Table 2.

Examples of cellular/tissue targets for microbial metabolites along the microbiota gut–brain axis involved in the intestinal inflammatory response.

Metabolite/ Teatment	Cell Type/Tissue	Findings	Reference
SCFAs
Administration of a SCFA smixture (os)	Mouse colon mucosal Tregs	Regulation of cell function and size with protective effect against colitis via FFAR-2	[227]
Administration of n-butyrate (os)	Mouse colon mucosal macrophages	Downregulation of LPS-induced proinflammatory mediators, including nitric oxide, IL-6, and IL-12, via HDAC inhibition	[228]
High-fiber feeding	Mouse colon epithelial cells	Promotion of NLRP3 inflammasome-mediated IL-18 release contributing to gut homeostasis and protection from colitis via FFAR-2 and GPR109A	[230]
Administration of n-butyrate (ip)	Mouse hippocampus, prefrontal cortex	Anti-depressant effect associated with short-term HDAC inhibition and increased BDNF levels (only in prefrontal cortex)	[238]
Endogenous SCFA levels	Mouse colon mucosa, stools	Reduction of SCFAs and Lactobacillus spp fecal content, increase in GPR109A colonic expression after stressor exposure during infection with Citrobacter Rodentium underlying gut inflammation	[241]
Administration of a SCFAs mixture (os)	Mouse hypothalamus, hippocampus, colon mucosa	-Decreased stress-induced CRF expression in the hypothalamus, and CRF-receptor 1 in the hippocampus -Amelioration of psychosocial stress-induced responses -Anti-depressant and anxiolytic effects -Rescue of stress-induced enhancement of colonic mucosa permeability	[242]
Bile acids
Administration of the FXR agonist, INT-747, (i.p.)	Mouse colon mucosal macrophages	-Reduced activation and release of IL-1β, IL-2, IL-6, IFN-γ, and TNF-α -Amelioration of TNBS- and DSS-colitis	[253]
-Administration of INT-747 (os, in mice) -INT effect in vitro on LMPCs cultures	-Mouse colon epithelial cells - IBD patient’s LMPCs	-Amelioration of TNBS- and DSS-colitis, rescue of the mouse epithelial barrier function and reduced proinflammatory cytokine release in the mouse colon -Decrease TNF-α secretion in LMPCs from patients with IBD,	[254]
Administration of ciprofloxacin (i.p.) or oleanolic acid (os) to activate TGR5	Mouse and human colon mucosa	-Increased levels of TGR5 in the mouse colon after TNBS- and DSS-colitis, and in the colon of IBD patients -reduced colonic TLR4-mediated TNF-α secretion in TNBS-treated mice	[258]
-Administration of TGR5 agonists -BAR501, (os) (ref 352) -BTA (os) (ref 253) -Several TGR5 agonist in vitro (ref 254)	-Mouse colon mucosa macrophages -LMPCs from IBD patient’s intestinal mucosa	-Amelioration of the severity of colitis in TNBS, DSS and oxazolone-treated mice -Shift of intestinal macrophages from a classically activated proinflammatory M1 to an anti-inflammatory M2 phenotype in mice -reduced colonic expression of pro-inflammatory genes (TNF-α, IFN-γ, IL-1β, IL-6, and CCL2 mRNAs) and increased expression of IL-10 and TGF-β mRNAs in mice -reduced TNF-α release from proinflammatory macrophages isolated from IBD patient’s LMPCs	[260,261,262]
Administration of UDCA, TUDCA, GUDCA (os)	Mouse colon	-Amelioration of the severity of colitis in DSS-treated mice -Normalization of Firmicutes to Bacteroidetes ratio after colitis-induced dysbiosis -Prevention of Clostridium cluster XIVa loss and increased abundance of the protective species, Akkermansia muciniphila	[263]
Tryptophan metabolites
Kynurenines
IDO1	-Mouse colon crypt epithelial cells -Mouse colon lamina propria infiltrating APCs	- IDO1 levels of expression are fundamental to reduce Treg immune suppression and the severity of the inflammatory injury after TNBS-, DSS- and T-cell transfer-colitis	reviewed in ref [291]
