The role of gut microbiome and fecal microbiota transplantation in liver cancer and related complications: mechanisms and therapeutic potentials
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, , Abstract
Liver cancer is the sixth commonest cancer and the third leading cause of cancer mortality worldwide. Accumulating evidence suggests a pivotal role of the gut microbiome in the progression of chronic liver disease and the subsequent development of liver cancer. Additionally, gut microbiome has been shown to contribute to the hosts’ antitumor responses following immunotherapy and chemotherapy for liver cancers, highlighting the therapeutic potential of gut microbiome modulation in enhancing treatment efficacy and reducing drug resistance. Fecal microbiota transplantation (FMT), a novel therapeutic modality to deliver a healthy donor's stool by endoscopy or capsule, has demonstrated potential in managing liver diseases and cancers by restoring and modulating the recipient’s gut microbiome composition. However, existing data on the clinical application of FMT in liver cancers are still limited. This review summarizes the underlying roles and mechanisms of gut microbiome in liver cancer and discusses the therapeutic potential of FMT in liver cancer treatment and the management of its related complications (e.g., hepatic encephalopathy).
Keywords
INTRODUCTION
Primary liver cancer is the sixth commonest cancer and the third leading cause of cancer mortality worldwide in 2020, with approximately 906,000 new cases and 830,000 deaths respectively[1]. Primary liver cancer includes 75%-85% of hepatocellular carcinoma (HCC), 10%-15% of intrahepatic cholangiocarcinoma(CCA), and some other rarer histological subtypes[1]. Hepatitis B, hepatitis C, heavy alcohol consumption, non-alcoholic fatty liver disease (NAFLD), type 2 diabetes, and smoking are major risk factors for HCC[2]. Although the molecular pathways leading to carcinogenesis in HCC are complex, recent evidence suggests that the gut microbiome plays a significant role in the progression of chronic liver disease and the subsequent development of HCC[3,4]. In addition, emerging evidence indicates that the gut microbiome may play a role in the host responding to antitumor treatment during immunotherapy and chemotherapy. This highlights the therapeutic potential of gut microbiome modulation in enhancing treatment efficacy and reducing drug resistance for liver cancer[3,4].
FMT is a novel treatment modality to modulate and restore the recipient’s gut microbiome composition by transplanting the functional gut microbiota from healthy donors to patients[5]. FMT solution can be delivered into the recipient’s gastrointestinal tract through various routes such as oral capsules, esophagogastroduodenoscopy, nasojejunal tube, rectal enema, and colonoscopy[6,7]. FMT has shown high efficacy in patients with recurrent and refractory Clostridioides difficile infection (CDI), which has now been recommended as a viable treatment option according to the United States, British, and European guidelines[8-11]. FMT has also demonstrated therapeutic potential in liver diseases, including alcoholic hepatitis[12], NAFLD[13], hepatitis B[14], and liver cirrhosis[15,16].
This review aims to summarize the current literature by exploring the mechanism of the gut microbiome in liver cancer and related complications and to discuss the recent advances in the role of FMT in antitumor therapies and responses.
DYSBIOSIS IN LIVER CANCERS
HCC is usually the sequelae of chronic liver disease (CLD). The majority of HCCs (80%-90%) are found in patients with advanced fibrosis or cirrhosis[17,18]. The development of HCC in patients with viral hepatitis is associated with persistent liver inflammation, but the precise mechanism in NAFLD cases remains unclear[19]. There is increasing evidence from both animal and human studies that suggests a connection between gut microbiota and the development of HCC. Changes in gut microbiome composition and microbiome-derived metabolites are thought to be responsible for promoting the progression of CLD and HCC occurrence[19,20].
It is widely acknowledged that dysbiosis occurs in HCC[21]. The α-diversity, which refers to the number of species present in each stool sample, has been found to be notably reduced in patients with HCC[22-24]. In addition, tissue samples from HCC also showed reduced α-diversity compared to patients with benign liver disease (e.g., hemangioma)[25]. At the phylum level, compared with the fecal microbiota of healthy individuals, the abundance of Firmicutes species was decreased. In contrast, that of Proteobacteria species was increased in both CLD and HCC patients[26]. In addition, the intrahepatic analysis indicated that HCC patients had a higher abundance of specific microbes in the Stenotrophomonas genus and the Proteobacteria phylum. This specific bacterium was very rare among the normal control group[25]. The dysbiosis in HCC also displayed a significant decrease in the relative abundance of short-chain fatty acids (SCFAs)-producing bacteria, such as Ruminococcaceae, Butyricicoccus, and Lachnospiraceae[27,28].
