Multifunctional role of oral bacteria in the progression of nonalcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD)encompasses a spectrum of liver disorders of varying severity,ultimately leading to fibrosis.This spectrum primarily consists of NAFL and non-alcoholic steatohepatitis.The pathogenesis of NAFLD is closely associated with disturbances in the gut micr-obiota and impairment of the intestinal barrier.Non-gut commensal flora,particularly bacteria,play a pivotal role in the progression of NAFLD.Notably,Porphyromonas gingivalis,a principal bacterium involved in periodontitis,is known to facilitate lipid accumulation,augment immune responses,and induce insulin resistance,thereby exacerbating fibrosis in cases of periodontitis-associated NAFLD.The influence of oral microbiota on NAFLD via the“oral-gut-liver”axis is gaining recognition,offering a novel perspective for NAFLD management through microbial imbalance correction.This review endeavors to encapsulate the intricate roles of oral bacteria in NAFLD and explore underlying mechanisms,emphasizing microbial control strategies as a viable therapeutic avenue for NAFLD.

Diarrheal Diseases: A Review on Gastroenteritis Bacteria Global Burden and Alternative Control of Multidrug-Resistant Strains

Diarrheal diseases represent a significant and pervasive health challenge for humanity. The aetiology of diarrheal diseases is typically associated with the presence of enteropathogens, including viruses, bacteria and parasites. The implementation of preventive measures, including the maintenance of good food hygiene, effective water sanitation, and the development of rotavirus vaccines, has resulted in a notable reduction in the prevalence of the disease. However, the emergence of bacterial multidrug resistance due to the past or present inappropriate use of antibiotics has rendered bacterial infections a significant challenge. The objective of this review is threefold: firstly, to provide an overview of diarrheal diseases associated with bacteria;secondly, to offer a concise analysis of bacterial multidrug resistance on a global scale;and thirdly, to present the potential of filamentous fungi as an alternative solution to the challenge posed by multidrug-resistant strains. Campylobacter spp. is the most dangerous bacteria, followed by Shigella spp. and Vibrio cholerae in all age groups combined. However, Shigella spp. was the deadliest in children under five years of age and, together with E. coli, are the most antibiotic-resistant bacteria. With their highly developed secondary metabolism, fungi are a reservoir of natural bioactive compounds.

Relationship between nutritional therapy and beneficial bacteria ratio in severe disease

Objective:To evaluate relationship between changes in the beneficial bacteria in intensive care unit(ICU)patients and nutritional therapy type.Methods:Ten patients aged≥18 years admitted to the ICU between January and December 2020,were included.Good enteral nutrition was defined as early achievement of target calorie intake through enteral feeding.The ratio of beneficial bacteria at the first and second bowel movements after each patient’s admission was calculated and the patients were classified into the increase or decrease group.Among all patients,five each were in the increase and decrease groups.We investigated patient background,changes in sequential organ failure assessment(SOFA)and acute physiology and chronic health evaluation(APACHE)Ⅱscores,nutritional doses or methods,and clinical outcomes.Results:No relationship was found between changes in the ratio of beneficial bacteria and changes in SOFA/APACHEⅡscores at the time of admission.The rate of good enteral nutrition was significantly higher in the increase group than in the decrease group(4/5 vs.0/5,P=0.01).Conclusions:An increase in beneficial bacteria may be significantly related to the early establishment of enteral nutrition.In the future,accumulating cases may make it possible to establish a new nutritional strategy for critically ill patients from an intestinal microbiota perspective.

Isolation and Identification of Antifungal Bacterial Strain KL-1 against Plant Wilt Disease

[Objective] The antifungal bacteria of plant wilt disease was screened and identified to provide foundation for the study on bio-control preparation of plant wilt disease.[Method] Confrontation culture method was adopted to screen the bio-control bacteria with good antifungal effect against plant wilt disease,Biolog bacteria automatic identification system and 16S rDNA sequence analysis method were selected to identify its taxonomic status,the biological safety of the strain towards cotton and mice was also determined.[Result] 12 bacterial strains were isolated from rhizosphere of cotton.Among those strains,5 isolates showed antifungal activity against F.decemcellulare Brick,F.oxysporum f.sp.Diathi,F.oxysporum f.sp.vasinfectum.The antifungal effect of KL-1 strain against three target strains of pathogen reached 69.09%,80.78% and 78.89% respectively.Identification results of Biolog bacteria automatic identification system and 16S rDNA sequence analysis method showed that KL-1strain was Bacillus amyloliquefaciens;primary determination results of biological safety also showed that the strain KL-1 was safe and non-toxic towards cotton and mice.[Conclusion] KL-1strain of B.amyloliquefaciens had antifungal effect against several pathogens of plant wilt diseases,which was safe and non-toxic towards cotton and mice,being the bio-control strain with research and development potential.