Endogenous IDO1 and KynA	Epithelial cells and LMPCs from IBD patients’ biopsies	Increased IDO1 expression in epithelial and mononuclear cells positively related to the severity of inflamed region	[293]
	UC patients’s serum and mucosa	Increased IDO mucosal expression and increased KynA serum levels, positively correlated with endoscopic inflammation	[294]
Exposure in vitro to KynA and synthetic analogues	Human monocytic isolated cells	Reduced production of proinflammatory TNF-α induced by Staphylococcus aureus and Chlamydia pneumoniae, via TSG-6 expression	[297,298]
Endogenous IDO1, TRP, KynA	Mouse brain, spleen, Peyer’s patches	-Psychological stress-induced IDO1 activity, blocked by anti-TNFα and IFNγ treatment, and increased plasmatic KynA/TRP ratio	[299]
Administration of KynA (i.v.)	Dog colon ENS	-KynA antagonized hypermotility and inflammatory changes (increased XOR and MPO activity) associated with transitory colonic obstruction, via enteric NMDA receptors	[300]
Administration of KynA and its analogue, SRZ-72 (i.v.)	Rat colon ENS	-Reduced proinflammatory cytokine release, nitrite/nitrate and nitrotyrosine formation after TNBS-induced colitis -Normalization of microcirculation and of the rate of bowel movements after TNBS-induced colitis NMDA receptors located on enteric neurons	[302]
Endogenous Kyn/TRP	Rat intestine and CNS	FMT from depressed patients to bacterial microbiota-depleted animals induced: -Increased anxiety-like and anhedonic behavior -Increased Kyn/TRP plasma ratio -Increased bowel movements -Reduced microbiota richness	[303]
Kyn/TRP and Kyn	Mouse colon and hippocampus	Kyn and Kyn/TRP and cytokine plasma levels increased after Trichuris muris-induced mild to moderate colonic inflammation associated with -anxiety-like behaviors and reduced hippocampal BDNF mRNA levels	[210]
AhR ligands
-Endogenous AhR -administration of AhR agonist FICZ in vitro and ip	-UC and CD biopsies -Mouse colon	-Reduced AhR levels in DSS-treated mice colon and IBD biopsies -Reduced iIFNγ levels and IL-22 upregulation in patients’ LPMCs - Reduction of the severity of TNBS-, DSS and T-cell transfer-induced colitis in mice by Ficz -Downregulation of proinflammatory cytokines and upregulation of IL-22 in TNBS-treated mice which was reversed by FICZ antagonism -AhR activation by FICZ ameliorates DSS-induced colitis in mice via the MK2/p-MK2/TTP pathway	[329,336]
Administration of AhR agonist, ITE (ip)	Mouse colon	-Reduction of colitis severity in a humanized murine model of human CD4+ T cells transfer after TNBS administration -Increased CD39, Granzyme B, and IL-10-secreting human Treg cells isolated from colonic LPMCs.	[330]
Endogenous IAA	-Mouse colon and stools -IBD patients’ stools	-Susceptibility to colitis and altered microbiota in Card9 −/− mice associated with significant reduction of IAA fecal levels Reduced IAA and TRP levels and increased Kyn levels in fecal samples from IBD patients, particularly in those with CARD9 risk alleles associated with IBD	[331]
Endogenous and exogenous IPA	-IBD patient’s serum -Mouse colon and serum	-Reduced serum indole and IPA levels -Reduced serum indole and IPA levels after DSS colitis in mice -Improvement of DSS-colitis by exogenously administered IPA via epithelial IL-10 signaling	[332]
Endogenous IA	-Mouse colon goblet cells -Stools from CD and UC patients	-Administration of IA producing Peptostreptococcus russellii carrying the phenyllactate gene cluster (fldAIBC) to mice, reduced susceptibility to DSS, improved mucin producing goblet cell differentiation, promoted immune tolerance -reduced abundance of phenyllactate gene cluster in UC by metagenomic analysis	[335]

Abbreviations: Antigen-Presenting Cells, (APCs); betulinic acid (BTA); glycoursodeoxycholic acid (GUDCA), Lamina propria mononuclear cells LPMCs, tauroursodeoxycholic acid (TUDCA), ursodeoxycholic acid (UDCA).