. Author manuscript; available in PMC: 2023 Apr 17.

Published in final edited form as: Trends Immunol. 2021 Feb;42(2):137–150. doi: 10.1016/j.it.2020.12.005

Table 1.

Correlative and Causal Immunomodulatory Consequences of Gut Bacterial Translocation during Extraintestinal Diseases and Homeostasis in Mice and Humans

Disease model	Detection	Impact on systemic immunity	Causality	Refs
Disease: myeloid cancer - preleukemic myeloid proliferation Model: Tet2^fl/fl VAV^cre	Culture, sequencing Organs: spleen, mLN, blood	Spleen: splenomegaly, ↑ GMP cells, ↑CD11b⁺Gr1⁺ cells, ↑ IL-6 Blood: ↑GMP cells, ↑CD11b⁺Gr1⁺ cells, ↑IL-6 Bone marrow: ↑GMP	Requirement: ABX in GF mice Sufficiency: DSS, Pam3CSK4 Specificity: TLR-2 signaling	[31]
Disease: PDAC Model: K-ras^LSLG12D/+; Trp53^R172H/+; Pdx-1-Cre (KPC) mice	Culture, imaging, sequencing Organs/tissue: tumor	Human LTS: Tumor: ↑CD3⁺ T cells, ↑CD8⁺ T cells, ↑Granzyme B FMT with LTS feces: Blood: −IL-2, ↑ (IFN)γ Tumor: ↑CD8⁺ T cells, ↓ MDSCs, ↓FoxP3⁺ CD4⁺ Treg cells FMT with STS feces: Tumor: ↑MDSCs, ↑Treg cells	Requirement: ABX Sufficiency: FMT from human STS/LTS or control donors	[35]
Disease: PDAC Model: KPC mice; K-ras^LSLG12D/+; Pdx-1-Cre (KC) mice	Imaging, sequencing Organs: pancreas	Pancreas: ↑Intratumoral fibrosis, ↑pancreatic dysplasia, ↑MDSCs, ↑immunosuppressive TAMs, ↓proinflammatory TAMs, ↓IFNγ ⁺ CD4⁺ T cells (Th1), ↓IFNγ ⁺ CD8⁺ T cells (Tc1), ↓CD3⁺ T cell infiltration, ↓CD8⁺:CD4⁺ T cell ratio	Requirement: ABX, GF mice Sufficiency: FMT KPC feces, Bifidobacterium pseudolongum monocolonization	[36]
Disease: Cancer Model: Nod2^−/− mice; MCA205 sarcoma, MC38 colon carcinoma, TC-1 cervical cancer or RET melanoma	Culture Organs/tissue: tumor, spleen, mLN	Spleen: ↑IL-17A producing CD4⁺ T cells (Th17), ↑IFNγ⁺ Th17, ↑Thl, ↑Tcl Tumor: E. hirae-induced:↑ CD8⁺ T cell/Treg cell ratio, ↓Foxp3⁺Treg cells, ↓IL-17A⁺ γδT cells B. intestihominis induced: ↑IFNγ⁺ γδT cells, ↓IL-17A⁺ γδT cells	Requirement: ABX Sufficiency: Oral administration of B. intestihominis or E. hirae in B6 or Nod2^−/− mice treated with cyclophosphamide Specificity: Comparison to L. johnsonii and B. intestihominis	[52]
Disease: Type 1 diabetes Model: Nod2^−/− mice	Culture, sequencing Organs: mLN, pancreatic LN	Pancreas: ↑Th17, ↑Thl, insulitis Pancreatic LN: ↑ DCs, ↑macrophages, ↑IL-6, ↑IL-12, ↑Thl, ↑Th17	Requirement: ABX	[72]
Disease: Model: (NZW × BXSB) F₁ mice; autoimmune hepatitis (AIH) patients	Culture, imaging, sequencing Organs: mesenteric veins, mLN, liver, spleen	Systemic autoantibodies: ↑Anti-dsDNA IgG, ↑anti-RNA IgG, ↑anti-endogenous retrovirus glycoprotein-70, ↑anti-β2 glycoprotein mLN and spleen: ↑Th17, ↑T follicular helper cells (Tfh) Liver: ↑IFN-α1, ↑IFN-α2, ↑ TNF-α	Requirement: ABX Sufficiency: E. gallinarum monocolonization of GF C57BL/6 (B6) mice Specificity: Comparison to E. faecalis, B. thetaiotaomicron and S. typhimurium	[62]
Disease: SLE Model: TLR7.1 mice; IMQ-treated WT mice	Culture, sequencing Organs: mesenteric veins, mLN, liver, spleen	Systemic:↑Type I IFN, ↑plasmacytoid DCs Spleen: Splenomegaly Bone marrow: ↑GMP, ↑common myeloid progenitors, ↑ megakaryocyte-erythrocyte progenitors Kidney: ↑Immune cell infiltration, ↑extramedullary hematopoiesis, nephritis, proteinuria	Requirement: ABX, GF Sufficiency: FMT of TLR7.1 mice cecal contents, L. reuteri oral administration Specificity: Comparison to L. johnsonii and B. thetaiotamicron	[63]
Disease: SLE Model: Triple congenic (TC) B6. Sle1. Sle2. Sle3	Culture, sequencing Organs: mLN, liver	Systemic autoantibodies: ↑Anti-dsDNA IgG mLN: ↑Germinal center B cells, ↑Tfh cells Spleen: ↑IFNγ, ↑IL-17A and IL-10 producing CD4⁺T cells, ↑eftector memory CD4⁺ T cells, splenomegaly	Requirement: ABX Sufficiency: FMT from aged TC mouse feces into GF B6 mice	[65]
Disease: Primary sclerosing cholangitis (PSC) Model: DDC-fed WT mice with FMT from PSC patients	Culture, sequencing Organs: mLN, liver, spleen	Liver: ↑Th17, ↑inflammatory genes (serum amyloid A (Saa) and //1b), ↑fibrosis (Colla, and Tmp1) Blood: ↑SAA, ↑bilirubin, ↑alkaline phosphatase	Requirement: ABX, pore-forming function of K. pneumonia Sufficiency: GF mice inoculated with K. pneumoniae, P. mirabilis E. gallinarum	[78]
Disease: None Model: J_H ^−/−, TLR2^−/− 4^−/−, TLR4^-/ mice	Culture, sequencing Organs: mLN, liver, blood, spleen	Mouse blood: tanticommensal IgG (IgG recognizing murein lipoprotein (MLP) antigen) Human blood: ↑Anti-gut commensal IgG, ↑anti-MLP IgG	Requirement: GF mice; TLR4; bacterial MLP Specificity: Anti-Gram-negative commensal IgG	[82]

Abbreviations: ABX, antibiotic treatment; DC, dendritic cell; DDC, 3,5-diethoxycarbonyl-1,4-dihydrocollidine; DSS, dextran sodiumsulfate; FMT, fecalmicrobiota transplant; GF, germ free; GMP, granulocyte–monocyte progenitor; IFN, interferon; Ig, immunoglobulin; IL, interleukin; IMQ, imiquimod; LTS, long-term survivor; MDSC, myeloid derived suppressor cells; mLNs,mesenteric lymph nodes; SLE, systemic lupus erythematosus; STS, short-termsurvivor; TAM, tumor-associated macrophage; Tfh, follicular T cell; TLR, Toll-Like receptor; TNF, tumor necrosis factor; Treg cell, T regulatory cell.