Fecal microbiota transplantation has therapeutic effects on chronic hepatits B patients via altering composition of gut microbiota

Ji-Min Lou , b , Zhi-Gng Ren , b , Ang Li , b , Ben-Chen Ro , b , Zu-Jing Yu , b , ∗

a Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou 450052, China

b Gene Hospital of Henan Province, Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China

Chronic hepatits B (CHB) is an increasingly disturbing public health issue worldwide.Currently, interferon and oral antiviral drugs such as entecavir (ETV) or tenofovir disoproxil fumarate(TDF) are two internationally recognized drugs for the treatment of CHB.However, the HBeAg clearance or seroconversion rate is low even in patients with long-term antiviral therapy.Many patients have to increase the dosage of antiviral therapy drugs [1].Intestinal microorganisms are confirmed to play an important role in the pathogenesis of different chronic liver diseases including CHB, and fecal microbiota transplantation (FMT) may be a novel treatment strategy for CHB.

It has been found that the diversity of gut microbiota was significantly decreased in CHB patients in comparison with the healthy individuals [2 , 3].Xing et al.[4]in 2006 demonstrated that liver ischemia-reperfusion injury results in the decrease ofBifidobacteriumandlacticacidbacteria, and the increase ofEnterobacteriaceaeandEnterococcus.Bacterial translocation, the damage of intestinal microvillus and amplification of intestinal mucosal space were likely to contribute to those bacterial alterations [5].Moreover, similar bacterial alterations were subsequently observed in HBV carriers, CHB patients and cirrhotics.

A recent research [6]analyzed intestinal microbiota in Chinese cohorts with HBV carriers, CHB patients, patients with decompensated liver cirrhosis due to CHB, and healthy controls.The abundance ofEnterobacteriaceaewas positively correlated with that ofVeillonella, whereas a significant negative correlation was observed betweenBacteroidetesand Child-Turcotte-Pugh scores [7].The abundance of some bacteria in patients with CHB were increased or reduced compared with healthy controls, which implies a potential therapeutic effects of FMT on treating CHB patients via altering the intestinal microbial composition.Furthermore, when compared with healthy controls, fecal microbial diversity in cirrhotic patients was significantly reduced [8].

FMT is defined as infusion of fecal bacteria from a healthy donor to a recipient, aiming to treat a specific disease via altering the component or distribution of intestinal microbiota [9].The operating processes of FMT are as follows.(i) Screening of fecal donors: there are two main sources of healthy donors including allogenic and autologous, and the allogenic donors are the mainstream.In order to ensure that fecal donors are healthy, the history of drug use, medical history, infection and common pathogen test indexes were screened to exclude the factors that might affect the intestinal flora.Moreover, donors will accept a series of tabular questionnaires in 8 aspects including age, physiology, pathology, psychology, integrity, time, environment, status of recipients.(ii) Preparation of fecal bacteria: Intelligent Separation System of fecal bacteria (GenFMTer) is used to achieve enrichment and purification of fecal bacteria within 1 h following the microfiltration and centrifugal enrichment method.The time from stool collection to the recipient should be limited within 1 h, which is call onehour FMT protocol.(iii) Sample management, storage, transport and usage: it is recommended that endoscopic physicians evaluate the sample quality based on the following standards: the color of fecal bacteria should be milk yellow or light yellow; there are no abnormal impurities under magnifying endoscopy; and there are no visible particles under magnifying endoscopy.If the sample needs to be transported remotely, dry ice is used.(iv) The route of transplantation: gastroscope to the duodenum; transnasal gastrointestinal tube; fistula tube through jejunum or ileum; colonoscopy;transendoscopic enteral tubing; rectal or sigmoid colon enema and other ways.The patient needs to stop antibiotics for 3 days.It has been argued that oral administration of vancomycin or other antibiotics before transplantation is necessary so as to “clear”and use laxatives to remove intestinal contents.However, there is no solid evidence that “clear”intestinal flora improves the efficacy of FMT.

It is widely accepted that FMT reconstructs a new healthy intestinal flora which help the patients to recover from the diseased status.The mechanisms of FMT for CHB treatment include immunoreactions.It is widely accepted that the alterations of the gut microbiotas significantly influence the activity of host immune system including a variety of immune cells and cytokines, which is associated with the disease status of CHB.Similar studies in many diseases showed a close relationship with gut microbiota.