The etiologies of HCC can be divided into viral-related and non-viral-related, with different degrees of dysbiosis. Liu et al. compared the microbiota profile of HBV-related HCC (HBV-HCC) and non-HBV non-HCV related HCC (NBNC-HCC) and found that the HBV-HCC patients had a much higher level of species richness in fecal microbiota than NBNC-HCC patients[29]. An increase in the levels of proinflammatory bacteria (Escherichia-Shigella, Enterococcus) and a decrease in the levels of anti-inflammatory bacteria
Microbial dysbiosis has also been reported in different samples of patients with CCA[23,30-33]. An increased abundance of Prevotella species was identified in the oral, gut, and bile samples in patients with CCA[23]. In addition, the abundance of Actinomyces has been found to increase in the gut and bile[30] but decreased in oral samples in patients with CCA[32]. Actinomyces is associated with the disruption of mucosal membranes[34]. Zhang et al. found that the impaired gut barrier function could make gut-derived bacteria and lipopolysaccharide into hepatocytes, increasing polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) to create an immunosuppressive environment, which will promote liver carcinogenesis[35]. The increased Actinomyces in the gut might be associated with the impaired gut barrier function, leading to the increase of Actinomyces in bile and the association with CCA. Therefore, it is now believed that dysbiosis has a pivotal role in the pathogenesis of both HCC and CCA.
GUT MICROBIOME-RELATED PATHOGENESIS OF LIVER CANCERS AND COMPLICATIONS
The hepatic portal circulation is a process that transports nutrients from the intestines to the liver. During this process, the liver is exposed to metabolites and products derived from gut microbiota. This crosstalk between the gut and liver is termed as “gut-liver-axis”[3]. As alcoholic liver disease (ALD), NAFLD, liver cirrhosis, and associated complications are closely linked to increased bacterial translocation and dysbiosis[36,37], it is thought to be one of the key drivers that lead to hepatic microenvironment inflammation and progression toward cirrhosis and HCC[3,4].
Experiments in animal models have provided pre-clinical evidence that both microbiota-derived metabolites and their activated pathways may play a role in the development of HCC. Fox et al. investigated the role of a specific bacteria, Helicobacter hepaticus, in promoting tumorigenesis by chemicals or viruses in a transgenic mice model[38]. Their results showed that colonization with H. hepaticus in the gut could promote aflatoxin- and HCV transgene-induced HCC without hepatic bacterial translocation or induction of hepatitis[38]. In addition, the study from Dapito et al. using an HCC mice model induced by diethylnitrosamine (DEN) and hepatotoxin carbon tetrachloride (CCl4) further demonstrated that gut microbiota and Toll-like receptor 4 (TLR4) activation were essential in the hepatocarcinogenesis in chronically injured livers[39]. It was demonstrated by Zhang et al. that long-term DEN treatment led to a notable reduction in the level of Lactobacillus, Bifidobacterium, and Enterococcus species and inflammation in the gut[20]. The presence of penicillin or dextran sulfate sodium (DSS)-induced intestinal dysbiosis or inflammation significantly increases the risk of tumor formation[20]. Supplementation with probiotics significantly alleviated gut dysbiosis, improved intestinal inflammation, and suppressed liver tumor growth and multiplicity[20]. Another experiment conducted by Yoshimoto et al. investigated obesity-related HCC by using a 7,12-dimethylbenz[a]anthracene (DMBA)-high-fat diet (HFD)-induced HCC mice model[40]. They found that obesity could lead to a rise in deoxycholic acid (DCA) levels. Elevated levels of DCA may trigger the senescence-associated secretory phenotype (SASP) in hepatic stellate cells, in turn causing the release of inflammatory and tumor-promoting molecules in the liver, promoting the progression of HCC in mice[40]. Similarly, Zhang et al. used a high-fat/high-cholesterol (HFHC) diet-induced NAFLD-HCC model[41]. They were able to demonstrate that cholesterol-induced NAFLD-HCC formation was associated with gut microbiome dysbiosis. They also used germ-free mice receiving FMT products from donor mice fed with HFHC, which led to hepatic lipid accumulation, inflammation, and cell proliferation[41].
