Objectives:

2

To determine the pharmacological impact of hesperidin

the main component of

Citri Reticulatae Pericarpium

on depressive behavior and elucidate the mechanism by which hesperidin treats depression

focusing on the gut–brain axis.

Methods:

2

Fifty-four Sprague Dawley male rats were randomly allocated to 6 groups using a random number table

including control

model

hesperidin

probiotics

fluoxetine

and

Citri Reticulatae Pericarpium

groups. Except for the control group

rats in the remaining 5 groups were challenged with chronic unpredictable mild stress (CUMS) for 21 days and housed in single cages. The sucrose preference test (SPT)

immobility time in the forced swim test (FST)

and number in the open field test (OFT) were performed to measure the behavioral changes in the rats. Enzyme-linked immunosorbent assay was used to determine the levels of 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF) in brain tissue

and the histopathology was performed to evaluate the changes of colon tissue

together with sequencing of the V3–V4 regions of 16S rRNA gene on feces to explore the changes of intestinal flora in the rats.

Results:

2

Compared to the control group

the rats in the model group showed notable reductions in body weight

SPF

and number in OFT (

P

<

0.01). Hesperidin was found to ameliorate depression induced by CUMS

as seen by improvements in body weight

SPT

immobility time in FST

and number in OFT (

P

<

0.05 or

P

<

0.01). Regarding neurotransmitters

it was found that at a dose of 50 mg/kg hesperidin treatment upregu

lated the levels of 5-HT and BDNF in depressed rats (

P

<

0.05). Compared to the control group

the colon tissue of the model group exhibited greater inflammatory cell infiltration

with markedly reduced numbers of goblet cells and crypts and were significantly improved following treatment with hesperidin. Simultaneously

the administration of hesperidin demonstrated a positive impact on the gut microbiome of rats treated with CUMS

such as Shannon index increased and Simpson index decreased (

P

<

0.01)

while the abundance of

Pseudomonadota

and

Bacteroidota

increased in the hesperidin-treated group (

P

<

0.05).

Conclusion:

2

The mechanism responsible for the beneficial effects of hesperidin on depressive behavior in rats may be related to inhibition of the expressions of BDNF and 5-HT and preservation of the gut microbiota.