A study by Lamas et al.[10]revealed a potential relationship between gut microbiota and caspase recruitment domain family member 9 (CARD9), a susceptibility gene for inflammatory boweldisease that plays a part in the immune response against microorganisms.CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands.

In terms ofClostridiumdifficileinfection [11], the niche exclusion due to microbial competition for nutrient resources was considered a potential mechanism of FMT.It was also suggested that FMT improves the metabolism of secondary bile acid, which produced compounds that inhibited theClostridiumdifficilespore germination and expansion.A small portion of intestinal microbiomes participates in the 7-α-dehydroxylation of these secondary bile acids and plays a key role inClostridiumdifficileinhibition.Thus, FMT is also considered the best option for the treatment ofClostridiumdifficileinfection.

The mechanisms of FMT on CHB treatment are complex.It is not enough to just focus on certain molecule or bacteria.It is impossible to explain the mechanism of FMT based on a single bacteria or a certain signal pathway.

According to several randomized controlled trials, FMT has been recommended to be effective on CHB treatment.One clinical trial used FMT to treat HBeAg-positive CHB patients with ongoing ETV/TDF therapy [12].Robust decrease in HBeAg titer was observed at the end of follow-up compared to baseline.In comparison, the patients with ETV/TDF therapy without FMT had no HBeAg reduction.The intestinal microbial communities are significantly differed between donors and patients in FMT group.Indeed, there were intestinal microflora disorders in patients with CHB, as demonstrated by the decline in microbial diversity.Moreover, the diversity of gut microbiota of patients increased remarkably after FMT treatment, which also reminds us of the potential link between CHB and the gut microbiota [13].FMT could expedite the elimination of HBeAg liter in HBeAg-positive patients who were detected sustaining positive HBeAg in spite of long-term conventional antiviral therapy.It is bound to be a prospective breakthrough of the new therapy strategy of CHB.

We compared the FMT process between CHB and inflammatory bowel disease, and some differences between them were concluded including differences in fecal microbiota preparation techniques (fresh material vs.frozen material); the procedure for preparing the recipient for transplant of the new microbiota(cleansing colon with polyethylene glycol or use large spectrum antibiotics or no preparation at all); route of administration (via the upper or the lower gastrointestinal tract) [14].

With promising application value in various extra-intestinal diseases, FMT is an increasingly estimable method of intestinal microbiological regulation.Apparently, FMT has break a new path in a wide range of investigation areas and has proven to be involved in many diseases, including inflammatory bowel disease,irritable bowel syndrome, autoimmune disease, multiple sclerosis,metabolic diseases, cancer, anorexia, and cardiovascular diseases.

FMT is considered a relatively uncomplicated process, with lower cost and shorter time when compared with conventional antiviral therapy.That is, FMT is thought to be a potentially beneficial treatment for HBV-related diseases in the near future.

At present, the FMT research on HBV-related diseases is still very limited.Accordingly, it is an aspect that deserves intensive study.It is urgent to pay more attention to accumulating our knowledge in the field of FMT therapy to HBV-related disease.In order to evaluate the efficacy and safety of FMT for these diseases, well-designed randomized controlled trials are necessary.Priority should focus on the alteration of composition of the gut microbiota before and after FMT so that researchers can better seek the mechanisms of this therapy.

Acknowledgments

None.

CRediT authorship contribution statement

Jia-Min Lou:Writing - original draft.Zhi-Gang Ren:Funding acquisition, Methodology, Supervision.Ang Li:Formal analysis.Ben-Chen Rao:Data curation.Zu-Jiang Yu:Conceptualization,Funding acquisition, Supervision, Writing - review & editing.

Funding

The study was supported by grants from the National Key Research and Development Program of China ( 2018YFC20 0 0501 ),National S&T Major Project of China ( 2018ZX10301201-008 ),National Natural Science Foundation of China ( 81600506 and 81702757 ), China Postdoctoral Science Foundation ( 2017M610463 and 2018M632814 ).

Ethical approval

Not needed.

Competing interest

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.