Bile acids in immunity: Bidirectional mediators between the host and the microbiota

Godlewska, Urszula; Bulanda, Edyta; Wypych, Tomasz P.

doi:10.3389/fimmu.2022.949033

Cited by 29 publications

(29 citation statements)

References 49 publications

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“…No differences in fecal microbiota composition between Sham AL and Sham PF mice were detected 5 weeks after the interventions ( Supplemental Table 1 ). Intestinal products can translocate into the portal vein and reach the liver where they can regulate immune homeostasis and inhibit inflammation 31 . Thus, we measured the concentrations of bile acids (BA) and short-chain fatty acids (SCFA) in the portal vein blood.…”

Section: Resultsmentioning

confidence: 99%

Hepatic lipid-associated macrophages mediate the beneficial effects of bariatric surgery against MASH

Fredrickson,

Florczak,

Barrow

et al. 2023

Preprint

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Immune mechanisms are considered a major contributing factor to the inflammatory process and progression of non-alcoholic steatohepatitis (NASH). Bariatric procedures such as vertical sleeve gastrectomy (VSG) have been shown successful in ameliorating the progression of the disease. Several mechanisms of weight-loss-independent improvements due to bariatric surgery have been proposed including bile acid signaling, gut hormones, intestinal tissue reprogramming, and changes in the gut microbiome. However, whether bariatric surgery ameliorates the progression of NASH through anti-inflammatory mechanisms has not been investigated. To determine the effects of VSG on hepatic inflammation, we fed mice a high-fat high-carbohydrate (HFHC) diet for 12 weeks and assigned them to either VSG or Sham surgeries. Independent from weight loss, VSG resulted in reduced hepatic lipid accumulation and ameliorated NASH as early as 5 weeks after VSG. To profile the gene expression of macrophages in the NASH liver following VSG, we performed single-cell RNA sequencing and identified 18 clusters of monocytes and macrophages with a unique gene expression signature. We found substantial alterations in macrophage subsets in association with VSG-induced reversal of NASH. In particular, hepatic lipid-associated macrophages (LAMs), which are enriched in genes associated with lipid metabolism and collagen degradation, were highly responsive to VSG. Differential gene expression analysis revealed that VSG increased the expression of genes involved in lysosomal activity, antigen presentation, and repression of inflammation in LAMs, suggesting that VSG sustains their protective function. Spatial transcriptomic analysis of human liver sections confirmed the enrichment of LAM genes within periportal regions during NASH and a marked reduction following VSG. To determine a causal role for hepatic LAMs in the restorative process induced by VSG against NASH, we performed VSG in mice deficient for the triggering receptor expressed on myeloid cells 2 (Trem2). TREM2-deficiency ablated the protective effects of VSG against NASH, suggesting that LAMs mediate this reparative process. Mechanistically, Trem2 prevents the inflammatory activation of bone marrow-derived macrophages, in agreement with the anti-inflammatory effects of VSG in LAMs. Overall, our findings suggest that bariatric surgery improves NASH through a reparative process driven by hepatic lipid-associated macrophages.

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Section: Resultsmentioning

confidence: 99%

Hepatic lipid-associated macrophages mediate the beneficial effects of bariatric surgery against MASH

Fredrickson,

Florczak,

Barrow

et al. 2023

Preprint

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“…Bile acids (BAs) are generated by hepatocytes and have a role in dietary lipid absorption and cholesterol homeostasis (22,23). BAs bind to FXR, a member of the nuclear receptor super-family that has transcriptional activity.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of the farnesoid X receptor promotes M2 macrophage polarization

Jaroonwitchawan

Arimochi²,

Sasaki³

et al. 2023

Front. Immunol.

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FXR is a key molecule that modulates anti-inflammatory activity in the intestinal-liver axis. Although FXR has pleiotropic functions including regulation of liver inflammation and activation of macrophages, it remains unclear whether it is involved in macrophage polarization. In this paper we demonstrated that stimulation of macrophages derived from the bone marrow using an FXR agonist activated polarization toward M2 but not M1 macrophages. The treatment of mice with chitin skewed macrophage polarization towards M2 macrophages, while co-treatment with an FXR agonist further promoted the polarization toward M2 macrophages in vivo. This skewed polarization towards M2 macrophages by an FXR agonist was accompanied by increased expression of signaling molecules related to the retinoic acid receptor. Inhibition of the retinoic acid receptor suppressed FXR agonist-mediated M2 macrophage polarization, indicating that this polarization was, at least, partly dependent on the retinoic acid receptor pathway. These data demonstrate that FXR has a role in polarization toward M2 macrophages and suggest a possible therapeutic potential of FXR agonists in M2 macrophage-related conditions.

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“…Most bile synthesis occurs through the ‘classical’ pathway in the adult liver. In adults, the expression of the rate-controlling enzyme of the classical pathway, CYP7A1, determines the level of bile synthesis [ 2 , 106 , 107 ]. Classical bile synthesis is under feedback control, with enterocytes in the lower gut monitoring bile levels via NR1H4.…”

Section: Discussionmentioning

confidence: 99%

“…The gastrointestinal (GI) tract is another system that grants immune privilege to ‘non-self’ antigens and epitopes. Our bodies digest many foreign proteins in the presence of microflora, and without some form of immune evasion, there could be off-target inflammation and immune responses during digestion [ 2 ]. Prostaglandins and bile salts play essential roles in producing immune evasion in the GI tract, thus preventing inappropriate immune attacks [ 3 , 4 , 5 , 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Acquisition of Immune Privilege in GBM Tumors: Role of Prostaglandins and Bile Salts

Sharpe

Baskin

Johnson

et al. 2023

IJMS

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Based on the postulate that glioblastoma (GBM) tumors generate anti-inflammatory prostaglandins and bile salts to gain immune privilege, we analyzed 712 tumors in-silico from three GBM transcriptome databases for prostaglandin and bile synthesis/signaling enzyme-transcript markers. A pan-database correlation analysis was performed to identify cell-specific signal generation and downstream effects. The tumors were stratified by their ability to generate prostaglandins, their competency in bile salt synthesis, and the presence of bile acid receptors nuclear receptor subfamily 1, group H, member 4 (NR1H4) and G protein-coupled bile acid receptor 1 (GPBAR1). The survival analysis indicates that tumors capable of prostaglandin and/or bile salt synthesis are linked to poor outcomes. Tumor prostaglandin D2 and F2 syntheses are derived from infiltrating microglia, whereas prostaglandin E2 synthesis is derived from neutrophils. GBMs drive the microglial synthesis of PGD2/F2 by releasing/activating complement system component C3a. GBM expression of sperm-associated heat-shock proteins appears to stimulate neutrophilic PGE2 synthesis. The tumors that generate bile and express high levels of bile receptor NR1H4 have a fetal liver phenotype and a RORC-Treg infiltration signature. The bile-generating tumors that express high levels of GPBAR1 are infiltrated with immunosuppressive microglia/macrophage/myeloid-derived suppressor cells. These findings provide insight into how GBMs generate immune privilege and may explain the failure of checkpoint inhibitor therapy and provide novel targets for treatment.

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Bile acids in immunity: Bidirectional mediators between the host and the microbiota

Cited by 29 publications

References 49 publications

Hepatic lipid-associated macrophages mediate the beneficial effects of bariatric surgery against MASH

Hepatic lipid-associated macrophages mediate the beneficial effects of bariatric surgery against MASH

Stimulation of the farnesoid X receptor promotes M2 macrophage polarization

Acquisition of Immune Privilege in GBM Tumors: Role of Prostaglandins and Bile Salts

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