6 and normal spleen longitudinal diameter may be useful in excluding NASH from NAFLD[34]. IL-6 tissue expression is controversial in liver of NAFLD[57,72]
IL-8
In vitro: IL-8 with TNF-α are ↑ in NAFLD and in NASH compared to FL[64]. FFA induces IL-8 expression[60]
Human: Blood levels of IL-8, IL-6 and TNF-α are ↑ in NASH[68,69]
IL-1β
Animal: NAFLD rats express similar IL-1β, TNF-α and IL-6 levels in liver and in muscle[64]
Human: TNF-α, IL-6 and IL-1β blood levels are ↑ in NAFLD and NASH[68,69]
TGF-β1
In vitro: IL-17 and FFA induce IL-6 in hepatocytes and IL-6, with TGF-β1, enhance Th17 response[49]
Human: TGF-β1 blood levels in NAFLD are ↑ than CHC[78]
IL-10
Animal: After IL-10 inhibition, TNF-α, IL-6 and IL-1β levels increase in liver of HFD mice[81]. IL-10 knock-out mice have ↑ FFA plasma levels and hepatic TG[79]
Human: In NAFLD and obese children, lower IL-10 blood levels correlate with markers of visceral and subcutaneous fat, insulin, HOMA-IR, ALT, AST and GGT[77]
IL-17
In vitro: IL-17 and FFA induce IL-6 production[49]
Animal: LPS-induced liver injury ameliorated after IL-17 blockade in HFD rats[49]
Th2 cytokines (IL-4, IL-5, IL-13)
Animal: Rats genetically oriented to a Th1 response develop steatosis and lobular inflammation more than others oriented toTh2 response[44,45]

TNF-α: Tumor necrosis factor-α; FFA: Free fatty acids; KC: Kupffer cells; NAFLD: Non-alcoholic fatty liver disease; NASH: Non alcoholic steatohepatitis; FL: Fatty liver; PBMCs: Peripheral blood mononuclear cells; IL: Interleukin; IR: Insulin resistance; TGF-1β: Tumor growth factor 1 β; Th17: T helper 17; CHC: Chronic hepatitis C; HFD: High fat diet; TG: Triglycerides; HOMA-IR: Homeostasis model of assessment-insulin resistance; ALT: Alanine-aminotransferase; AST: Aspartate-aminotransferase; GGT: γ-Glutamyltransferase; LPS: Lipopolysaccharide; Th2: T helper 2; Th1: T helper 1.

Table 2 Principal findings on inflammatory cytokines in irritable bowel syndrome in humans, and in in vitro and animal models

Principal findings
TNF-α
Animal: D-IBS supernatants have ↑ levels of proinflammatory cytokines and they cause hypersensitivity in mouse colonic afferent endings[122]
Human: IBS has ↑ circulating TNF-α levels[109,112], especially D-IBS[112] or in patients with comorbidities such as fibromyalgia, premenstrual dysmorphic disorder and chronic fatigue syndrome[109]. Baseline and LPS-stimulated levels in PBMCs of proinflammatory cytokines as TNF-α, in IBD and D-IBS, are ↑ and are related to symptom intensity[108]. TLR-2, TLR-4 and TLR-5 antagonists induce TNF-α production[128]. No difference in TNF-α and other proinflammatory cytokine production (IL-6 and IL-1β) in the gut of IBS subjects compared to controls[116]
IL-6
In vitro: No differences in colonic production between IBS and controls 116. IL-6 have excitatory action on colonic cells from IBS rats producing neuronal activation and absorption/secretory responses[115]
Animal: IL-6 colonic secretion is ↑ in IBS rats and activate submucosal neurons[127]
Human: IL-6 blood levels are ↑ in all IBS subtypes[109-111]. IL-6 levels are related to ACTH response and ∆ACTH/∆Cortisol ratio[110]. Baseline and LPS or TLR agonist-stimulated PBMC levels are ↑ in IBS[108]
IL-8
In vitro: Reduced expression of mRNA of IL-8 in ex vivo biopsy cultures[116]
Human: Circulating levels of IL-8 are ↑ in IBS[109-111,119]. TLR-3 and TLR-7 agonists induce IL-8 production in PBMCs[128]
IL-1β
Animal: In stressed rats with previous acute colitis IL-1β mRNA expression is ↓[117]
Human: ↑ IL-1β levels in IBS[108,128], in C-IBS and in D-IBS[108]. With TNF-α, IL-1β↑ levels are found in IBS subjects with fibromyalgia, premenstrual dysmorphic disorder and chronic fatigue syndrome[109]. IL-1β↑ production in PBMCs stimulated by antiCD3/CD28 antibody[91] and by TLR-4 and TLR-5 agonists[128]. Increased IL-1β expression in rectum of PI-IBS[121]
TGF-1β
Animal: No different expression of TGF-β1 protein in colon of IBS rats[11]
Human: TGF-1β intermediate producers may be at risk of developing IBS[114]
IL-10
Human: IBS subjects have ↓ circulating levels of IL-10[112]. Altered IL-10/IL-12 ratio in PBMCs with Th1 proinflammatory state[113]. IL-10 levels are ↓ and IFNγ levels are ↑ in colon of PI-IBS compared to non PI-IBS and controls[119]. IL-10 high producer genotype is protective against IBS[114]
Th2 cytokines (IL-4, IL-5, IL-13)
Animal: Th2 cytokines may have a role in intestinal hypercontractility[123]
Human: Stimulated PBMCs IL-5 and IL-13 levels are ↑ in IBS[124]

TNF-α: Tumor necrosis factor α; D-IBS: Diarrhoea-predominant irritable bowel disease (IBS); IBD: Inflammatory bowel disease; LPS: Lipopolysaccharide; PBMCs: Peripheral blood mononuclear cells; TLR: Toll like receptor; IL: Interleukin; ACTH: Adrenocorticotropic hormone; C-IBS: Constipation-predominant IBS; PI-IBS: Post-infectious IBS; TGF-1β: Tumor growth factor 1 β; IFNγ: Interferon γ; Th2: T-cell mediated helper response.