The effect of Sennoside A on the improvement of lipopolysaccharide -associated encephalopathy through gut microbiota

doi:10.21203/rs.3.rs-201567/v1

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The effect of Sennoside A on the improvement of lipopolysaccharide -associated encephalopathy through gut microbiota

https://doi.org/10.21203/rs.3.rs-201567/v1

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Background

Accumulating evidence suggests that the intestinal flora is involved in many neurodegenerative diseases. Sepsis can lead to severe intestinal flora imbalance and brain dysfunction. In this study, we investigated Sennoside A may relieve lipopolysaccharide(LPS)-associated encephalopathy via its effect on the gut microbiota in rats.

Methods

Adult male Sprague-Dawley (SD) rats and germ free (GF) rats were used. The ordinary and germ free SD rats were adopted as a LPS-associated encephalopathy model with or without Sennoside A administration. We investigated gut microbiota diversity and structure, conducted electroencephalograms (EEG) and measured the levels of TNF-α, IL-1β and IL-6 in the cortexes of Sprague Dawley (SD) rats with or without Sennoside A administration. Horizontal fecal microbiota transplantation (FMT) and germ-free rats were used to confirm the important roles of gut microbiota in the mitigation of LPS-associated encephalopathy in rats after Sennoside A supplementation.

Results

We found that Sennoside A treatment markedly improved brain function in septic rats including decreased ratios of abnormal EEG and lowered levels of TNF-α, IL-1β, and IL-6 in the rat cortexes. While the gut microbiota changed in septic SD rats, Sennoside A improved gut microbial composition, which might mediate its brain protective effects in sepsis. Sennoside A also reduced inflammation in the cortexes of septic rats via gut microbiota improvement. In germ-free rats that received lipopolysaccharide(LPS),Sennoside A could not lower the ratios of abnormal EEG, and could not alleviate TNF-α, IL-1β, and IL-6 levels in the rats’ cortexes. FMT lowered the ratios of abnormal EEG and alleviate TNF-α, IL-1β, and IL-6 levels in rats’ cortexes, which confirmed our hypothesis that the effect of Sennoside A on the improvement of LPS-associated encephalopathy through gut microbiota.

Conclusion

Our data confirm our hypothesis that Sennoside A likely exerts its brain protective effects through gut microbiota alteration.

Neurology

Sennoside A

Sepsis

lipopolysaccharide-associated encephalopathy

intestinal microbiota

Sepsis is one of the leading causes of morbidity and mortality in patients in critical care and acute care wards^[1]. Sepsis-induced brain dysfunction is called sepsis-associated encephalopathy (SAE), the mechanisms underlying these complications remain unclear and an effective intervention is lacking^[2]. Thus, exploring the pathogenesis of SAE is important to develop more effective prevention and treatment strategies.

Accumulating evidence suggests that the intestinal flora is involved in many neurodegenerative diseases. Ma et al. discovered Bifidobacterium infantis M-63 elevated mental health in individuals with irritable bowel syndrome that developed after a major flood disaster^[3]. Lowe et al. found that acute-on-chronic alcohol administration induces alcohol-associated central nervous system and gut inflammation, which could be reduced by gut microbiome intervention^[4]. A previous study from our group proved that modulation of the intestinal microbiota in septic rats could alleviate SAE^[5].

Sepsis can lead to severe intestinal flora imbalance. Chen discovered that the structure and composition of intestinal flora change significantly in rats with sepsis^[6]. Gong determined that gut microbiota imbalance was an important mediator of sepsis-induced liver injury^[7]. Beckmann found that burn injury patients had a high risk of sepsis-related mortality, and these patients had significant changes in their intestinal microbiome composition^[8]. To Modulating this microbiota dysbiosis may be a potential method to improve SAE in septic rats.

Therefore, targeting the gut microbiota with appropriate drugs is hypothesized to be an effective therapy for SAE. Sennoside A, an inactive glycoside in rhubarb, is the major purgative component of rhubarb^[9]. Rhubarb is a common traditional Chinese medicine used to regulate enteric function. It is known that rhubarb can rectify an intestinal flora imbalance^[10].Yao discovered that rhubarb can rectify intestinal flora in rats with severe acute pancreatitis^[11]. The anti-tumor properties of rhubarb have stimulated research to assess its effect in shaping the gastrointestinal bacterial diversity of young animals when used as a feed additive^[10]. Accumulating evidence supports the finding that Sennoside A and rhubarb can alter intestinal bacterial composition and hence exert multiple pharmacological effects^[12]. Nevertheless, it remains unknown whether Sennoside A affects LPS-associated encephalopathy via the gut microbiota. Fecal microbiota transplantation (FMT), as an effective methods to improve the dysbosis of intestinal microbiota, is an effective method in SAE treatment^[5].

