Acetate & RSV
2021-03-25
ABSTRACT
Background:
Gut microbiota-derived short-chain fatty-acid (SCFA) acetate protects mice against RSV infection by increasing interferon-β production and expression of interferon-stimulated genes (ISGs). However, the role of SFCAs in RSV bronchiolitis in infants has not been studied.
Methods
We first investigated the relationship of gut microbiota and fecal SCFAs with disease severity among infants hospitalized with RSV bronchiolitis, and whether treating their respiratory epithelial cells with acetate ex-vivo impacts upon viral load and ISG expression. We then examined whether acetate treatment is beneficial in a mouse model of RSV infection using clinical isolates. In further in vitro models in HPECs, we ascertained the effect of pre-treatment with acetate, and probed mechanisms by which acetate may protect against RSV infection.
Results
Gut microbial profile was associated with bronchiolitis severity and with SCFAs in stool. Increasing acetate levels were significantly associated with increasing oxygen saturation at admission, and shorter duration of fever. Ex-vivo treatment of patients’ respiratory cells with acetate significantly reduced RSV load and expression of ISGs OAS1 and ISG15, and virus recognition receptors MAVS and RIG-I, but not IFNB1. In mice, animals treated with acetate intranasally recovered significantly faster, with a detectable reduction in the RSV clinical isolates viral load in the lung, and increased lung expression of IFNB1 and the RIG-I receptor. In vitro pre-treatment of HPECs with acetate reduced RSV load after infection with clinical isolates and increased the expression of RIG-I and ISG15. Experiments in RIG-I knockout HPECs demonstrated that protection relies on RIG-I presence.
Conclusion:
Acetate reduces the severity of RSV infection and RSV viral load through modulation of RIG-I expression.
Table with clinical data (bronchiolitis)
Clinical Data
## hosp_days sathb acetate o2_days
## Min. : 2.000 Min. : 86.00 Min. :0.000 Min. : 0.000
## 1st Qu.: 3.000 1st Qu.: 95.00 1st Qu.:0.000 1st Qu.: 2.000
## Median : 4.000 Median : 97.00 Median :1.176 Median : 2.000
## Mean : 6.235 Mean : 95.94 Mean :1.466 Mean : 3.176
## 3rd Qu.: 5.000 3rd Qu.: 98.00 3rd Qu.:2.139 3rd Qu.: 4.000
## Max. :28.000 Max. :100.00 Max. :5.515 Max. :12.000
## bacteroidaceae dysgonomonadacea mollicutes
## Min. : 0 Min. : 0 Min. : 0
## 1st Qu.: 11 1st Qu.: 0 1st Qu.: 1
## Median : 42 Median : 0 Median : 2
## Mean : 7847 Mean : 18 Mean : 3
## 3rd Qu.: 9636 3rd Qu.: 6 3rd Qu.: 6
## Max. :52062 Max. :120 Max. :10Correlations (Spearman)
Clinical data, acetate & family
Correction method for frequentist correlations: Holm