Antibacterial activity of leaves extracts of Trifolium alexandrinum Linn,against pathogenic bacteria causing tropical diseases

Objective:To investigate antibacterial potential of Trifolium alexandrinum(T.alexandrinum) Linn,against seven gram positive and eleven gram negative hospital isolated human pathogenic bacterial strains responsible for many tropical diseases.Methods:Non-polar and polar extracts of the leaves of T.alexandrinum i.e.,hexane,dichloromethane(DCM),ethyl acetate(EtOAc), methanol(MeOH) and aqueous(AQ) extracts at five different concentrations(1,2,5,10 and 15 mg/ mL) were prepared to evaluate their antibacterial value.NCCL standards were strictly followed to perform antimicrobial disc susceptibility test using disc diffusion method.Results:Polar extracts demonstrated significant antibacterial activity against tested pathogens.EtOAc and MeOH extracts showed maximum antibacterial activity with higher inhibition zone and were found effective against seventeen of the tested pathogens.While AQ plant extract inhibited the growth of sixteen of the test strains.EtOAc and MeOH plant extracts inhibited the growth of all seven gram positive and ten of the gram negative bacterial strains.Conclusions:The present study strongly confirms the effectiveness of crude leaves extracts against tested human pathogenic bacterial strains causing several tropical diseases.Since Egyptian clover is used as a fodder plant,it could be helpful in controlling various infectious diseases associated with cattle as well.

Gram-Positive Bacteria Associated with Rice in China and Their Antagonists Against the Pathogens of Sheath Blight and Bakanae Disease in Rice

It is necessary to understand the bacterial populations associated with rice so as to provide more information and natural resources for effective management of major diseases in rice. A survey on screening and identification of gram-positive bacteria was conducted during 1998 2004. Seven hundred and fifty-six rice samples were collected from Zhejiang, Jiangsu, Fujian and Yunnan Provinces, China. Over 1000 bacterial isolates were isolated and tested for colony morphology, pathogenicity, and some characteristics of bacteriology including Gram staining, fluorescent pigment on Kings medium B and microscopic observation for endospore. Together with five standard reference strains, 74 representative gram-positive bacterial isolates were confirmed by Biolog and gas chromatographic analysis of fatty acid methyl esters. Five bacterial species of Bacillus and other three genera were identified and isolates from Bacillus sublitis and Bacillus megaterium, exhibited the most effective inhibition against the pathogens of sheath blight and bakanae disease of rice. A few isolates from Bacillus pumilus and Bacillus megaterium showed weak virulent on rice together with some virulent isolates, risk should be considered when isolates from these species were screened for biocontrol agents.

16S rRNA Gene Phylogenesis of Culturable Predominant Bacteria from Diseased Apostichopus japonicus(Holothuroidea,Echinodermata)

Cultured Apostichopus japonicus in China suffers from a kind of skin ulceration disease that has caused severe economic loss in recent years. The disease,pathogens of which are supposed to be bacteria by most researchers,is highly infectious and can often cause all individuals in the same culture pool to die in a very short time. The 16S rRNA gene phylogenesis of the culturable bacteria from the lesions of diseased individuals was conducted to study the biodiversity of the bacterial communities in the lesions and to identify probable pathogen(s) associated with this kind of disease. S. japonica samples were selected from a hatchery located in the eastern part of Qingdao,China. Bacterial universal primers GM5F and DS907R were used to amplify the 16S rRNA gene of bacteria colonies,and touchdown PCR was performed to amplify the target sequences. The results suggest that γ-proteobacteria(Alteromonadales and Vibrionales) of CFB group,many strains of which have been also determined as pathogens in other marine species,are the predominant bacterial genera of the diseased Apostichopus japonicus individuals.

May bacterial or pancreatic proteases play a critical role in inflammatory bowel disease?

