Abstract
Background
Chronic diarrhea is a common disease causing morbidity and mortality of captive rhesus macaques (RMs, Macaca mulatta). Chronic diarrhea in RMs is typically characterized by long-term diarrhea and a weak response to antibiotic treatment. Diarrhea is also a common disease in humans and can cause death. However, the etiology of about half of diarrheal cases of humans is still unclear. Therefore, we performed shotgun metagenomic sequencing to characterize the differences in the gut microbiome and resistome of chronic diarrhea RMs and asymptomatic individuals.
Results
Our results showed Lactobacillus spp. (mainly L. johnsonii, L. reuteri and L. amylovorus) were significantly depleted in chronic diarrhea RM guts compared to asymptomatic individuals (5.2 vs 42.4%). Functional annotation of genes suggested these Lactobacillus spp. carried genes involved in the adhesion of intestinal epithelial cells and production of bacteriocin. Chronic diarrhea RM guts also had a significantly greater abundance of many other gut bacteria, including mucin-degrading bacteria and opportunistic pathogens. The metabolic pathways of chronic diarrhea RM gut microbiome were enriched in aerobactin biosynthesis, while the metabolic pathways of asymptomatic RM gut microbiome were enriched in the production of short-chain fatty acids (SCFAs). Chronic diarrhea RM guts had a significantly greater abundance of antibiotic resistance genes (ARGs), such as ermF, aph(3’)-IIIa, ermB, and floR. The strains isolated from feces and tissue fluid of chronic diarrhea RMs had higher resistance rates to the majority of tested antibiotics, but not cephamycin and carbapenem antibiotics. Gut microbial composition comparisons showed that several captive nonhuman primate (NHP) guts were more similar to the guts of humans with a non-westernized diet than humans with a westernized diet. Chronic diarrhea RM gut microbiome was strikingly similar to rural-living humans with diarrhea and humans with a non-westernized diet than asymptomatic RMs.
Conclusions
Our results suggested chronic diarrhea significantly altered the composition and metabolic pathways of the RM gut microbiome. The frequent use of antibiotics caused antibiotic resistance in chronic diarrhea RM gut microbiome with serious consequences for individual treatment and survival. The findings of this study will help us to improve the effective prevention and treatment of diarrhea in RMs.
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Background
Chronic diarrhea is a common disease of captive rhesus macaques (RMs, Macaca mulatta) [1, 2]. Chronic diarrhea in RMs is often manifested by chronic inflammatory response of the colon, and long-term and recurrent diarrhea, yet there has been no specific pathogen identified and antibiotics treatment is frequently ineffective [3]. Chronic diarrhea in RMs can cause dehydration, malnutrition, growth retardation, weight loss, weak immune response, and even death, resulting in great losses of captive RM breeding potential [2, 4]. This diarrheal disease of humans is also one of the most widespread diseases across the world, which threatens human health and is a particular threat for children who experience higher morbidity and mortality [5,6,7]. Compared to developed countries, the incidence rate of diarrhea is higher in develo** countries due to poor hygiene and sanitation [7, 8]. However, the etiology of about half of human diarrheal cases cannot be clearly defined [97]. Nevertheless, the opposite dietary features shaped the different gut microbiome [97]. Since captive NHPs have a similar diet to humans with a non-westernized diet, this might highly influence the similarities in gut microbiome between captive NHPs and humans with a non-westernized diet [96, 98, 99]. However, the human gut microbiome was not consistently similar across all NHP species, with the captive P. troglodytes gut microbiome being most similar to the gut microbiome of humans. This higher similarity in gut microbiome composition may be due to the closer phylogeny and similar diet [100, 101].
Although the symptoms of chronic diarrhea of RMs are similar to UC disease in humans [30], the gut microbiome compositions of them were obviously different in our study. The differences may be caused by these humans with UC disease consuming a westernized diet, because the gut microbiome of RMs was more similar to humans with a non-westernized diet than humans with a westernized diet. We did not collect samples of the humans with IBD consuming a non-westernized diet, but we found that the gut microbiome of chronic diarrhea RMs was more similar to rural diarrheal humans and humans with a non-westernized diet. Therefore, due to more similarities in gut microbiomes, chronic diarrhea RMs could be more suitable models in diarrheal research of rural dwellers or humans with a non-westernized diet.
The frequent use of antibiotics has resulted in antibiotic selection pressure causing the prevalence of antibiotic resistance bacteria [102]. We found that there were most abundant tetracycline ARG in RM guts and most isolates from RM guts were resistant to tetracycline. Although tetracycline antibiotics were not used in the treatment of diarrhea of RMs, long-term and widespread use of tetracycline antibiotics has caused an extensive global tetracycline resistance [103]. Bacteroides spp. are reportedly the main carriers of the tetQ gene [104, 105]. Therefore, a prevalence of tetQ in RM guts might be due to abundant Bacteroides. Similarly, the widespread aminoglycoside ARGs in the chronic diarrhea RM gut microbiome may have resulted from the use of aminoglycoside antibiotics, and it also led to a high resistance rate to kanamycin. The use of florfenicol antibiotics may have caused a high abundance of floR in the guts of RMs [106]. Therefore, abundant ARGs in the guts of chronic diarrhea RMs may be strongly associated with the frequent use of antibiotics.
