There has been a striking generational increase in life-threatening food allergies in Westernized societies 1 , 2 One hypothesis to explain this rising prevalence is that 21 st century lifestyle practices, including misuse of antibiotics, dietary changes, and higher rates of Caesarean birth and formula feeding have altered intestinal bacterial communities; early life alterations may be particularly detrimental. 3 , 4 To better understand how commensal bacteria regulate food allergy in humans we colonized germ free (GF) mice with feces from healthy or cow’s milk allergic (CMA) infants 5 . We show here that GF mice colonized with bacteria from healthy, but not CMA, infants were protected against anaphylactic responses to a cow’s milk allergen. Differences in bacterial composition separated the healthy and CMA populations in both the human donors and the colonized mice. Healthy and CMA colonized mice also exhibited unique transciptome signatures in the ileal epithelium. Correlation of ileal bacteria with genes upregulated in the ileum of healthy or CMA colonized mice identified a Clostridial species, Anaerostipes caccae , that protected against an allergic response to food. Our findings demonstrate that intestinal bacteria are critical for regulating allergic responses to dietary antigens and suggest that interventions that modulate bacterial communities may be therapeutically relevant for food allergy.
The microbiome modulates host immunity and aids the maintenance of tolerance in the gut, where microbial and food-derived antigens are abundant. Yet modern dietary factors and the excessive use of antibiotics have contributed to the rising incidence of food allergies, inflammatory bowel disease and other non-communicable chronic diseases associated with the depletion of beneficial taxa, including butyrate-producing Clostridia. Here we show that intragastrically delivered neutral and negatively charged polymeric micelles releasing butyrate in different regions of the intestinal tract restore barrier-protective responses in mouse models of colitis and of peanut allergy. Treatment with the butyrate-releasing micelles increased the abundance of butyrate-producing taxa in Clostridium cluster XIVa, protected mice from an anaphylactic reaction to a peanut challenge and reduced disease severity in a T-cell-transfer model of colitis. By restoring microbial and mucosal homoeostasis, butyrate-releasing micelles may function as an antigen-agnostic approach for the treatment of allergic and inflammatory diseases.
Persisters represent a small bacterial population that is dormant and that survives under antibiotic treatment without experiencing genetic adaptation. Persisters are also considered one of the major reasons for recalcitrant chronic bacterial infections. Although several mechanisms of persister formation have been proposed, it is not clear how cells enter the dormant state in the presence of antibiotics or how persister cell formation can be effectively controlled. A fatty acid compound, cis-2-decenoic acid, was reported to decrease persister formation as well as revert the dormant cells to a metabolically active state. We reasoned that some fatty acid compounds may be effective in controlling bacterial persistence because they are known to benefit host immune systems. This study investigated persister cell formation by pathogens that were exposed to nine fatty acid compounds during antibiotic treatment. We found that three medium chain unsaturated fatty acid ethyl esters (ethyl trans-2-decenoate, ethyl trans-2-octenoate, and ethyl cis-4-decenoate) decreased the level of Escherichia coli persister formation up to 110-fold when cells were exposed to ciprofloxacin or ampicillin antibiotics. RNA sequencing analysis and gene deletion persister studies elucidated that these fatty acids inhibit bacterial persistence by regulating antitoxin HipB. A similar persister cell reduction was observed for pathogenic E. coli EDL933, Pseudomonas aeruginosa PAO1, and Serratia marcescens ICU2-4 strains. This study demonstrates that fatty acid ethyl esters can be used to disrupt bacterial dormancy to combat persistent infectious diseases.
Persister cell formation and biofilms of pathogens are extensively involved in the development of chronic infectious diseases. Eradicating persister cells is challenging, owing to their tolerance to conventional antibiotics, which cannot kill cells in a metabolically dormant state. A high frequency of persisters in biofilms makes inactivating biofilm cells more difficult, because the biofilm matrix inhibits antibiotic penetration. Fatty acids may be promising candidates as antipersister or antibiofilm agents, because some fatty acids exhibit antimicrobial effects. We previously reported that fatty acid ethyl esters effectively inhibit Escherichia coli persister formation by regulating an antitoxin. In this study, we screened a fatty acid library consisting of 65 different fatty acid molecules for altered persister formation. We found that undecanoic acid, lauric acid, and N-tridecanoic acid inhibited E. coli BW25113 persister cell formation by 25-, 58-, and 44-fold, respectively. Similarly, these fatty acids repressed persisters of enterohemorrhagic E. coli EDL933. These fatty acids were all medium-chain saturated forms. Furthermore, the fatty acids repressed Enterohemorrhagic E. coli (EHEC) biofilm formation (for example, by 8-fold for lauric acid) without having antimicrobial activity. This study demonstrates that medium-chain saturated fatty acids can serve as antipersister and antibiofilm agents that may be applied to treat bacterial infections.
The gut microbiome modulates the body’s response to food antigens1. Beneficial taxa, specifically butyrate-producing Clostridia, are depleted in food-allergic individuals2,3. Although butyrate is known to play important roles in regulating gut immunity and maintaining epithelial barrier function4–6, its clinical translation is challenging due to its offensive odor and quick absorption in the upper gut. Here, we developed two polymeric micelle systems, one with a neutral charge (NtL-ButM) and one with a negative charge (Neg-ButM), that release butyrate from their polymeric core in the ileum or the cecum, respectively. Treatment with NtL-ButM in germ-free (and thus butyrate-depleted) mice up-regulated genes expressing antimicrobial peptides in the ileal epithelium. We show that these butyrate-containing micelles, used in combination, restore a barrier-protective response in mice treated with either dextran sodium sulfate or antibiotics. Treatment with the micelles protects peanut-allergic mice from an anaphylactic reaction to peanut challenge and rescues their dysbiosis by increasing the abundance of Clostridium Cluster XIVa. By restoring microbial and mucosal homeostasis, these butyrate-prodrug polymeric micelles may function as a new, antigen-agnostic approach to the treatment of food allergy.
A marked increase in disease prevalence has made food allergies a major public health concern. One hypothesis for this rise is that recent lifestyle factors have altered the composition of the intestinal microbiota, increasing susceptibility to allergic disease. Host-microbiota interactions are essential for immune homeostasis, and perturbations of naturally-selected bacterial populations, a condition called dysbiosis, are linked to many different pathologies. To investigate the role of the microbiota in regulating food allergies, we colonized germ free mice with bacteria from healthy or cow’s milk allergic (CMA) infants. We found that colonization with bacteria from healthy infants is sufficient to protect against sensitization to the milk allergen β-lactoglobulin (BLG). In contrast, colonization with bacteria from CMA infants fails to protect, resulting in high concentrations of BLG-specific IgE and anaphylactic responses following BLG challenge. Analysis of bacterial taxa in feces from multiple healthy and CMA infants identified significant differences in bacterial composition that distinguished health status in both the human donors and the colonized mice, emphasizing the clinical relevance of our gnotobiotic model. RNAseq of ileal epithelial cells revealed differentially expressed genes (DEGs) that separate healthy- and CMA-colonized mice. Integration of ileal bacteria and ileal DEGs identified taxa that were significantly correlated with gene expression changes. Together, these results demonstrate that the composition of the intestinal microbiota regulates systemic responses to dietary antigen and suggest that modulation of these communities may be useful in treatment or prevention of food allergy.
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