To test the hypothesis that gut microbiota alteration may be involved in the pathogenesis of LPS-associated encephalopathy, and may be ameliorated by Sennoside A, LPS-induced sepsis was used, LPS can make "model of acute inflammation", which can be used to study sepsis^[13]. Ordinary and germ free SD rats were adopted as a model. The ratio of abnormal EEGs, levels of TNF-α, IL-1β, and IL-6 in the rat cortexes were assessed after Sennoside A administration or FMT. The effects of Sennoside A on intestinal microbiotas were evaluated by analyzing the bacterial V3-V4 regions of 16S rRNA genes by Illumina sequencing and multivariate statistical analysis.

Animals

Eighty adult male Sprague-Dawley (SD) rats and forty germ free (GF) rats were purchased from Hebei Medical University, Shijiazhuang, China. The protocol was approved by the Ethics Committee of Hebei General Hospital, and all procedures were performed in accordance with the Guideline for the Care and Use of Laboratory Animals from the National Institutes of Health, USA. The animals were housed under a 12-h light/dark cycle in a temperature-controlled room at 24±1°C with free access to food and water. Germ free rats were given free access to germ free food and water (all food, water, bedding and other supplies that were put in the isolator were sterilized in advance)^[14].

Experimental procedures

Eighty ordinary SD rats were randomly divided into four equal groups: Sham treatment group, LPS group (LPS+saline), LPS with Sennoside A treatment group (LPS+SA), LPS with FMT treatment group (LPS+FMT). Germ free SD rats were randomly divided into two groups: rats given LPS (LPS+GF+saline), and rats given LPS and Sennoside A treatment (LPS+GF+SA). In the LPS+SA group, rats were gavaged with Sennoside A at 25mg.kg^-1 every 8 hours; in the sham and LPS +saline groups, rats were given normal saline instead of Sennoside A. For the rats in LPS +FMT group, fecal microbiota transplantation was performed with fresh feces from the healthy donor rats three times a day for 7 days. Germ free rats in the LPS+GF+SA group were gavaged with Sennoside A at 25mg.kg^-1 every 8 hours. In the LPS+GF+saline group, rats were given normal saline instead of Sennoside A. Sennoside A and saline were sterilized in advance. Rats in all groups except the sham group received an intravenous injection of 10mg/kg body weight lipopolysaccharide(LPS from Escherichia coli, O111:B4; Sigma-Aldrich Chemie GmbH, Germany) through the caudal vein, while rats in the sham group were given the same volume of saline. After the 7^th day, fecal samples were collected, and 1g of each sample was immediately stored at −80°C until DNA extraction and subsequent use to study microbiota composition with 16S rDNA analysis.

Enzyme-linked immunosorbent (ELISA) assay

The brains were removed, stored at −80°C; the brain cortex samples were collected for TNF-α, IL-1β, and IL-6 detection 48h after LPS or saline administration. The concentrations of TNF-α, IL-1β, and IL-6 were detected by ELISA kits according to the manufacturer’s instructions. Standard curves were constructed using various dilutions of manufacturer-supplied TNF-α, IL-1β, and IL-6 standards. The levels of the cytokines were calculated according to the standard curves.

PCR and sequence analysis

Fecal samples were harvested and used for bacterial DNA extraction and sequencing of the V3-V4 hypervariable region in the 16S rDNA gene.

EEG Recordings and analysis

EEGs were recorded at 48h after LPS or saline administration. Standard EEG was performed using a Nihon Kohden manufactured EEG-9100J/K portable digital EEG system. EEG recordings and analysis followed the guidelines of the International Federation of Clinical Neurophysiology.

Statistics analysis

All data are presented as mean±standard error of the mean (SEM) or standard deviation (SD). Statistical analyses were performed using a one-way analysis of variance. In cases of significance, a Fisher post hoc test was applied (Statview, SAS, Cary, NA, USA). Correlation between two variances was estimated using linear regression analysis with a Pearson test. The significance level was set to P<0.05.

1.Gut microbiota analysis

1.1 The diversity of the fecal microbiota

The fecal microbiota diversity in the four groups of SD rats was assessed on the 7^th day based on the Chao1 index and observed species richness. The LPS+saline group had signiﬁcantly lower phylogenetic diversity compared to the sham group, indicating a less diverse fecal microbial composition. The LPS+SA and the LPS+FMT groups had approximately equal phylogenetic diversities compared to the sham group on the 7^th day post Sennoside A administration and FMT treatment（FIG.1a, FIG.1b）. These data indicated that LPS significantly impacted the richness of the gut microbiota, and that Sennoside A and FMT can protect this gut microbial diversity in the LPS induced septic rats.