The testing of resistant phenotypes of isolates further demonstrated serious antibiotic resistance of chronic diarrhea RMs gut microbiome. Not only was there a high abundance of ARG in the gut microbiome of chronic diarrhea RMs, but these RM guts also had high antibiotic resistance rates within isolates. These isolates from chronic diarrhea RMs generally had higher antibiotic resistance rates to florfenicol, tetracycline, aminoglycoside, quinolone, and cephalosporin antibiotics according to our susceptibility testing. Most of these antibiotics were used in previous treatments of diarrhea. Therefore, a directed use of antibiotics in the treatment of diarrheal RMs is necessary to avoid more serious antibiotic resistance. It is worth noting that almost all isolates were susceptible to imipenem and cefoxitin. Due to a stronger stabilization compared to other cephalosporins, bacteria usually had low resistance rates to cefoxitin (a type of cephamycin antibiotics) and imipenem (a type of carbapenem antibiotics) [107, 108]. Therefore, cephamycin and carbapenem antibiotics may be effective to treat diarrhea in RMs and provide new treatment protocols. Nonetheless, the use of cephamycin and carbapenem antibiotics still needs to be treated with caution to avoid novel antibiotic resistance. It is also necessary to monitor resistance phenotype(s) of common antibiotic resistance bacteria, such as Escherichia coli, in RM guts and the captive environment. These measures could effectively decrease the emergence and spread of antibiotic resistance in captive RMs.
Conclusions
In conclusion, our results indicated that individuals with chronic diarrhea had significantly different gut microbiomes compared with asymptomatic individuals. We also identified that frequent use of antibiotics caused antibiotic resistance in RM guts, with serious consequences for the treatment of chronic diarrhea. According to our results, beneficial strains of Lactobacillus from RM guts could be regarded as a potential probiotic to prevent or relieve RM diarrhea in future research and treatment. It was necessary to monitor antibiotic resistance of bacteria in RMs’ environments to reduce the propagative risks from ARGs and multidrug-resistant bacteria. Our results also revealed a greater similarity in gut microbial compositions between captive NHPs including RMs and humans with a non-westernized diet. This result suggests that diarrheal RM could be considered a suitable model to research diarrhea in humans with a non-westernized diet. Overall, our results provided a clearer understanding of the gut microbiome and antibiotic resistome of chronic diarrhea RMs.
Availability of data and materials
The data that support the findings of this study have been deposited into the CNGB Sequence Archive (CNSA) of China National GeneBank DataBase (CNGBdb) with accession number CNP0001810.
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Acknowledgements
We thank Miss Jiao Wang and Mr. Guanglun Lei for the sample collection.
Funding
This work was supported by the Sichuan Science and Technology Program (2020YJ0303) and the Key Research and Development Projects of the Science and Technology Department of Sichuan Province (Grant No.2019YFS0319).
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Contributions
Shengzhi Yang, Yu Liu, Nan Yang, and Yue Lan performed the bioinformatics analyses and collected the samples; Weiqi Lan and **yi Feng performed the experiments; Shengzhi Yang and Yu Liu wrote the manuscript; Bisong Yue, Miao He, Liang Zhang, Anyun Zhang, and Megan Price revised the manuscript; **g Li and Zhenxin Fan designed and supervised the study. The authors read and approved the final manuscript.
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This study was approved by the Ethics Committee of the College of Life Sciences, Sichuan University (No. 20210308001). We strictly obeyed the guidelines of the management committee of experimental animals of Sichuan Province, China (SYXK-Sichuan, 2019-192) in the sample collection and utility protocols.
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Supplementary Information
Additional file 1: Table S1.
The summary of information of RMs. Table S2. The antibiotic resistant profiles of isolates from RMs
Additional file 2: Figure S1.
The gut microbiome of chronic diarrhea RMs and asymptomatic RMs. Figure S2. The functional comparison of gut microbiome. Figure S3. The gut bacterial composition of NHPs and human. Figure S4. The antibiotic resistance in gut microbiome of asymptomatic and chronic diarrhea RMs.
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Yang, S., Liu, Y., Yang, N. et al. The gut microbiome and antibiotic resistome of chronic diarrhea rhesus macaques (Macaca mulatta) and its similarity to the human gut microbiome. Microbiome 10, 29 (2022). https://doi.org/10.1186/s40168-021-01218-3
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DOI: https://doi.org/10.1186/s40168-021-01218-3