Background/Objectives: Current inflammatory bowel disease (IBD) treatments focus on symptomatic relief, highlighting the need for innovative approaches. Dysregulation of the cannabinoid 1 (CB1) receptor, part of the endocannabinoid system, is linked to colitis. While tetrahydrocannabinol (THC) alleviates colitis via CB1 activation, its psychotropic effects limit clinical use. ZCZ011, a CB1R allosteric modulator, and cannabidiol (CBD), a non-psychoactive cannabinoid, offer alternatives. This study investigated combining sub-therapeutic THC doses with ZCZ011 or CBD in a murine model of dextran sodium sulphate (DSS)-induced colitis. Methods: Acute colitis was induced with 4% DSS for 7 days, followed by 3 days of water. Chronic colitis was modelled over 24 days with alternating DSS concentrations. The combination of 2.5 mg/kg THC with 20 mg/kg ZCZ011 or 10 mg/kg CBD was evaluated. Key markers were assessed to determine efficacy and safety, including disease activity index (DAI), inflammation, cytokine levels, GLP-1, and organ health. Results: DSS-induced colitis resulted in increased DAI scores, cytokines, organ inflammation and dysregulation of GLP-1 and ammonia. THC at 10 mg/kg significantly improved colitis markers but was ineffective at 2.5 and 5 mg/kg. ZCZ011 alone showed transient effects. However, combining 2.5 mg/kg THC with either 20 mg/kg ZCZ011 or 10 mg/kg CBD significantly alleviated colitis markers, restored colon integrity and reestablished GLP-1 homeostasis. This combination also maintained favourable haematological and biochemical profiles, including a notable reduction in colitis-induced elevated ammonia levels. Conclusions: This study demonstrates the synergistic potential of low-dose THC combined with CBD or ZCZ011 as a novel, effective and safer therapeutic strategy for ulcerative colitis.

Cannabinoids are emerging as promising treatments for inflammatory diseases such as ulcerative colitis. Specifically, cannabinoid 2 (CB2) receptors, which are upregulated during inflammation, have been distinctively linked to anti-inflammatory and analgesic effects. HU308, a synthetic cannabinoid developed to activate CB2 receptors selectively, aims to minimize unwanted off-target side effects. This study evaluated the effectiveness of both cannabidiol (CBD) and HU308 in mouse models of dextran sodium sulphate (DSS)-induced colitis, which mimic the acute and chronic phases of ulcerative colitis. Mice were treated with DSS in drinking water (four percent for the acute model and one to two percent for the chronic model) to induce colitis, as indicated by increased disease activity index (DAI) scores and inflammatory markers. Treatment with 60 mg/kg of CBD, but not lower doses, significantly reduced colitis symptoms, such as inflammation, cytokine levels, and MPO activity, while also normalizing glucagon-like peptide-1 (GLP-1) levels. HU308 showed comparable efficacy to high-dose CBD (60 mg/kg) but at a much lower dose (2.5 mg/kg), without observable toxicity. HU308 effectively normalized DAI scores, colon inflammation, ammonia levels, and GLP-1 expression in both colitis models. These results suggest that both CBD and HU308 are promising treatments for ulcerative colitis. However, HU308 demonstrates enhanced therapeutic potential by achieving similar outcomes at a fraction of the dose required for CBD, reducing the risk of off-target side effects. The ability of HU308 to modulate GLP-1, a biomarker of gut endocrine function, further underscores its promise as a novel treatment option.

Since its first outbreak in 2020, the pandemic caused by the Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) has caused the death of almost 7 million people worldwide. Vaccines have been fundamental in disease prevention and to reduce disease severity especially in patients with comorbidities. Nevertheless, treatment of COVID-19 has been proven difficult and several approaches have failed to prevent disease onset or disease progression, particularly in patients with comorbidities. Interrogation of drug data bases has been widely used since the beginning of pandemic to repurpose existing drugs/natural substances for the prevention/treatment of COVID-19. Steroids, including bile acids such as ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) have shown to be promising for their potential in modulating SARS-CoV-2/host interaction. Bile acids have proven to be effective in preventing binding of spike protein with the Angiotensin Converting Enzyme II (ACE2), thus preventing virus uptake by the host cells and inhibiting its replication, as well as in indirectly modulating immune response. Additionally, the two main bile acid activated receptors, GPBAR1 and FXR, have proven effective in modulating the expression of ACE2, suggesting an indirect role for these receptors in regulating SARS-CoV-2 infectiveness and immune response. In this review we have examined how the potential of bile acids and their receptors as anti-COVID-19 therapies and how these biochemical mechanisms translate into clinical efficacy.

Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are chronic disorders characterized by dysregulated immune response and persistent inflammation. Recent studies suggest that bile acid receptors, particularly GPBAR1, and the transcription factor RORγt play critical roles in modulating intestinal inflammation. This study evaluates the therapeutic potential of PBT002, a dual GPBAR1 agonist and RORγt inverse agonist, in IBD models. The effects of PBT002 were assessed through in vitro and in vivo experiments. Macrophages and T lymphocytes obtained from the buffy coat were exposed to PBT002 to evaluate its immunomodulatory activity. The beneficial effects in vivo were evaluated in mouse models of colitis induced by TNBS, DSS or DSS + IL-23 using also a Gpbar1 knock-out male mice. PBT002 exhibited an EC50 of 1.2 µM for GPBAR1 and an IC50 of 2.8 µM for RORγt. In in vitro, PBT002 modulated macrophage polarization towards an anti-inflammatory M2 phenotype and reduced Th17 cell markers while increasing Treg markers. In the TNBS-induced colitis model, PBT002 reduced weight loss, CDAI, and colon damage, while it modulated cytokine gene expression towards an anti-inflammatory profile. In GPBAR1-/-, the anti-inflammatory effects of PBT002 were attenuated, indicating partial GPBAR1 dependence. RNA sequencing revealed significant modulation of inflammatory pathways by PBT002. In DSS+IL-23 induced colitis, PBT002 mitigated disease exacerbation, reducing pro-inflammatory cytokine levels and immune cell infiltration. In conclusion, PBT002, a GPBAR1 agonist and RORγt inverse agonist, modulates both the innate and adaptive immune responses to reduce inflammation and disease severity in models of IBD.

Bile acids are steroids formed at the interface of host metabolism and intestinal microbiota. While primary bile acids are generated in the liver from cholesterol metabolism, secondary bile acids represent the products of microbial enzymes. Close to 100 different enzymatic modifications of bile acids structures occur in the human intestine and clinically guided metagenomic and metabolomic analyses have led to the identification of an extraordinary number of novel metabolites. These chemical mediators make an essential contribution to the composition and function of the postbiota, participating to the bidirectional communications of the intestinal microbiota with the host and contributing to the architecture of intestinal-liver and -brain and -endocrine axes. Bile acids exert their function by binding to a group of cell membrane and nuclear receptors collectively known as bile acid-regulated receptors (BARRs), expressed in monocytes, tissue-resident macrophages, CD4+ T effector cells, including Th17, T regulatory cells, dendritic cells and type 3 of intestinal lymphoid cells and NKT cells, highlighting their role in immune regulation. In this review we report on how bile acids and their metabolitesmodulate the immune system in inflammations and cancers and could be exploiting for developing novel therapeutic approaches in these disorders.

Metabolic-associated fatty liver disease (MAFLD) is a risk factor for severe COVID-19. This study explores the potential influence of gut hormone receptor and immune response gene expression on COVID-19 outcomes in MAFLD patients.

We investigated gene expression levels of AHR, FFAR2, FXR, and TGR5 in patients with MAFLD and COVID-19 compared to controls. We examined associations between gene expression and clinical outcomes.

COVID-19 patients displayed altered AHR expression, potentially impacting immune response and recovery. Downregulated AHR in patients with MAFLD correlated with increased coagulation parameters. Elevated FFAR2 expression in patients with MAFLD was linked to specific immune cell populations and hospital stay duration. A significantly lower FXR expression was observed in both MAFLD and severe COVID-19.

Our findings suggest potential modulatory roles for AHR, FFAR2, and FXR in COVID-19 and MAFLD.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been significantly alleviated. However, long-term health effects and prevention strategy remain unresolved. Thus, it is essential to explore the pathophysiological mechanisms and intervention for SARS-CoV-2 infection. Emerging research indicates a link between COVID-19 and bile acids, traditionally known for facilitating dietary fat absorption. The bile acid ursodeoxycholic acid potentially protects against SARS-CoV-2 infection by inhibiting the farnesoid X receptor, a bile acid nuclear receptor. The activation of G-protein-coupled bile acid receptor, another membrane receptor for bile acids, has also been found to regulate the expression of angiotensin-converting enzyme 2, the receptor through which the virus enters human cells. Here, we review the latest basic and clinical evidence linking bile acids to SARS-CoV-2, and reveal their complicated pathophysiological mechanisms.