2．The relative abundances of the fecal microbiota

Analyses of microbiomes showed shifts in bacterial relative abundances upon FMT and Sennoside A supplementation. As illustrated FIG.2a, at the phylum level, the most abundant microbiota in the gut of LPS-treated rats were Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. The microbiome composition was altered in the LPS+saline group: there was significantly greater abundance of Proteobacteria and significantly lower abundance of Firmicutes compared with the sham group. Meanwhile, the abundance of Bacteroidetes was decreased, whereas Actinobacteria was almost unchanged. These values reflect the percentage of the mean relative abundance of this bacterial group in the four groups (not including the germ free groups). Sennoside A supplementation and FMT were found to markedly modify relative percentages of detected phyla when compared to the LPS+saline rats. Sennoside A and FMT supplementation were able to marginally (P=0.00, P=0.00) increase Firmicutes, and Bacteroidetes. Bacterial community composition was similar in Sennoside A and FMT groups compared to the sham group.

As illustrated FIG.2b, at the family level, in the LPS+saline rats, the mean relative abundances of Ruminococcaceae, Clostridiaceae, Lactobacillaceae, Erysipelotrichaceae, Bacteroidaceae, and Eubacteriaceae, were significantly reduced compared to the sham-treated rats, meanwhile, the mean relative abundances of Lachnospiraceae, Prevotellaceae, Graciibacteraceae, Acidaminococcaceae, and Acholeplasmataceae were significantly increased compared to the sham-treated rats. The mean relative abundances of Ruminococcaceae, Clostridiaceae, and Lachnospiraceae were the most affected bacterial groups after Sennoside A supplementation and FMT; the mean relative abundance of Ruminococcaceae and Clostridiaceae were significantly increased compared to the LPS+saline rats, and the mean relative abundance of Lachnospiraceae was significantly decreased compared to the LPS+saline rats.

Regarding the genus level, LPS+saline rats had significantly reduced levels of Faecalibacterium when compared to sham-treated rats. In contrast, LPS+saline rats had significantly increased levels of Alistipes, compared to the sham group. Sennoside A and FMT treatments significantly increased the levels of Faecalibacterium when compared to LPS+saline rats, and reduced the abundance of Alistipes compared to the sham group (FIG.3a,3b ).

3.Analysis of TNF-α, IL-1β, and IL-6 levels in rat cortex.

SAE rats usually present with higher levels of inflammatory cytokines, including TNF-α, IL-1β, and IL-6 in cortex tissues^[5]. We measured the levels of these cytokines after the 7^th day of Sennoside A feeding. We determined that the levels of these cytokines were lower in the cortex tissues of Sennoside A-fed rats. More interestingly, germ-free rats that received the LPS and Sennoside A, did not reduce TNF-α,IL-1β, and IL-6 levels in cortex tissues (FIG.4a,4b,4c). These results showed that the supplementation of Sennoside A significantly lowered the levels of TNF-α, IL-1β, and IL-6 in the cortex through gut microbiota alteration (P<0.05) (FIG.4a,4b,4c).

4.Sennoside A improved LPS-associated encephalopathy

Abnormal EEGs indicate the degree of SAE^[13]. EEGs showed that in rats treated with LPS there was a remarkable increase of reactivity, excessive theta and delta activity, electrographic seizures (ESZ) and periodic discharges (PD) compared with the sham-treated group. However, these abnormalities were reduced in the groups of rats treated with Sennoside A and FMT. These results suggest that Sennoside A improves brain function of rats with sepsis (Table1). Thus, both Sennoside A and FMT relieved inflammation in the cortex tissues of rats with sepsis.

To further confirm the hypothesis that SAE was affected by the gut microbiome, germ free rats were studied. The ratios of abnormal EEGs were not improved after Sennoside A therapy in germ free rats(Table1). In short, Sennoside A likely exerts its brain protective effects through gut microbiota alteration.

This study demonstrated that Sennoside A treatment improved the dysbiosis of intestinal microbiota in LPS-associated encephalopathy rats. Sennoside A supplementation had a substantial impact on gut microbiota diversity and composition at different taxonomic levels. We were particularly interested in the abundance of bacterial species such as Faecalibacterium and Alistipes, which had previously been associated with brain function. The incidence of abnormal EEGs, the cortex levels of TNF-α, IL-1β, and IL-6, were also significantly decreased in the Sennoside A group compared with the LPS group. More interestingly, in GF rats, Sennoside A did not lower the ratio of abnormal EEG, or lower TNF-α, IL-1β, and IL-6 levels in rat cortexes. Abnormal EEG and elevated inflammatory mediators indicate the degree of SAE^[14]. The present results support the hypothesis that gut microbiota is involved in the pathogenesis of LPS-associated encephalopathy and that Sennoside A exerts its brain protective effects through gut microbiota alteration.