In a recent review paper,Carroll and Maharshak discussed a critical role of enteric bacterial proteases in the pathogenesis of inflammatory bowel disease(IBD).I take a great interest in this paper as I also suspected proteases,not from the bacteria,but those originated from the pancreas that failed to be inactivated in the lower gut due to a reduction in gut bacteria,may have played a critical role in the pathogenesis of IBD,which was first published more than a decade ago and discussed again in more detail in a recent paper published in this journal.Antibiotics may result in a big reduction in gut bacteria and bacterial proteases,but multiple studies demonstrated dramatic increased of pancreatic proteases like trypsin and chymotrypsin in the feces of animals or patients treated with antibiotics.Multiple large-scale studies also demonstrated use of antibiotics caused an increase but not decrease in the risk of developing IBD,suggesting impaired inactivation and degradation of pancreatic proteases may have played a more critical role in the pathogenesis of IBD.

Bacterial biofilms in human gastrointestinal tract: An intricate balance between health and inflammatory bowel diseases

Inflammatory bowel disease (IBD) has been a worldwide health problem. It is characterized by severe intestinal inflammation due to immune responses against the gut microbes in genetically susceptible individuals. The understanding of gut microbiota for its composition and complex interaction in normal and diseased conditions has been assisted by the use of molecular, metagenomics and meta transcriptomics studies. The alteration of intestinal microbiota is the key determinant in the degree of inflammation caused and the prolonged course of disease. The relationship between luminal gut bacteria and innate immunity is also of prime significance. Such developments have further led to the search of specific (including bacteria and fungi) as a causative agent of IBD. Although detailed research has been done for the role of gut microbiota in IBD, molecular mechanisms and related gene expression are still not well understood in this disease, which hampers the generation of effective therapeutic agents for IBD. This paper assessed various factors contributing to IBD, genetic dysbiosis and pathogenic influence in the gut microbiota, interactions such as microbiome-host immune system interaction and microbe-microbe interactions involved in IBD, currently available IBD therapies, followed by a detailed review on bacterial infections that might be involved in IBD, globally and specifically in India.

The effects of the environmental factors on Laminaria disease caused by alginic acid decomposing bacteria

-The rot disease of Laminaria occurs often in nurseries of sporeling and commercial cultivation in the sea and results in economic loss greatly. Usually the disease outbreaks accompanied with massive multiplication of alginic acid decomposing bacteria. From the section of the decaying Lamuutria which resulted from the inoculation of alginic acid decomposing bacteria, it was observed that the bacteria invaded the epiderm of the Laminaria surface at first, then entered the ex-odermis, endodermis and pith. In addition, there were a great amount of bacteria in the intercellular region and a lot of free cells of the algae in the decaying areas. The wall of some free cells was decomposed, which led to soft tissue or disintegration. Alginic acid decomposing bacteria are normal epiphytic microorganisms growing on Lamuutria surface. These bacteria do not cause disease at normal environmental conditions. The experiments showed that the unfavourable conditions, e. g. , wounding, overcrowding, high temperature reduced the ability of antibacterial activity and made the algae more susceptible to the pathogens and favoured the multiplication of alginic acid decomposing bacteria and finally led to the disease outbreak. The unfavourable environmental factors which resulted from a variety of reasons were the main cause of the disease.

A study on relation between heterotrophic bacteria and shrimp disease

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Helicobacter pylori and Crohn's disease: A retrospective single-center study from China