## # Correlation table (spearman-method)
##
## Parameter1 | Parameter2 | rho | 95% CI | S | p
## ----------------------------------------------------------------------------------
## hosp_days | sathb | -0.44 | [-0.76, 0.07] | 1172.55 | > .999
## hosp_days | acetate | -0.21 | [-0.64, 0.32] | 986.26 | > .999
## hosp_days | o2_days | 0.62 | [ 0.19, 0.85] | 309.30 | 0.148
## hosp_days | bacteroidaceae | 0.54 | [ 0.07, 0.82] | 373.64 | 0.442
## hosp_days | dysgonomonadacea | -0.21 | [-0.64, 0.32] | 985.95 | > .999
## hosp_days | mollicutes | -0.46 | [-0.78, 0.04] | 1194.60 | 0.970
## sathb | acetate | 0.36 | [-0.16, 0.72] | 523.97 | > .999
## sathb | o2_days | -0.27 | [-0.67, 0.26] | 1034.79 | > .999
## sathb | bacteroidaceae | -0.23 | [-0.65, 0.30] | 1004.16 | > .999
## sathb | dysgonomonadacea | 0.64 | [ 0.22, 0.86] | 292.03 | 0.109
## sathb | mollicutes | -0.03 | [-0.51, 0.47] | 838.64 | > .999
## acetate | o2_days | 0.11 | [-0.40, 0.57] | 723.14 | > .999
## acetate | bacteroidaceae | -0.22 | [-0.65, 0.30] | 998.68 | > .999
## acetate | dysgonomonadacea | 0.81 | [ 0.53, 0.93] | 153.40 | 0.002**
## acetate | mollicutes | 0.08 | [-0.43, 0.55] | 750.59 | > .999
## o2_days | bacteroidaceae | 0.51 | [ 0.03, 0.80] | 398.12 | 0.605
## o2_days | dysgonomonadacea | 2.98e-03 | [-0.49, 0.49] | 813.57 | > .999
## o2_days | mollicutes | -0.30 | [-0.69, 0.22] | 1062.76 | > .999
## bacteroidaceae | dysgonomonadacea | -0.35 | [-0.72, 0.17] | 1099.51 | > .999
## bacteroidaceae | mollicutes | -0.17 | [-0.61, 0.35] | 955.83 | > .999
## dysgonomonadacea | mollicutes | 0.03 | [-0.47, 0.52] | 789.85 | > .999
##
## p-value adjustment method: Holm (1979)
## Observations: 17Without correction for frequentist correlation
## # Correlation table (spearman-method)
##
## Parameter1 | Parameter2 | rho | 95% CI | S | p
## ------------------------------------------------------------------------------------
## hosp_days | sathb | -0.44 | [-0.76, 0.07] | 1172.55 | 0.079
## hosp_days | acetate | -0.21 | [-0.64, 0.32] | 986.26 | 0.422
## hosp_days | o2_days | 0.62 | [ 0.19, 0.85] | 309.30 | 0.008**
## hosp_days | bacteroidaceae | 0.54 | [ 0.07, 0.82] | 373.64 | 0.025*
## hosp_days | dysgonomonadacea | -0.21 | [-0.64, 0.32] | 985.95 | 0.422
## hosp_days | mollicutes | -0.46 | [-0.78, 0.04] | 1194.60 | 0.061
## sathb | acetate | 0.36 | [-0.16, 0.72] | 523.97 | 0.158
## sathb | o2_days | -0.27 | [-0.67, 0.26] | 1034.79 | 0.298
## sathb | bacteroidaceae | -0.23 | [-0.65, 0.30] | 1004.16 | 0.373
## sathb | dysgonomonadacea | 0.64 | [ 0.22, 0.86] | 292.03 | 0.005**
## sathb | mollicutes | -0.03 | [-0.51, 0.47] | 838.64 | 0.916
## acetate | o2_days | 0.11 | [-0.40, 0.57] | 723.14 | 0.664
## acetate | bacteroidaceae | -0.22 | [-0.65, 0.30] | 998.68 | 0.388
## acetate | dysgonomonadacea | 0.81 | [ 0.53, 0.93] | 153.40 | < .001***
## acetate | mollicutes | 0.08 | [-0.43, 0.55] | 750.59 | 0.760
## o2_days | bacteroidaceae | 0.51 | [ 0.03, 0.80] | 398.12 | 0.036*
## o2_days | dysgonomonadacea | 2.98e-03 | [-0.49, 0.49] | 813.57 | 0.991
## o2_days | mollicutes | -0.30 | [-0.69, 0.22] | 1062.76 | 0.238
## bacteroidaceae | dysgonomonadacea | -0.35 | [-0.72, 0.17] | 1099.51 | 0.172
## bacteroidaceae | mollicutes | -0.17 | [-0.61, 0.35] | 955.83 | 0.511
## dysgonomonadacea | mollicutes | 0.03 | [-0.47, 0.52] | 789.85 | 0.903
##
## p-value adjustment method: none
## Observations: 17Figure 2
TRUE