Other authors have also shown that Sennoside A, the main glycoside in rhubarb, can normalize the gut microbiota. Wei et al., found that Sennoside A could effectively improve the abundance of the intestinal flora, and alleviate Type 2 diabetes symptoms and reduce obesity^[15]. Sennoside A restored the gut microbiota profile, increased short chain fatty acids (SCFAs), improved mucosal structure in the colon and restored the function of the microbiota-GLP1 axis to improve glucose metabolism in obese mice^[16].Yao et al., found that rhubarb supplementation increased the abundance of intestinal lactobacilli and bifidobacteria, and decreased the amount of intestinal Escherichia coli. In rats with severe acute pancreatitis^[11]. These findings are consistent with our study. Sennoside A exerted its corrective effects at phylum and genus levels, especially affecting the abundance of Faecalibacterium and Alistipes, which play key roles in brain function. Numerous studies showed that FMT is an effective method to modulate the dysbiosis of intestinal microbiota in many diseases^{[5, 17]}. This study showed that Sennoside A and FMT have similar effects in modulating the dysbiosis of intestinal flora in septic rats.

Previous human studies investigated the influence of the intestinal microbiota on the brain and behavior, which is referred to as the gut-brain axis. Han et al., demonstrated decreased β diversity and intestinal microbiota richness (including Faecalibaculum) that led to cognitive dysfunction after surgery in APP/PS1 mice; however, probiotics’ alteration of the intestinal microbiota attenuated this cognitive dysfunction^[18]. Alterations in gut microbial composition have also been observed in children with autism spectrum disorder (ASD), with a decrease in the Firmicutes/Bacteroidetes ratio^[19] compared to children without ASD. Depression was negatively associated with Lachnospiraceae abundance. Patients with anxiety were characterized by elevated Bacteroidaceae^[20]. Rifaximin administration is associated with microbial changes, including an increase in Eubacteriaceae and a decrease in Veillonellaceae abundance, which is accompanied by improved cognitive function in minimal hepatic encephalopathy^[21]. Nogay et al., demonstrated that high growth rates of Clostridium histolyticum, C. perfringens, and Sutterella, high ratios of Escherichia/Shigella, and low ratios of Bacteroidetes/Firmicutes were generally related to GI problems, while relative abundance of Desulfovibrio, Clostridium spp., and Bacteroides vulgatus were associated with behavioral disorders. However, the available information is not yet detailed enough to develop a gut microbiota-based nutritional intervention to treat GI symptoms in people with autism^[22]. Alistipes was over-represented in patients with depression, an increase in Alistipes was observed in chronic social stress and was correlated with increases in proinflammatory cytokines IL-6 and TNF-α^[23]. Notably, enrichment of Alistipes and reduction of Faecalibacterium, was shown to be associated with brain injury^[24]. The genus Faecalibacterium is populated by bacterial species that produce SCFAs, which have an anti-inflammatory effect and are therefore beneficial to the host. Butyrate-producing Faecalibacterium and Coprococcus bacteria were consistently associated with higher quality brain function, and are implicated in relieving alcohol-induced anxiety^[25]. This study proved that Sennoside A supplementation can correct the dysbiosis of intestinal flora structure in sepsis, especially the abundance of bacteria closely related to brain function, which may be a key reason why treatment with Sennoside A played an effective role in alleviating SAE symptoms.

The main pathogenesis of SAE is inflammation in the brain, including increased levels of TNF-α, IL-1β, and IL-6 in the cortex. Abnormal EEG can be used to diagnose SAE^[26]. Evaluation of microbiota diversity indicated that a reduced microbial diversity is associated with inflammation, and changes in the relative abundance of Firmicutes and Bacteroidetes have been determined to affect the balance of inflammation. In particular, a rise in the Firmicutes/Bacteroidetes ratio is related to low-grade inflammation^[27]. Reductions in the abundance of certain microbes, such as Faecalibacterium, which produce SCFAs, were associated with higher levels of inflammation in inﬂammatory bowel disease and autoimmune diseases^[28]. Moreover, Faecalibacterium produces a 15kDa anti-inﬂammatory protein that inhibits the NF-κB pathway in intestinal epithelial cells and was shown to decrease the level NF- кB,IL-1β, IL-6 and TNF-α in a mouse model^[29]. In addition, a rise in Alistipes has previously been observed in chronic social stress, and is correlated with increases in proinflammatory cytokines IL-6 and TNF-α^[30]. This study showed that Sennoside A supplementation decreased the levels of IL-6, TNF-α, and IL-1β in SD rats’ cortexes. In germ-free rats that received LPS, Sennoside A supplementation did not lower the ratios of abnormal EEGs, nor lower TNF-α, IL-1β, and IL-6 levels in rats’cortex. Sennoside A likely exerted its brain protective effects through gut microbiota alteration.