AIM: To investigate the association between Helicobacter pylori (H. pylori ) infection and the prevalence of Crohn's disease (CD). METHODS: Subjects were selected from patients admitted the gastrointestinal (GI) department at The First Affiliated Hospital School of Medicine (Zhejiang University)for abdominal pain, hematochezia, diarrhea and other GI symptoms between January 2008 and September 2012. CD was diagnosed by endoscopy and biopsy. H. pylori infection was detected by a 14 C-urea breath test and culturing of the biopsy sample. Demographic, anthropometric and serologic data were collected for each patient. H. pylori infection rate was compared between CD and control groups, followed by a subgroup analysis based on extent and severity of CD. Student's t , Mann-Whiney U , and χ 2 tests were used to analyze the data. RESULTS: A total of 447 patients were analyzed, including 229 in the CD group and 248 in the control group. There were no significant differences in age, sex, and rates of hypertension or diabetes. However, the CD group showed significantly higher rates of smoking history (34.9% vs 18.1%), alcohol intake (17.4% vs 8.1%), white blood cell count (9.7 ± 2.9 × 10 9 /L vs 4.3 ± 0.9 × 10 9 /L), and C-reactive protein (36.3 ± 20.8 mg/L vs 5.5 ± 2.3 mg/L) but lower body mass index (24.5 ± 2.0 kg/m 2 vs 26.0 ± 2.2 kg/m 2 ) than the control group. The H. pylori infection rate in the CD group was 27.1%, significantly lower than that of 47.9% in the control group. Furthermore, the H. pylori infection rates in patients with colonic, small intestine, ileocolonic and extensive CD were 31.1%, 28.9%, 26.8% and 25.9% respectively, all of which were significantly lower than in the control group. Finally, the H. pylori infection rates in patients with remission, moderate and severe CD were 34.3%, 30.7% and 22.0% respectively, which were also significantly lower than in the control group. CONCLUSION: Lower H. pylori infection in CD patients suggests a correlation between bacterial infection and CD, suggesting caution when considering H. pylori eradication in CD patients.

Washed microbiota transplantation reduces proton pump inhibitor dependency in nonerosive reflux disease

BACKGROUND The pathogenesis of gastroesophageal reflux disease(GERD)is closely associated with the intestinal bacteria composition and their metabolites.AIM To investigate whether washed microbiota transplantation(WMT)improves symptoms of nonerosive reflux disease(NERD)with proton pump inhibitor(PPI)dependency.METHODS Patients with recurrent NERD and PPI dependency at the First Affiliated Hospital of Guangdong Pharmaceutical University from 2017 to 2018 were included and divided into a WMT or PPI group treated with PPI with/without WMT.The endpoint was NERD symptom frequency evaluated 1 mo after WMT using reflux disease questionnaire(RDQ)and GERD questionnaire(GERDQ)scores,remission time,PPI dose,and the examination of intestinal mucosal barrier function.RESULTS In the WMT(n=15)and PPI(n=12)groups,the total remission rate at 1 mo after treatment was 93.3%vs 41.7%.Compared with the PPI group,the WMT group showed better results in GERDQ(P=0.004)and RDQ(P=0.003)and in remission months(8 vs 2,P=0.002).The PPI dose was reduced to some extent for 80%of patients in the WMT group and 33.3%in the PPI group.In 24 patients,intestinal mucosal barrier function was examined before treatment,and changes in the degree of damage were observed in 13 of these patients after treatment.Only one of the 15 patients had minor side effects,including a mushy stool two or three times a day,which resolved on their own after 1 wk.CONCLUSION This study is the first to demonstrate that WMT may be safe and effective for relieving NERD symptoms and reducing PPI dependency and recurrence.

Pathogenesis of Crohn's disease: Bug or no bug

The possibility of an infectious origin in inflammatory bowel disease(IBD)has been postulated since the first description of Crohn’s disease(CD).Many observations implicate bacteria as a trigger for the development of CD:lesions occur in regions with higher bacterial concentrations;aphthous ulcers occur in Peyer’s patches;inflammation resolves when the fecal stream is diverted and is reactivated following reinfusion ofbowel contents;severity of the disease is correlated with bacterial density in the mucosa;granulomas can contain bacteria;and susceptible mice raised in germfree conditions develop inflammation when bacteria are introduced in the 1990’s,several studies sought to establish a relationship with viral infections and the onset of IBD,finally concluding that no direct link had been demonstrated.In the past fifteen years,evidence relating IBD pathogenesis to Mycobacterium avium paratuberculosis,salmonella,campylobacter,etc.,has been found.The tendency now under discussion to regard microbiota as the primary catalyst has led to the latest studies on microbiota as pathogens,focusing on Escherichia coli,mainly in ileal CD.The present review discusses the literature available on these"bugs".

