Intestinal reengineering: Scientific advances in intestinal transplantation

Table 1 Potential functions and mechanisms of immune cells in small intestine transplantation

Immune cell type	Infiltration characteristics and functions	Related mechanisms/molecular markers	Clinical significance	Ref.
T cell (CD8+)	Key effector cells in early AR; may develop exhausted-like phenotype under persistent antigen stimulation	PD-1, TIM-3, IFN-γ	AR biomarker; PD-1 inhibition must consider graft-vs-host disease risk	[209-211]
T cell (CD4+)	Th1/Th17 subsets drive rejection; Treg maintains mucosal homeostasis by suppressing inflammation	Th17: IL-17; Treg: FoxP3, IL-10, TGF-β	Th17/Treg ratio reflects rejection risk; modulating this axis improves outcomes	[91,92,212]
Regulatory T cells (Tregs)	Inhibit effector T cell activation; key regulatory cells promoting transplant tolerance	FoxP3, CTLA-4, IL-10, TGF-β	Treg expansion strategies may enhance tolerance and reduce rejection	[104,105,213]
B cell	Mediate chronic rejection and vascular injury via DSA production	IgG/IgM, complement activation, intimal hyperplasia	DSA levels correlate with chronic rejection; rituximab as therapeutic option	[164,214,215]
Natural Killer Cell (NK)	Contribute to rejection via ADCC; low-activity NK may support tolerance	NKG2D, perforin/granzyme, IL-10 inhibition	Regulating NK may reduce antibody-mediated rejection and mucosal injury	[101,216,217]
DC	Activate T cells in lymph nodes; tolerogenic DCs induce Treg differentiation	cDC1/cDC2 antigen presentation; pDC: IFN-α; tolerogenic DC: PD-L1	DC subpopulation imbalance promotes Th1 polarization; targeting PD-L1 can enhance transplant tolerance	[218-220]
Macrophage	M1 aggravates ischemia reperfusion injury; M2 promotes tissue repair and immune suppression	M1: TNF-α, IL-6; M2: ARG1	M1/M2 balance affects prognosis and barrier preservation	[221-224]
Mast cell	Disrupt mucosal barrier; associated with anastomotic leakage and infection	Histamine, IL-4, IL-13, eosinophil recruitment	Antihistamines or stabilizers may prevent complications	[225,226]
Myeloid inhibitory cells (MDSC)	Suppress T cell responses; excessive accumulation may lead to fibrosis	ARG1, ROS, M-MDSC	Targeted MDSC modulation needed to avoid immune imbalance	[227-229]
γδT cell	Regulate epithelial repair and microbial homeostasis; produce IL-17 and IL-22	γδT17 subset, IL-17, IL-22, villous regeneration	Support mucosal regeneration; crucial in post-ITx repair	[230,231]
ILC	ILC3 preserve epithelial integrity via IL-22; ILC2 mediate type 2 responses and may influence fibrosis	ILC3: RORγt, IL-22; ILC2: IL-5, IL-13	Dysfunction linked to chronic inflammation; IL-22 as repair target	[232,233]

AR: Acute rejection; PD-1: Programmed cell death 1; IFN: Interferon; DSA: Donor-specific antibody; DC: Dendritic cells; ILC: Innate lymphoid cells.

Table 2 The immune characteristics of intestinal specific microbiota and their correlation with small intestine transplantation

Bacterial genus	Specific species	Immune mechanism	Receptor/pathway	Association with intestinal transplantation	Potential applications/risks	Ref.
Bifidobacterium	B. longum	Promotes mucosal immune maturation, enhances epithelial integrity	TLR2/4	Loss post-transplant linked to GVHD predisposition	Probiotic supplementation may mitigate GVHD risk	[234,235]
	B. infantis	Balances Th1/Th2 response, modulates cytokine milieu	GPR43 (SCFA-mediated)	Suppresses systemic inflammation, fosters tolerance	May enhance immunosuppressive efficacy	[236]
Lactobacillus	L. plantarum	Downregulates pro-inflammatory cytokines (IL-6, IL-8)	TLR2	Limits endotoxemia and systemic inflammation	Helps prevent post-transplant sepsis	[237]
	L. reuteri	Promotes IL-10 production and Treg induction	AhR	Enhances barrier repair, reduces mucosal inflammation	Therapeutic for immune enteropathies	[238]
Bacteroides	B. fragilis	Induces Treg via PSA antigen	TLR2	Shown to promote tolerance in transplant models	Potential microbial immunotherapy target	[239]
	B. thetaiotaomicron	Promotes IgA secretion, modulates dendritic cell response	TLR4	Supports mucosal immunity, limits pathogen overgrowth	May prevent Enterobacteriaceae dominance	[240,241]
Escherichia coli	Commensal E. coli	Activates basal innate immunity	TLR5/MyD88	Maintains immune tone, but overgrowth risks rejection	Surveillance for strain virulence needed	[242]
	Pathogenic E. coli (e.g., EHEC)	Secretes shiga-like toxins, induces strong cytokine storm	GB3 receptor	Triggers mucosal necrosis, worsens ischemia-reperfusion injury	Requires antibiotic prophylaxis	[243]
Clostridium	C. perfringens	Produces α-toxin, damages tight junctions	-	Can cause graft necrosis, sepsis	Early diagnosis critical	[244]
	C. difficile	Induces pseudomembranous colitis via toxin A/B		Common post-transplant pathogen	Fecal microbiota transplantation emerging as a salvage therapy	[245]
Fusobacterium	F. nucleatum	Activates NF-κB, enhances IL-6/IL-8 release	TLR2/4	Linked to chronic inflammation and neoplasia	Considered a pro-inflammatory marker	[246,247]
Enterococcus	E. faecalis	Inhibits inflammasome, alters antimicrobial peptide balance		Contributes to barrier disruption and bacteremia	Targeted decolonization recommended	[248]
Prevotella	P. copri	Modulates Th17 response		Implicated in dysregulated immunity post- intestinal transplantation	Microbiome-guided regulation needed	[249]
Akkermansia	A. muciniphila	Enhances mucus production, improves tight junctions	GPR43	Shown to improve gut permeability and glucose homeostasis	Probiotic candidate under investigation	[250]
Roseburia	Roseburia spp.	Butyrate production, anti-inflammatory effect	FFAR3 (GPR41)	Maintains Treg differentiation and epithelial repair	Supports mucosal tolerance post-transplant	[251]
Sutterella	Sutterella spp.	Alters IgA response and epithelial interaction		Poorly understood but potentially modulates rejection	Requires further research	[252]

B. longum: Bifidobacterium longum; B. infantis: Bifidobacterium infantis; L. plantarum: Lactiplantibacillus plantarum; L. reuteri: Limosilactobacillus reuteri; B. fragilis: Bacteroides fragilis; B. thetaiotaomicron: Bacteroides thetaiotaomicron; E. coli: Escherichia coli; C. perfringens: Clostridium perfringens; C. difficile: Clostridioides difficile; F. nucleatum: Fusobacterium nucleatum; E. faecalis: Enterococcus faecalis; P. copri: Prevotella copri; A. muciniphila: Akkermansia muciniphila; EHEC: Enterohemorrhagic Escherichia coli; GVHD: Graft-vs-host disease; IL-1: Interleukin-1; SCFA: Short-chain fatty acid; Treg: Regulatory T cell; PSA: Prostate-specific antigen; TLR: Toll-like receptor; NF-κB: Nuclear factor kappa-B.