Impact of the microbial derived short chain fatty acid propionate on host susceptibility to bacterial and fungal infections in vivo

Abstract

Short chain fatty acids (SCFAs) produced by intestinal microbes mediate anti-inflammatory effects, but whether they impact on antimicrobial host defenses remains largely unknown. This is of particular concern in light of the attractiveness of developing SCFA-mediated therapies and considering that SCFAs work as inhibitors of histone deacetylases which are known to interfere with host defenses. Here we show that propionate, one of the main SCFAs, dampens the response of innate immune cells to microbial stimulation, inhibiting cytokine and NO production by mouse or human monocytes/macrophages, splenocytes, whole blood and, less efficiently, dendritic cells. In proof of concept studies, propionate neither improved nor worsened morbidity and mortality parameters in models of endotoxemia and infections induced by gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae), gram-positive bacteria (Staphylococcus aureus, Streptococcus pneumoniae) and Candida albicans. Moreover, propionate did not impair the efficacy of passive immunization and natural immunization. Therefore, propionate has no significant impact on host susceptibility to infections and the establishment of protective anti-bacterial responses. These data support the safety of propionate-based therapies, either via direct supplementation or via the diet/microbiota, to treat non-infectious inflammation-related disorders, without increasing the risk of infection.

Sirtuin 3 deficiency does not alter host defenses against bacterial and fungal infections

“…Real-time PCR was conducted using the Fast SYBR® Green Master Mix and a QuantStudio™ 12 K Flex system (Life Technologies, Carlsbad, CA) 44, 45 . Primers have been described 45, 51 .…”

Microbiome diurnal rhythmicity and its impact on host physiology and disease risk

“…Furthermore, the gut microbiota was shown to provide several cofactors needed for enzymes involved in epigenetic modifications such as acetyl‐CoA and NAD + . For histone‐deacetylases (HDAC) in particular, gut microbiome‐derived short‐chain fatty acids such as butyrate or propionate were shown to be key regulators of activity , which in turn can have many downstream effects in mediating human disease, such as type 2 diabetes or obesity . One key mechanism by which the microbiome regulates host circadian transcriptomic oscillations is through the modulation of the chromatin landscapes.…”

Loving the poison: the methylcitrate cycle and bacterial pathogenesis

“…Interestingly, it has also been suggested that the production of propionate by intestinal microflora may be a protective mechanism to control the host response to commensals. This way, the host would avoid local inflammation and tissue damage [66].…”