Role of regenerating islet-derived proteins in inflammatory bowel disease

Inflammatory bowel disease(IBD)is an inflammatory disorder of the gastrointestinal tract that affects millions of patients worldwide.It has a complex and multifactorial etiology leading to excessive exposure of intestinal epithelium to microbial antigens,inappropriate activation of the immune system and ultimately to the damage of intestinal tissues.Although numerous efforts have been made to improve the disease management,IBD remains persistently recurring and beyond cure.This is due largely to the gaps in our understanding of the pathogenesis of IBD that hamper the development of timely diagnoses and effective treatment.However,some recent discoveries,including the beneficial effects of interleukin-22(IL-22)on the inflamed intestine,have shed light on a self-protective mechanism in IBD.Regenerating islet-derived(REG/Reg)proteins are small secretory proteins which function as IL-22’s downstream effectors.Mounting studies have demonstrated that IBD patients have significantly increased REG expressions in the injured intestine,but with undefined mechanisms and roles.The reported functions of REG/Reg proteins in intestinal homeostasis,such as those of antibacterial,anti-inflammatory and tissue repair,lead us to discuss their potential mechanisms and clinical relevance in IBD in order to advance IBD research and management.

Immunogenomics for identification of disease resistance genes in pigs: a review focusing on Gram-negative bacilli

Over the past years, infectious disease has caused enormous economic loss in pig industry. Among the pathogens, gram negative bacteria not only cause inflammation, but also cause different diseases and make the pigs more susceptible to virus infection. Vaccination, medication and elimination of sick pigs are major strategies of controlling disease. Genetic methods, such as selection of disease resistance in the pig, have not been widely used. Recently, the completion of the porcine whole genome sequencing has provided powerful tools to identify the genome regions that harboring genes controlling disease or immunity. Immunogenornics, which combines DNA variations, transcriptorne, immune response, and QTL mapping data to illustrate the interactions between pathogen and host immune system, will be an effective genomics tool for identification of disease resistance genes in pigs. These genes will be potential targets for disease resistance in breeding programs. This paper reviewed the progress of disease resistance study in the pig focusing on Gram-negative bacilli. Major porcine Gram-negative bacilli and diseases, suggested candidate genes/pathways against porcine Gram-negative bacilli, and distributions of QTLs for immune capacity on pig chromosomes were summarized. Some tools for immunogenomics research were described. We conclude that integration of sequencing, whole genome associations, functional genomics studies, and immune response information is necessary to illustrate molecular mechanisms and key genes in disease resistance.

A Rapid Identification Method for Germplasm Materials Resistant to Citrus Huanglongbing Disease

[Objectives]This study was conducted to develop a rapid identification method for citrus germline materials resistant to Huanglongbing disease and lay a basis for accelerating citrus breeding for resistance to Huanglongbing and increasing the breeding efficiency.[Methods]Thirty-six citrus germplasms suspected to be resistant to citrus Huanglongbing disease were collected.The method of direct high grafting to citrus trees infected with Huanglongbing pathogen was adopted.The resistance of the test materials was identified and evaluated by field symptoms combined with quantitative PCR.It was defined as the top grafting identification method.[Results]The test materials that were grafted in spring started to germinate after one month,and three months late(June 5,2018)typical mottled yellowing on leaves was observed on KH-14 for the first time.After four months(July 5,2018)of top grafting,typical mottled yellowing occurred on 23 materials,and 11 materials showed no such symptom.After six months(September 4,2018)of top grafting,although the growth of KH-18,KH-12,KHY-4,KHY-5 and KHY-6 were normal,yellowing was observed on their leaves.Only KH-21 grew well,and showed no yellow shoots and yellowing leaves.It was identified as the material with resistance to Huanglongbing disease.Quantitative PCR tests on the above six materials showed that KH-21 was negative and other five were positive.Real-time fluorescence quantitative PCR test indicated that the average Huanglongbing bacteria amount in KH-21 was 1870.0 cell/μg DNA,and the average Huanglongbing bacteria amount in the control material was 372285.5 cell/μg DNA,indicating KH-21 was resistant to Huanglongbing bacteria.[Conclusions]The method for infecting bacteria by top grafting takes six months,can detect large amount of seedlings,and is time-saving,efficient,cost-saving and accurate.This method can quickly identify the resistance of citrus varieties to citrus Huanglongbing disease,and can be popularized and used in the identification of citrus Huanglongbing disease resistance.

