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Published on: September 9, 2022
Gut Microbiota-Derived Lipopolysaccharides and Short-Chain Fatty Acids Regulate Immune Responses via FFAR2/FFAR3 in
Daisuke Maruyama1, Thien N M Doan1, Xiaoli Tian1
1Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, USA.
Abstract:
Lung ischemia-reperfusion (IR) injury is a sterile inflammatory process seen in conditions such as hemorrhage-resuscitation and pulmonary embolism. Our previous work suggests that alveolar macrophages (AMs) drive the inflammatory cascade via NLRP3 inflammasome activation, and that gut-derived lipopolysaccharides (LPS) and short-chain fatty acids (SCFAs) influence these responses. However, the precise mechanisms by which gut microbiota signals govern AM function during lung IR remain unclear. Here, we show that germ-free mice exhibit reduced inflammatory responses compared to specific pathogen-free mice following lung IR injury in vivo. In contrast, mice lacking free fatty acid receptor (FFAR)2 or FFAR3-receptors for SCFAs-display heightened inflammation relative to wild-type controls. Ex vivo and in vitro nutritional IR experiments further demonstrate that AMs, primed with LPS, produce IL-1β via NLRP3 inflammasome and caspase-1 activation. Notably, SCFAs significantly diminish IR-induced IL-1β release, indicating a protective effect. These findings support a gut-lung axis in which gut microbiota modulate baseline lung immune capacity or lung immune tone through the transmission of LPS and SCFAs, thereby shaping the lung's response to sterile injury. Gut microbiota-based therapies, including dietary fiber interventions, may thus represent a promising therapeutic strategy for regulating inflammatory processes in the lung.
Insights
Gut microbiota influence lung inflammation after injury. Short-chain fatty acids (SCFAs) protect against lung ischemia-reperfusion (IR) injury by reducing inflammatory responses, suggesting microbiota-based therapies could be beneficial.
Area of Science:
- Immunology
- Microbiology
- Pulmonary Medicine
Background:
- Lung ischemia-reperfusion (IR) injury involves sterile inflammation, with alveolar macrophages (AMs) and gut-derived signals like lipopolysaccharides (LPS) and short-chain fatty acids (SCFAs) implicated.
- The exact mechanisms by which gut microbiota regulate AM function during lung IR are not fully understood.
Purpose of the Study:
- To elucidate the role of gut microbiota-derived signals in modulating AM function and lung inflammation during IR injury.
- To investigate the impact of SCFAs and their receptors on lung IR injury responses.
Main Methods:
- Comparison of inflammatory responses in germ-free versus specific pathogen-free mice following lung IR.
- Assessment of lung inflammation in mice lacking free fatty acid receptors (FFAR2/3) crucial for SCFA signaling.
- Ex vivo and in vitro experiments using LPS-primed AMs to evaluate IL-1β production and the effect of SCFAs on NLRP3 inflammasome activation.
Main Results:
- Germ-free mice showed reduced lung IR inflammation compared to SPF mice.
- Mice lacking FFAR2 or FFAR3 exhibited heightened inflammation post-lung IR.
- SCFAs significantly reduced IR-induced IL-1β release from LPS-primed AMs, indicating a protective role.
Conclusions:
- A gut-lung axis exists where gut microbiota, via LPS and SCFAs, shapes the lung's immune response to sterile injury.
- Targeting gut microbiota, potentially through dietary fiber, offers a promising therapeutic strategy for managing lung inflammatory conditions like IR injury.
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