Summary The gut microbiota can be altered by dietary interventions to prevent and treat various diseases. However, the mechanisms by which food products modulate commensals remain largely unknown. We demonstrate that plant-derived exosomes-like nanoparticles (ELNs) are taken up by the gut microbiota and contain RNAs that alter microbiome composition and host physiology. Ginger ELNs (GELNs) are preferentially taken up by Lactobacillaceae in a GELN lipid-dependent manner and contain microRNAs that target various genes in Lactobacillus rhamnosus (LGG). Among these, GELN mdo-miR7267-3p-mediated targeting of the LGG monooxygenase ycnE yields increased indole-3-carboxaldehyde (I3A). GELN RNAs or I3A, a ligand for aryl hydrocarbon receptor (AHR), are sufficient to induce production of IL-22, which is linked to barrier function improvement. These functions of GELN RNAs can ameliorate mouse colitis via IL-22-dependent mechanisms. These findings reveal how plant products and their effects on the microbiome may be used to target specific host processes to alleviate disease.

Lung inflammation is a hallmark of coronavirus disease 2019 (COVID-19). Here, we show that mice develop inflamed lung tissue after being administered exosomes released from the lung epithelial cells exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Nsp12 and Nsp13 (exosomes Nsp12Nsp13 ). Mechanistically, we show that exosomes Nsp12Nsp13 are taken up by lung macrophages, leading to activation of NF-κB and the subsequent induction of an array of inflammatory cytokines. Induction of tumor necrosis factor (TNF)α, interleukin (IL)-6 and IL-1β from exosomes Nsp12Nsp13 activated lung macrophages contributes to inducing apoptosis in lung epithelial cells. Induction of exosomes Nsp12Nsp13 mediated lung inflammation was abolished with ginger exosome-like nanoparticle (GELN) miRNA aly-miR396a-5p. The role of GELNs in inhibition of SARS-CoV-2 induced cytopathic effect (CPE) was further demonstrated via GELN aly-miR396a-5p and rlcv-miR-rL1-28-3p mediated inhibition of expression of Nsp12 and spike genes, respectively. Together, our results reveal exosomes Nsp12Nsp13 as potentially important contributors to the development of lung inflammation and GELNs are a potential therapeutic agent to treat COVID-19.

SummaryPlant exosomes protect plants against infection; however, whether edible plant exosomes can protect mammalian hosts against infection is not known. In this study, we show that ginger exosome-like nanoparticles (GELNs) are selectively taken up by the periodontal pathogen Porphyromonas gingivalis in a GELN phosphatidic acid (PA) dependent manner via interactions with hemin-binding protein 35 (HBP35) on the surface of P. gingivalis. Compared with PA (34:2), PA (34:1) did not interact with HBP35, indicating that the degree of unsaturation of PA plays a critical role in GELN-mediated interaction with HBP35. On binding to HBP35, pathogenic mechanisms of P. gingivalis were significantly reduced following interaction with GELN cargo molecules, including PA and miRs. These cargo molecules interacted with multiple pathogenic factors in the recipient bacteria simultaneously. Using edible plant exosome-like nanoparticles as a potential therapeutic agent to prevent/treat chronic periodontitis was further demonstrated in a mouse model.

High-fat diet (HFD) decreases insulin sensitivity. How high-fat diet causes insulin resistance is largely unknown. Here, we show that lean mice become insulin resistant after being administered exosomes isolated from the feces of obese mice fed a HFD or from patients with type II diabetes. HFD altered the lipid composition of exosomes from predominantly phosphatidylethanolamine (PE) in exosomes from lean animals (L-Exo) to phosphatidylcholine (PC) in exosomes from obese animals (H-Exo). Mechanistically, we show that intestinal H-Exo is taken up by macrophages and hepatocytes, leading to inhibition of the insulin signaling pathway. Moreover, exosome-derived PC binds to and activates AhR, leading to inhibition of the expression of genes essential for activation of the insulin signaling pathway, including IRS-2, and its downstream genes PI3K and Akt. Together, our results reveal HFD-induced exosomes as potential contributors to the development of insulin resistance. Intestinal exosomes thus have potential as broad therapeutic targets.