Regulatory effects of the combination of berberine and ginsenoside Rb1 on high-fat diet-induced nonalcoholic fatty liver disease via AMPK pathway and improved pharmacokinetics

Objective： We evaluated the protective effects of berberine （BBR） combined with ginsenoside Rb1 （G-Rb1） on high-fatdiet （HFD）-induced nonalcoholic fatty liver disease （NAFLD） in rats and futher investigated the underlying mechanisms.Methods： Rats were fed an HFD for 6 weeks and then randomly divided into four groups and treated with BBR （50mg/kg）, G-Rb1 （100 mg/kg）, BBR （50 mg/kg） ＋ G-Rb1 （100 mg/kg）, or fenofibrate （40 mg/kg）. Histological examinationof liver tissue was performed. In human hepatocellular carcinoma cells HepG2, protein expression of AMP-activatedprotein kinase （AMPK） and acetyl-CoA carboxylase was detected by western blotting, and the mRNA expression ofcarnitine palmitoyl transferase 1 and 3-hydroxy-3-methyl glutaryl coenzyme A reductase was detected by quantitativePCR. Pharmacokinetic assessments included analysis of bioavailability of BBR and G-Rb1 in vivo and G-Rb1 metabolismby intestinal bacteria in vitro. Results： Compared to the single-use group, BBR combined with G-Rb1 significantlyameliorated hepatic fat accumulation in HFD-induced obese rats, as demonstrated by reduced hepatic triglyceridecontent, and histological evaluation of liver sections. Activation of hepatic AMPK and phosphorylation of acetyl-CoAcarboxylase were significantly elevated in hepatocytes treated with both BBR and G-Rb1. Consistent with the activationof AMPK, the mRNA expression of carnitine palmitoyl transferase 1 was stimulated, while the mRNA expression of3-hydroxy-3-methyl glutaryl coenzyme A reductase was suppressed. Pharmacokinetic analysis revealed that BBRincreased the bioavailability of G-Rb1 in Sprague-Dawley rats. Additionally, BBR prevented degradation of G-Rb1 infecal solution in vitro. Conclusion： BBR combined with G-Rb1 improved NAFLD through the AMPK signaling pathway,and BBR enhanced G-Rb1 bioavailability via promoting the intestinal absorption of G-Rb1. This combination may be auseful therapeutic agent for NAFLD.

Climate Induced Virus Generated Communicable Diseases:Management Issues and Failures

In the present review article human diseases caused by various groups of pathogens have been explained with its etiology,epidemiology and treatment.In addition,effect of climatic changes on parasites and pathogens has been demarcated with rising incidences of diseases.In response to environmental changes,mainly external and internal microenvironment of body and drug regimens taken by patients;virus is regularly changing its form and new mutant variants are coming out.These are circulating in many Indian states and cross border countries and causing high infectivity and mortality in human patients.These variants with new mutations are challenging existing drugs and other prophylactic measures and massively disrupting functions of a tissue,organ,or entire organism.Diseases caused by viruses are showing new trends in virulence,with high infectivity,morbidity and mortality.Due to climatic effect and drug resistance and new mutations in pathogens disease burden has been exacerbated enormously at global level.In all cases of helminthes,protozoan’s,fungi,bacteria,virus pathogens and parasites available drug structure seem to be failed or their usefulness has been much reduced due to evolution of new mutant variants with multiple drug resistance.There are serious failures at the level of operation,management and control of disease.The utmost failure is due to lack of appropriate vaccine,drug regimens,clinical care and awareness among people.These are major reasons that is why diseases become uncontrolled and unmanageable.

A new perspective of traditional Chinese and western medicine as a potential remedy to improve intestinal flora in the treatment of chronic kidney disease

Intestinal flora imbalance is closely related to the occurrence and development of various diseases,however,the relationship between intestinal flora and chronic kidney disease has also become a hot topic.Intestinal flora imbalance,intestinal pathogenic bacteria and toxins increase,causing renal damage,chronic kidney disease patients also have a decrease in intestinal beneficial bacteria,an increase in pathogenic bacteria,more and more experimental studies show that the treatment of chronic Kidney disease is closely related to maintaining the balance of intestinal flora.However,at this stage,it has not been widely used in clinical practice by improving the protection of intestinal flora imbalance and delaying the deterioration of renal function.Therefore,this paper mainly discusses the research on the improvement of intestinal flora imbalance in the treatment of chronic kidney disease by traditional Chinese and Western medicine,and provides a new perspective for the treatment of chronic kidney disease.