| Undernutrition is a global problem affecting human health.The direct cause is that nutrition and energy can not meet the needs of the body.The main sign is low body weight.At the same time,it is accompanied by kidney,liver,pancreas,spleen and other organ damages.In serious cases,it can even cause death of patients.At present,animal models for undernutrition research mainly include mice,rats and piglets.However,there is a big gap between such animal models and human genetic background,dietary characteristics and biological rhythm,and thus are unable to comprehensively characterize human undernutrition,resulting in great limitations in the study of undernutrition.Non human primates（NHP）are widely used in preclinical trials because of their similar genetic background,dietary habits,circadian rhythm and other biological characteristics with humans.This paper analyzes the descriptive signs（such as body length,body weight,hair gloss,muscle status,etc.）of 1636 Macaca fascicularis raised in a standardized breeding environment.It was found that some Macaca fascicularis showed signs such as sparse and lusterless hair,prominent skeleton,clear body lines and mental malaise,which are extremely consistent with the phenotypic characteristics of human undernutrition.Therefore,this paper first comprehensively evaluated the nutrition status of cynomolgus monkeys based on the evaluation method of human undernutrition,explored the main affected organs of undernutrition and their related damage functions and mechanisms,and gave nutritional intervention（soybean protein and soybean peptide）to the undernourished cynomolgus monkeys to explore the intervention effect and possible mechanism of the two on undernutrition.The main research work and results of this paper are as follows:（1）The nutritional status of cynomolgus monkeys was evaluated with reference to human undernutrition evaluation methods（such as body measurement indicators and blood biochemical indicators）.It was found that compared with normal cynomolgus monkeys with good nutrition status（BCS≥2.0）,the weight of malnourished cynomolgus monkeys（BCS<2.0）were significantly reduced,and other parameters such as age-specific body weight Z-score（WAZ）,height-specific body weight Z-score（WHZ）,age-specific height Z-score（HAZ）,middle upper arm circumference（MUAC）,head circumference（HC）,and skinfold thickness（SFT）were also significantly reduced（p<0.05）.At the same time,it was also found that the blood levels of total protein,albumin,prealbumin,urea nitrogen and creatinine in malnourished cynomolgus monkeys were significantly lower than those of their normal counterparts,while the levels of globulin,C-reactive protein（CRP）,Aspartate transaminase（AST）and triglyceride were significantly elevated（p<0.05）.Therefore,from the perspective of anthropometry and blood biochemical indicators,cynomolgus monkeys with growth faltering recapitulates the typical characteristics of human undernutrition,which not only indicates that cynomolgus monkeys can be used as animal models to study human undernutrition and related mechanisms,but also the relevant anthropometric data（body weight and WAZ）of 1636 cynomolgus monkeys accumulated in this study can provide references for relevant studies in cynomolgus monkeys.（2）Through the analysis of similarity structure,differential expression of genes and histopathology at the level of gene transcription,it was found that the liver is the main affected organ of undernutrition.First,transcriptomic data showed that there was a large difference between the liver gene transcription and expression levels between malnourished and normal cynomolgus monkeys,and histopathological staining showed that the liver of malnourished cynomolgus monkeys had inflammatory cell infiltration and potential hepatic steatosis.Secondly,the carboxylic acid and amino acid-related metabolic pathways in the liver tissue of undernourished cynomolgus monkeys were significantly inhibited,whiles and the bile acid-related metabolic pathways were disordered,resulting in triglyceride accumulation（11.27±3.04 vs 1±0.83,p<0.05）.Consequently,hepatic fatty acid composition was disordered as seen in the decreased saturated fatty acid（SFA,p<0.05）,increased Monounsaturated fatty acids（MUFA,p<0.001）and decreased Polyunsaturated fatty acids（PUFA,p<0.001）.It was observed through electron microscopy that the long axis of the mitochondria in hepatocytes of malnourished monkeys was significantly lengthened and the morphology was altered.The carnitine level in hepatocytes was also significantly decreased（0.007±0.009 v.s.1±0.136,p<0.001）.The above results indicated that hepatic lipid and energy metabolism functions in undernourished cynomolgus monkeys were seriously damaged.（3）Through the 26-day intervention experiment of giving soybean protein and soybean peptide to undernourished cynomolgus monkeys,it was found that soybean protein had no significant effect on the body weight（p=0.261）,WAZ（p=0.492）,WHZ（p=0.303）and the dysregulated blood biochemical levels in undernourished cynomolgus monkeys（p>0.05）.This phenomenon may be related to the efficiency of soybean protein digestion and absorption and the intervention time.However,soybean peptide supplementation could effectively improve the undernutrition symptoms in cynomolgus monkeys by significantly increasing the body weight(p=4×10-3),WAZ(p=3×10-3)and WHZ(p=3×10-3)and restored the abnormal blood biochemical parameter levels（such as albumin,albumin to globulin ratio,glutamic oxaloaminase,triglyceride and CRP）.In addition,soybean peptide could also lower the ratio of Firmicutes to Bacteroidetes（F/B）（from 2.908±2.36 to 1.277±0.749）in the intestinal tract of malnourished cynomolgus monkeys,which is helpful to maintain the steady state of intestinal flora composition.（4）Through transcriptomic and metabolomic analysis,this study found that soybean peptide could up regulate the carboxylic acid and amino acid-related metabolism in the liver of undernourished cynomolgus monkeys,and also reduce the triglyceride content（3.29±1.43 v.s.11.27±3.04,p<0.05）restore fatty acid composition（SFA level increased,p<0.05;MUFA decreased,p<0.001;PUFA increased,p<0.001）,and increase count（p<0.05）and repair the morphology of mitochondria in the liver.These indicated that soybean peptides have a significant repair effect on impaired hepatic nutrients and energy metabolism.In addition,through weighted correlation network analysis of liver metabolites and intestinal microflora abundance,the effect of soybean peptides on the intestinal liver axis in cynomolgus monkeys under undernutrition was explored.It showed that a liver metabolite module significantly related to the degree of undernutrition development.85%of the metabolites in this module were the differential metabolites between the liver of undernourished cynomolgus monkeys and the normal liver,of which 12%are affected by soybean peptides.Moreover,there was a significant correlation between this module and intestinal flora（q<0.2）,indicating that this module may be the main"participant"of the effect of soybean peptides on the intestinal liver axis of undernourished cynomolgus monkeys.To sum up,this study provided a animal model to comprehensively characterize human undernutrition and found the main affected organs of undernutrition,explored its impaired metabolic function and potential mechanism,proved the excellent performance of soybean peptide intervention to improve undernutrition,for the application of soybean peptide in undernutrition intervention provides theory and data support,and can provide reference for the related research of human undernutrition and the development of nutritional intervention means. |
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