Modulation of Microbiota-Gut-Brain Axis by Berberine Resulting in Improved Metabolic Status in High-Fat Diet-Fed Rats

Abstract

Objective: To investigate whether or not berberine could improve metabolic status of high-fat-fed rats through modulation of microbiota-gut-brain axis.

Methods: Berberine was administered on high-fat-fed Sprague-Dawley rats. Brain-gut hormones were detected, and changes of gut microbiota were analyzed by 16S rRNA gene sequencing.

Results: Berberine could reduce weight gain and lipolysis in the high-fat diet-fed group. Moreover, trends of ameliorated insulin resistance and decreased endogenous glucose production were observed. In addition, the microbiota-gut-brain axis was found to be modulated, including structural and diversity changes of microbiota, elevated serum glucagon-like peptide-1 and neuropeptide Y level, decreased orexin A level, up-regulated glucagon-like peptide-1 receptor mRNA level as well as ultra-structural improvement of the hypothalamus.

Conclusion: Taken together, our findings suggest that berberine improved metabolic disorders induced by high-fat diet through modulation of the microbiota-gut-brain axis.

Fig. 1

Berberine attenuates body weight gain, insulin resistance and serum LDL-C level and TC level of HFD-fed rats. A Body weight gain; B fasting blood glucose concentration; C fasting serum insulin concentration of the 0th,4th, and 8th month separately; D HOMA-IR index of the 0th,4th, and 8th month separately; E serum LDL-C concentration of the 0th,4th, and 8th month separately; F serum TC concentration of the 0th, 4th, and 8th month separately. Values are expressed as mean ± SEM. Difference were assessed by ANOVA and denoted as following: *p ℋ 0.05, NCD versus HFD; ^#p ℋ 0.05, HFD versus HFD + BBR; ^&p ℋ 0.05, HFD versus HFD+BBR.

Fig. 2

Berberine reduces the Ra of glucose and glycerol of HFD-fed rats. A Ra of glucose; B Ra of glycerol. Values are expressed as mean ± SEM. Difference were assessed by ANOVA and denoted as follows: *p ℋ 0.05.

Fig. 3

Overall structural changes of gut microbiota. A The rarefaction curves; B the Shannon curves; C rarefaction estimates, calculated after rarefying to an equal number of sequence reads for all samples; D Shannon-Wiener index, calculated after rarefying to an equal number of sequence reads for all samples. Values are expressed as mean ± SEM. Difference were assessed by ANOVA and denoted as *p ℋ 0.05.

Fig. 4

BBR regulates the intestinal composition of HFD-fed rats. A The bar charts represent average relative abundances of bacterial phylum. B B/F ratio. C The heat map reflects the bacterial abundances at the genus level. D PCoA were performed based on unweighted UniFrac metrics. Values are expressed as mean ± SEM. Difference were assessed by ANOVA and denoted as *p ℋ 0.05.

Fig. 5

Berberine results in the changes of gut-brain peptide and GLP-1 receptor of hypothalamus. A Serum GLP-1 concentration; B serum NPY concentration; C serum orexin A concentration; D expression of GLP-1R of hypothalamus. Values are expressed as mean ± SEM. Difference were assessed by ANOVA and denoted as *p ℋ 0.05.

Fig. 6

The ultrastructural changes of hypothalamus revealed by transmission electron telescope. Ia NCD: the nucleus and organelles. Ib NCD: the neuropil and axonal synaptic bouton. IIa HFD: the nucleus and organelles; the shrinked nuclear membrane, scattered nucleoli and swollen mitochondria. IIb HFD: the swollen axonal bouton and fuzzy synaptic cleft. IIIa HFD+BBR: the structural destruction of nucleus and organelles were alleviated. IIIb HFD+BBR: the structure of axonal bouton and synaptic cleft were ameliorated by BBR administration. Scale bars in Ia, IIa, IIIa : 2 µm; Ib, IIb, IIIb: 1 µm.

Fig. 7

The microbiota-gut-brain loop modulated by berberine in high-fat diet induced obesity. Administration of berberine could increase the B/F ratio and the ratios of SCFA-producing bacteria, which promoted an elevated level of GLP-1 expression in gut L cells. The expression of GLP-1R as well as hormones such as NPY and Orexin A in brain are upregulated. Ultra-structural changes could also be observed in hypothalamus. All of the above changes results in decreased weight gain, ameliorated insulin resistance, reduced endogenous glucose production and lipolysis.