Factoring the intestinal microbiome into the pathogenesis of autoimmune hepatitis

Table 1 Key Requirements for gut-derived systemic immune response

Key requirement	Features	Mechanisms
Activation of TLRs	Intestinal 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 inflammasomes	Protein 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 dysbiosis	Microflora 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 mimicry	Microbial 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 barrier	Gut-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]

AMA: Antimitochondrial antibodies; BEC: Biliary epithelial cells; DAMPS: Damage-associated molecular patterns; HSCs: Hepatic stellate cells; IL: Interleukin; LPS: Lipopolysaccharide; MAMPs: Microbe-associated molecular patterns; MHC: Major histocompatibility complex; MyD88: Myeloid differentiation factor 88; NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis; NF-κB: Nuclear factor kappa B; NLRs: Non-obese diabetes-like receptors; pANCA: Atypical perinuclear anti-neutrophil cytoplasm antibodies; TLRs: Toll-like receptors; Tregs: Regulatory T cells. Superscripted numbers in brackets are references.

Table 2 Microbial mechanisms for breeching intestinal barrier

Microbial Effect	Features	Mechanisms
Translocation	Migration 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 permeability	Intestinal 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 transport	Bacterial antigens actively transported across intestinal barrier[230]	M cells in Peyer’s patches capable of active transport[230]

Superscripted numbers in brackets are references. Cpg: Un-methylated cytosine-phosphorothioate-guanine oligonucleotide; LPS: Lipopolysaccharide; NF-κB: Nuclear factor kappa B; NLRs: Non-obese diabetes-like receptors; SCFA: Short chain fatty acids; TLRs: Toll-like receptors; Tregs: Regulatory T cells.

Table 3 Treatment considerations for investigation of gut-derived immune responses

Treatment Consideration	Nature	Findings
Dietary adjustments	Animal 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 preparations	Bifidobacterium 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 acid	Retinoic 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]
Antibiotics	Tetracycline, minocycline[257]	Reduces activity in RA[257]
	Vancomycin, metronidazole[269]	Improves tests and pruritus in PSC[269]
Re-colonization	Bacteroides fragilis[107]	Induces Tregs in colitis model[107,109,110]
Fecal transplantation	Clostridia species[109,110]
Intestinal barrier protectors	Gelatin 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 inhibitors	Oligodeoxynucleotides blocking TLR7 signaling[261]	Improves tests and reduces activity in murine model of lupus nephritis[261]
		Improves autoimmune lung injury[261]
Molecular interventions	Polysaccharide A[105,262]	Induces IL-10 producing Tregs[105,262]
		Protects against EAE in mice[105]
Short chain fatty acids	Acetate, propionate, butyrate[200]	Modulates gut signaling pathways[200]
		Inhibits histone deacetylases[200,264]
		Regulates gene expression[200]
		Enhances gut integrity[200]

Superscripted numbers in brackets are references. EAE: Experimental autoimmune encephalitis; IL: Interleukin; LPS: Lipopolysaccharide; NOD: Non-obese diabetes; PSC: Primary sclerosing cholangitis; RA: Rheumatoid arthritis; TLR: Toll-like receptor; TNF-α: Tumor necrosis factor-alpha; Tregs: Regulatory T cells.