Copyright ©The Author(s) 2016.
World J Gastroenterol. Nov 14, 2016; 22(42): 9257-9278
Published online Nov 14, 2016. doi: 10.3748/wjg.v22.i42.9257
Table 1 Key Requirements for gut-derived systemic immune response
Key requirementFeaturesMechanisms
Activation of TLRsIntestinal receptors responsive to MAMPs and DAMPS[34,47,48,120]Increases pro-inflammatory cytokines[126]
Signaling dependent on MyD88[124,125]Upregulates class II MHC[127]
Activates NF-κB[123,125,126]Increases co-stimulatory molecules[41,127]
Favors T lymphocyte activation[41]Promotes pathogen-specific responses[142]
Modulates actions of Tregs[141,142]LPS activates TLR4[123,134]
Present in hepatocytes, HSCs, Kupffer cells, sinusoidal epithelial cells, BEC[48]Sequences in bacteria activate TLR9[135]
TLR4 in HSCs promote fibrosis[46,144]
Implicated in other liver diseases[58,148]
Stimulation of inflammasomesProtein complexes that release pro-inflammatory IL-1β and IL-18[111-113]Upregulated in hepatocytes by LPS[113]
NLRs sense microbial products[156]Activates pro-caspase 1[156]
Upregulated in Kupffer cells, hepatocytes, and sinusoidal epithelial cells[113]Promotes hepatic fibrosis[50]
Activation by highly diverse ligands[112]Shapes innate and adaptive immunity[112,160]
Implicated in NAFLD[51]
Activation separate from TLRs[112,155]
Emergence of dysbiosisMicroflora differ from commensals[116]Can activate TLRs and NLRs[116,173]
Dysbiosis varies in specific diseases[116]Genetic factors may affect composition[177]
Less bacterial diversity common[170]Gender-related compositional differences[179]
Antibiotics most frequent basis[165,175]May affect gender-related autoimmunity[180]
Uncertain cause or effect of disease[116]Present in AIH and experimental NASH[47,69]
Molecular mimicryMicrobial and self-homologies[33,185]pANCA react with bacterial antigen[53]
Cross-reacting antibodies[53,57,184]AMA cross-reacts with Escherichia coli[56,57]
Promiscuous activity of effectors[186]Increasingly distant homologues targeted[187]
Epitope spread[187]
Breech of intestinal mucosal barrierGut-derived products enter system[195]Gut-derived lymphocytes in lymph nodes[118]
Translocation prime basis[46,195]Microbial components in peripheral blood[195]
Active transport also possible[230]Activates TLRs and NLRs[123,130]
Implicated in NASH and diabetes[197,198]
Table 2 Microbial mechanisms for breeching intestinal barrier
Microbial EffectFeaturesMechanisms
TranslocationMigration of gut-derived products[195,224]Gut-derived SCFA affect tight junctions[200]
Tight junctions weakened[218]Butyrate strengthens intestinal barrier[203]
Increased intestinal permeability[195,218]Induces mucin synthesis[201,203]
Paracellular migration[37,224]Reduces bacterial translocation[204]
Consequences[192]Increases peripheral Tregs[205]
LPS and CpG delivered to liver[123,130,195]Inhibits NF-κB and inflammation[207]
Activated immune cells translocate[118,193]Lactate strengthens intestinal barrier[37]
Translocated microbial antigens activate peripheral immune cells[185]Fermented to butyrate[215,216]
TLRs and NLRs activated[123,130]Low butyrate- and lactate- producing bacteria associated with weak barrier[217,218]
Increased mucosal permeabilityIntestinal epithelial cells bound together by junctional complex of proteins[222,223]TLRs affect molecular mediators[225,226]
Occludin main component[222]Signaling pathways disrupted[223]
Zona occludens couples cytoskeleton[222]Junctional binding proteins dissociated[224]
Cingulin contacts cells[222]Paracellular migration routes formed[37,224]
Actin and myosin anchor cells[222]E. coli and C. difficile key effectors[37]
Intermediate filaments bind cells[222]
Signaling pathways seal junction[223]
Protein kinase C modulates occludin[222]
Active transportBacterial antigens actively transported across intestinal barrier[230]M cells in Peyer’s patches capable of active transport[230]
Table 3 Treatment considerations for investigation of gut-derived immune responses
Treatment ConsiderationNatureFindings
Dietary adjustmentsAnimal protein, saturated fats[90]Bacteroides, Firmicutes (including Clostridia), and Prevotella favored by different dietary regimens[37,90]
High carbohydrate diets[90]
Low fat high fiber diet[90]
Probiotic preparationsBifidobacterium bifidum[253]Expands Tregs in cell culture[278]
Lactobacillus strains[254,263,266]Prevents diabetes in NOD mice[263]
Lactobacillus rhamnosus[276]Improves liver tests in rat model[266]
Anaerostipes caccae[277]Increases tight junction proteins[276]
Consumes lactate and produces butyrate[277]
Vitamin A and retinoic acidRetinoic acid supplement[255]Restores Lactobacilli in lupus model[255]
Dietary vitamin A[256]Regulates cytokines in lupus model[256]
Induces IL-10-producing Tregs[279]
AntibioticsTetracycline, minocycline[257]Reduces activity in RA[257]
Vancomycin, metronidazole[269]Improves tests and pruritus in PSC[269]
Re-colonizationBacteroides fragilis[107]Induces Tregs in colitis model[107,109,110]
Fecal transplantationClostridia species[109,110]
Intestinal barrier protectorsGelatin tannate[258-260]Enhances mucus barrier[258,259]
Reduces activity in murine colitis[259]
Alters composition of microbiota[259]
Limits inflammatory effects of LPS[260]
Inhibits IL-8 and TNF-α in LPS cells[260]
TLR inhibitorsOligodeoxynucleotides blocking TLR7 signaling[261]Improves tests and reduces activity in murine model of lupus nephritis[261]
Improves autoimmune lung injury[261]
Molecular interventionsPolysaccharide A[105,262]Induces IL-10 producing Tregs[105,262]
Protects against EAE in mice[105]
Short chain fatty acidsAcetate, propionate, butyrate[200]Modulates gut signaling pathways[200]
Inhibits histone deacetylases[200,264]
Regulates gene expression[200]
Enhances gut integrity[200]