In summary, the present study demonstrated that Sennoside A supplementation and FMT can improve the diversity of SD rats’ intestinal microbiota, and promotion of “beneficial bacteria” improved brain function. In short, Sennoside A can be used as a microbial regulator to improve LPS-associated encephalopathy. Sennoside A likely exerted its brain protective effects through gut microbiota alteration.

Acknowledgements

The authors thank AiMi Academic Services (www.aimieditor.com) for English language editing.

Authors’ contributions

Fenyan Zhang participated in the research design, experimental performance (including

animal surgery), but not the data analysis, and drafting of the manuscript. Yiguang Lin provided technical assistance and help with manuscript preparation.Xiaoli Niu and Jian Lv,and Ranliang Hua discussed the results and edited parts of manuscript. Qian Zhao and Liru Zhang,performed injection, and data analysis. Hui Guo participated in the research design. Suyan Li are the corresponding authors, participated in all aspects of the study, including research design, data analysis, and manuscript preparation. All authors read and approved the final manuscript.

Funding

This study was supported by the grants from Hebei science and technology planning project, China to Dr. Suyan Li (No. 17277720D), Hebei Health and Family Planning Commission Program, China to Dr. Suyan Li (No.20170262), and Hebei Administration of Traditional Chinese Medicine Program, China to Dr. Suyan Li(No.2017060).

Availability of data and materials

The datasets used and/or analyzed in the current study are available from the corresponding authors on reasonable request.

Ethics approval and consent to participate

All animal experimental protocols were approved by the Ethics Committee of Hebei General Hospital, and all procedures were performed in accordance with the Guideline for the Care and Use of Laboratory Animals from the National Institutes of Health, USA.

Consent for publication

Not applicable.

Competing interests

The authors declare no conflict of interest. All the authors listed have approved the manuscript.

Author details

1.Department of emergency, Hebei General Hospital, 348 Heping Road, Shijiazhuang, Hebei 050011, P. R. China.

2.Department of Gastroenterology, Beijing Geriatric Hospital, 118 Wenquan Town, Haidian District, Beijing 100095, P. R. China.
3.Department of Neurosurgery, Tianjin Medical University Second Hospital, 23 Pingjiang Road,Hexi District,Tianjin 300211,P. R. China.
4.Department of neurology, Hebei General Hospital, 348 Heping Road, Shijiazhuang, Hebei 050011, P. R. China.

5.Department of general practice, Hebei General Hospital, 348 Heping Road, Shijiazhuang, Hebei 050011,P.R.China.

FMT: Fecal microbiota transplantation; LPS: Lipopolysaccharide; SAE: Sepsis-associated encephalopathy; TNFα: Tumor necrosis factor-α; IL-1β: Interleukin-1β;IL-6: Interleukin-6; EEG: Electroencephalogram; ESZ:electrographic seizures; PD:Periodic discharges; SCFAs:Short chain fatty acids; ASD:Autism spectrum disorder.

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Table 1.The proportion of abnormal EEG results in each group

Variables	Sham	LPS+Saline	LPS+FMT	LPS+SA	LPS+GF+Saline	LPS+GF+SA
Delta-predominant	0(20)	8(9)#	6(13) #*	6(12)#*	8(8)	7(8)
Theta-predominant	0(20)	7(9)#	3(13) #*	2(12)#*	6(8)	6(8)
Low voltage	0(20)	8(9)#	2(13) #*	3(12)#*	6(8)	7(8)
Absence of reactivity	0(20)	8(9)#	1(13) #*	1(12)#*	7(8)	6(8)
Electrographic seizure	0(20)	6(9)#	2(13) #*	1(12)#*	5(8)	6(8)
Triphasic waves	0(20)	4(9)#	0(13) #*	1(12)#*	3(8)	4(8)
Periodic Discharges	0(20)	2(9)#	2(13) #*	1(12)#*	4(8)	3(8)

p < 0.05. # compared with Sham group, * compared with LPS+Saline group,＆ compared with LPS+GF+Saline group.

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The effect of Sennoside A on the improvement of lipopolysaccharide -associated encephalopathy through gut microbiota

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