Lactate and short chain fatty acids produced by microbial fermentation downregulate proinflammatory responses in...

Area of Science:

• Gastroenterology
• Immunology
• Microbiome Research

Background:

• Short chain fatty acids (SCFAs) show promise in managing gastrointestinal inflammation, including ulcerative colitis.
• Understanding the cellular and molecular targets of SCFAs is crucial for optimizing anti-inflammatory interventions.
• Innate immune cells in the gut play a significant role in inflammatory conditions.

Purpose of the Study:

• To investigate the in vitro interactions of lactate and SCFAs (acetate, propionate, butyrate) with gastrointestinal innate immune cells.
• To determine the dose-dependent effects of these molecules on Toll-like receptor (TLR)-activated immune responses.
• To identify potential therapeutic applications of SCFAs and lactate in inflammatory gut diseases.

Main Methods:

• In vitro evaluation of lactate, acetate, propionate, and butyrate.
• Assessment of cytokine production in TLR-4 and TLR-5 activated intestinal epithelial cells.
• Analysis of cytokine secretion and CD40 upregulation in TLR-activated bone marrow-derived macrophages and dendritic cells.
• Evaluation of dose-response effects and pertussis toxin sensitivity.

Main Results:

• Lactate and SCFAs modulate pro-inflammatory cytokine production by activated intestinal epithelial cells in a dose-dependent manner.
• These molecules also affect cytokine secretion and CD40 expression in TLR-activated macrophages and dendritic cells.
• Effective concentrations varied, with butyrate and propionate active at 1-5mM, and acetate and lactate at higher concentrations (20-50mM).
• Modulatory effects were observed at physiological concentrations found in the large bowel lumen and were independent of Gi signaling.

Conclusions:

• Lactate and SCFAs can modulate the activity of key sentinel cell types in the gastrointestinal tract activated by TLR signals.
• These findings support the potential use of SCFAs and lactate, individually or in combination, for therapeutic interventions in inflammatory conditions.
• The results highlight the importance of these metabolites in regulating innate immune responses within the gut, offering avenues for novel treatment strategies.