Bile acids (BA) are amphipathic molecules originating from cholesterol in the liver and from microbiota-driven biotransformation in the colon. In the gut, BA play a key role in fat digestion and absorption and act as potent signaling molecules on the nuclear farnesoid X receptor (FXR) and membrane-associated G protein-coupled BA receptor-1 (GPBAR-1). BA are, therefore, involved in the maintenance of gut barrier integrity, gene expression, metabolic homeostasis, and microbiota profile and function. Disturbed BA homeostasis can activate pro-inflammatory pathways in the gut, while inflammatory bowel diseases (IBD) can induce gut dysbiosis and qualitative and/or quantitative changes of the BA pool. These factors contribute to impaired repair capacity of the mucosal barrier, due to chronic inflammation. A better understanding of BA-dependent mechanisms paves the way to innovative therapeutic tools by administering hydrophilic BA and FXR agonists and manipulating gut microbiota with probiotics and prebiotics. We discuss the translational value of pathophysiological and therapeutic evidence linking BA homeostasis to gut inflammation in IBD.

To discuss current literature and provide practical recommendations for the safe and effective use of glucagon-like peptide 1 receptor agonists (GLP-1 RA) in people with inflammatory bowel disease (IBD) and type 2 diabetes (T2D) and/or obesity. The molecular mechanisms that justify the potential benefits of GLP-1 RA in IBD and the links between IBD, obesity, and cardiovascular disease are also discussed.

Preliminary data suggest that GLP-1 RA can modulate crucial pathways in the pathogenesis of IBD, such as chronic inflammation circuits, intestinal tight junctions, and gut microbiome dysbiosis, setting the stage for human trials to investigate the role of these agents in the treatment of IBD among people with or without diabetes and obesity. However, gastrointestinal side effects related to GLP-1 RA need appropriate clinical management to mitigate risks and maximize the benefits of therapy in people with IBD. GLP-1 RA originally emerged as drugs for the treatment of hyperglycemia and are currently licensed for the management of T2D and/or overweight/obesity. However, their wealth of pleiotropic actions soon raised expectations that they might confer benefits on non-metabolic disorders. Future studies are expected to clarify whether GLP-1 RA deserve an adjunct place in the arsenal of drugs against IBD.

Recent discoveries have demonstrated that the physiological function of bile acids extends to the regulation of diverse signaling processes through interactions with nuclear and G protein-coupled receptors, most notably the Farnesoid-X nuclear receptor (FXR) and the G protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5). Targeting such signaling pathways pharmacologically, i.e. with bile acid-derived therapeutics, presents great potential for the treatment of various metabolic, inflammatory immune, liver, and neurodegenerative diseases. Here we report the discovery of two potent and selective TGR5 agonists (NZP196 and 917). These compounds are the taurine conjugates of 6α-ethyl-substituted 12β-methyl-18-nor-bile acids with the side chain being located on the α-face of the steroid scaffold. The compounds emerged from a screening effort of a diverse library of 12β-methyl-18-nor-bile acids that were synthesized from 12β-methyl-18-nor-chenodeoxycholic acid and its C17-epimer. Upon testing for FXR activity, both compounds were found to be inactive, thus revealing selectivity for TGR5.

The renin-angiotensin system (RAS) is an important homeostatic pathway, with emerging evidence for the impact of its components on inflammation and fibrosis in gastrointestinal tissues. This review aims to review current knowledge of the physiological mechanism of RAS in inflammatory bowel disease (IBD), and potential therapeutic implications.

An extensive online literature review including Pubmed, Medline, and Google Scholar was undertaken. Discussion on the components of the RAS, localization, and physiological functions in the gastrointestinal tract, preclinical, and clinical data in IBD, and the relation with SARS-Cov-2 are covered in this review.

RAS inhibition may have a role as anti-fibrotic adjunct therapy. Targeting the local gastrointestinal RAS with novel modes of delivery may be a target for future therapeutics for IBD, given the widespread availability and safety of current options as utilized in other diseases. Further insight into the mechanism and downstream effects of gastrointestinal ACE2 may lead to a better understanding of the pathogenesis of IBD.