Inflammatory bowel disorders can be associated with alterations in gut microbiota (
dysbiosis) and behavioral disturbances. In experimental
colitis, administration of
fish oil (FO) or
cannabinoids, such as
cannabidiol (CBD), reduce
inflammation. We investigated the effect of combined FO/CBD administration on
inflammation and
dysbiosis in the
dextran sulphate
sodium (DSS) model of mouse
colitis, which also causes behavioral disturbances.
Colitis was induced in CD1 mice by 4% w/v DSS in
drinking water for five consecutive days followed by normal
drinking water. FO (20-75 mg/mouse) was administered once a day starting two days after DSS, whereas CBD (0.3-30 mg/kg), alone or after FO administration, was administered once a day starting 3 days after DSS, until day 8 (d8) or day 14 (d14).
Inflammation was assessed at d8 and d14 (resolution phase; RP) by measuring the Disease Activity Index (DAI) score, change in
body weight, colon weight/length ratio,
myeloperoxidase activity and colonic
interleukin (IL)-1β (IL-1β),
IL-10, and
IL-6 concentrations. Intestinal permeability was measured with the
fluorescein isothiocyanate-dextran. Behavioral tests (novel object recognition (NOR) and light/dark box test) were performed at d8. Fecal microbiota composition was determined by ribosomal 16S
DNA sequencing of faecal pellets at d8 and d14. DSS-induced
inflammation was stronger at d8 and accompanied by anxiety-like behavior and impaired recognition memory. FO (35, 50, 75 mg/mouse) alone reduced
inflammation at d8, whereas CBD alone produced no effect at any of the doses tested; however, when CBD (3, 10 mg/kg) was co-administered with FO (75 mg/mouse)
inflammation was attenuated. FO (20 mg/mouse) and CBD (1 mg/kg) were ineffective when given alone, but when co-administered reduced all inflammatory markers and the increased intestinal permeability at both d8 and d14, but not the behavioral impairments. FO, CBD, and their combination affected gut bacteria taxa that were not affected by DSS per se. Akkermansia muciniphila, a species suggested to afford anti-inflammatory action in
colitis, was increased by DSS only at d14, but its levels were significantly elevated by all treatments at d8. FO and CBD co-administered at per se ineffective doses reduce colon
inflammation, in a manner potentially strengthened by their independent elevation of Akkermansia muciniphila.