Crohn’s disease and intestinal inflammation — can butyrate help the gut?

Aim of the study: Background and objective: Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic inflammatory disorder characterized by abnormal immune responses and impaired barrier function in the gastrointestinal tract. IBD is associated with changes in gut microbiota and their metabolites in the colon.

Results: However, butyrate enemas had mixed effects. Butyrogenic diets, including germinated barley foodstuff and oat bran, have been found to increase fecal butyrate concentrations and reduce the disease activity index in both animal models and IBD patients. Conclusions: Current literature suggests that butyrate may be an add-on therapy to reduce inflammation and maintain IBD remission. Further clinical studies are needed to determine whether butyrate administration alone is an effective treatment for IBD.

Aim of the study: Butyrate can strengthen the intestinal epithelial barrier. However, the mechanisms by which butyrate affects intestinal epithelial cell (IEC) pyroptosis in Crohn's disease (CD) remain unclear.

Results: Co-treatment with a cGAS-STING pathway activator and butyrate showed that the activator reversed butyrate’s inhibitory effects on pyroptosis and cGAS-STING pathway activation in both the colitis rat model and HT-29 cells. Mechanistically, the cGAS-STING pathway was found to interact with NLRP3. Taken together, butyrate may reduce intestinal inflammation in CD by suppressing pyroptosis of IECs mediated by the cGAS-STING-NLRP3 axis. These findings offer new insights into potential strategies for treating CD.

Aim of the study: G Protein Coupled Receptor 109A (GPR109A), which belongs to the G protein-coupled receptor family, can be activated by niacin, butyrate, and β-hydroxybutyric acid. Here, we assessed the anti-inflammatory activity of sodium butyrate (SB) in mice with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, an experimental model that resembles Crohn's disease, and explored the potential mechanism of SB in inflammatory bowel disease (IBD).

Results: In vitro, pretreatment with SB dramatically inhibited the expression of TNF-α and IL-6 in LPS-induced RAW246.7 macrophages. SB inhibited LPS-induced phosphorylation of the NF-κB p65 and AKT signaling pathways, but failed to inhibit phosphorylation of the MAPK signaling pathway. Our data showed that SB improved the TNBS-induced inflammatory response and intestinal epithelial barrier dysfunction by activating GPR109A and inhibiting the AKT and NF-κB p65 signaling pathways. These findings therefore expand our understanding of GPR109A receptor function and provide a new theoretical basis for treating IBD.

Aim of the study: Background: Infection with Mycobacterium avium paratuberculosis (MAP) is closely associated with the development of Crohn's disease (CD), in which excessive inflammation and significant intestinal damage are observed. Objectives: This study evaluated the role of short-chain fatty acids, including propionic acid (PPA) and butyric acid (BA), in an in vitro model that mimics features of CD.

Results: The integrity and function of Caco-2 intestinal epithelial cells, impaired by MAP infection, were restored with PPA and BA treatment. Specifically, NOX1 expression was significantly reduced in cells treated with 10 mM PPA or BA (p < 0.001), as confirmed by RT-PCR and microscopy. PPA and BA restored tight junction integrity by reducing Claudin-2 expression in the MAP group. Conclusions: The data clearly showed that short-chain fatty acids have anti-inflammatory and antimicrobial properties, with beneficial effects on damaged intestinal epithelial cells. This suggests potential benefits as a dietary supplement for CD patients, particularly those who are not pregnant, because exposure to propionic acid may be associated with an increased risk of autism spectrum disorder (ASD) in offspring.

Aim of the study: Given the trillions of microbes that inhabit mammalian intestines, the host immune system must constantly balance tolerance to commensal microbes with immunity against pathogens to avoid unnecessary immune responses to otherwise harmless bacteria. Misregulated responses can lead to inflammatory bowel diseases such as ulcerative colitis or Crohn's disease.

Results: Treatment of macrophages with n-butyrate led to reduced levels of lipopolysaccharide-induced pro-inflammatory mediators, including nitric oxide, IL-6, and IL-12, but did not affect levels of TNF-α or MCP-1. These effects were independent of toll-like receptor signaling and activation of G-protein-coupled receptors, two pathways that may be affected by short-chain fatty acids. In this study, we provide several lines of evidence suggesting that these effects are due to n-butyrate’s inhibition of histone deacetylases. These findings describe a pathway by which the host may maintain tolerance to intestinal microbiota: by reducing pro-inflammatory effectors, it makes lamina propria macrophages less responsive to commensal bacteria.

Aim of the study: Gut bacteria benefit the host and have been implicated in inflammatory bowel disease (IBD), where adherent-invasive E. coli (AIEC) pathobionts (e.g., strain LF82) are associated with Crohn's disease.

Results: E. coli-LF82-infected T84 cells and organoids. These data indicate that butyrate helps maintain the form and function of epithelial mitochondria when challenged by E. coli-LF82, at least in part through FFAR3. Thus, the loss of butyrate-producing bacteria in IBD, in the presence of pathobionts, may lead to the loss of epithelial mitochondrial and barrier functions, which could trigger disease or worsen low-grade inflammation.

Aim of the study: The causes of inflammatory bowel disease (IBD) are multifactorial, with evidence suggesting that disturbed interactions between the gut and intestinal microbiota play a role. A defective mucosal barrier may increase intestinal permeability, exposing the body to intestinal contents and triggering an immune response that promotes intestinal inflammation.

Results: In clinical practice, several studies have shown that changes in intestinal permeability can predict the course of IBD. Functional tests, such as sugar absorption tests, and the newer imaging technique of confocal laser endomicroscopy allow in vivo assessment of gut barrier integrity. Anti-tumor necrosis factor-α (TNF-α) therapy reduces mucosal inflammation and restores intestinal permeability in IBD patients. Butyrate, zinc, and some probiotics also improve mucosal barrier dysfunction, but their use remains limited, and further studies are needed before considering manipulation of permeability as a therapeutic target in IBD.

Aim of the study: The metabolic factors that distinguish Crohn's disease (CD) from ulcerative colitis (UC), and their roles in driving immune dysregulation, remain unclear. We aimed to identify systemic metabolic signatures of inflammatory bowel disease (IBD) and clarify the mechanistic link between metabolite availability and regulatory T cell (Treg) homeostasis.

Results: This effect depended on carnitine palmitoyltransferase 1A (CPT1A), because pharmacological or genetic inhibition of CPT1A-mediated fatty acid oxidation (FAO) abolished butyrate’s ability to promote differentiation. In vivo, the ability of butyrate to reduce colitis and promote the accumulation of colonic iTregs was significantly reversed by the CPT1 inhibitor etomoxir. CPT1A-mediated fatty acid oxidation is a key metabolic switch through which butyrate signals to maintain immune tolerance. The systemic loss of FAO intermediates in CD patients directly contributes to impaired iTreg development, identifying the butyrate-CPT1A pathway as a potential target for precision metabolic intervention.