Epidemiological data showed that the incidence rates of HCC in males were two or three times higher than that in females[42], and it is well-acknowledged that sex hormones play a significant role in the gender disparity of HCC[43,44]. It is commonly considered that estrogens are protective, while androgens promote hepatocellular carcinogenesis[45]. Sex-specific enterotypes may influence the metabolism of hormones, subsequently affecting the development of HCC[46,47]. In addition, gut microbiota might be another source of sex hormones, as Clostridium scindens has been reported to convert glucocorticoids into androgens[48]. Mouse experiments showed that the bacteria involved in bile acid metabolism (e.g., Clostridiales, Corynebacterium, Bacillus, Desulfovibrio, Rhodococcus) were different between males and females, and the differences became more significant after induction of HCC model (streptozotocin-high fat diet)[49]. This study revealed that gut microbiota was involved in the sex-dependent effects on bile acid metabolism, which plays a pivotal role in the development of non-alcoholic steatohepatitis (NASH) and NASH-associated HCC[50,51]. On the other hand, Huang et al. studied the change of gut microbiota in male and female HCC mice models (i.e., liver-specific Tsc1 knockout mice)[52]. They found that the female mice had dysbiosis earlier than male mice in the process of developing HCC[52]. Specific bacteria associated with the risk of HCC in males (e.g., Paraprevotella, Paraprevotellaceae) and females (e.g., Allobaculum, Erysipelotrichaceae) were observed[52]. These studies based on animal models revealed the sex-dependent involvement of gut microbiota in the pathogenesis of HCC. More well-designed studies involving human or human-to-mice models to investigate the role of gut microbiota in the sexual dimorphism of HCC are needed.
The majority of HCC patients suffer from concurrent liver cirrhosis, which is not only the risk factor for liver cancers but also related complications (e.g., hepatic encephalopathy, HE)[53,54]. Concurrent HE can interfere with the antitumor therapy and thus negatively affect the prognosis of liver cancer. Multiple studies have demonstrated that the beneficial SCFAs-producing bacteria (i.e., Lachnospiraceae and Ruminococcaceae) were decreased, and the potentially pathogenic (i.e., Enterobacteriaceae) were increased in patients with HE[36,55-57]. This microbial profile has also been associated with cognitive impairment and the presence of systemic inflammation[57,58]. These emerging data support that the brain and the "gut-liver axis" are closely intertwined, and possibly these clinical manifestations are reflective of the "gut-liver-brain axis”[59]. The increasing understanding of the influence of gut microbiota on the development of liver cancers provides valuable insight into the use of microbiome modulation as a potential therapy for managing liver cancer and its associated complications.
THERAPEUTIC POTENTIAL OF MICROBIOME MODULATION IN ONCOLOGICAL TREATMENT FOR LIVER CANCER
Treatment options for liver cancer include surgical resection, chemotherapy, radiotherapy, radiofrequency ablation, hepatic artery chemoembolization, immunotherapy, and liver transplantation. In the case of advanced cancers, systemic therapy and multikinase inhibitors such as sorafenib and lenvatinib are the mainstay of treatment[60,61]. However, fewer than one-third of patients can benefit from these treatments as drug resistance and treatment-related adverse events are major roadblocks[62]. On the other hand, since 2017, the US Federal Drug Administration has approved immune checkpoint inhibitors (ICIs) as a second-line treatment for advanced HCC with sorafenib resistance. The combination of atezolizumab and bevacizumab has proven superior to sorafenib[63]. An infusion regimen termed STRIDE (Single Tremelimumab Regular Interval Durvalumab) significantly improved overall survival versus sorafenib (36 months overall survival rate 30.7% vs. 20.2%)[64]. However, the overall success rate of ICI monotherapy or combination therapy has been reported to be only around 36%[65,66]. In addition, some patients develop drug resistance after treatment. Therefore, it would be beneficial if there is an adjunctive therapy to enhance the treatment efficacy and reduce the risk of drug resistance for chemotherapy and immunotherapy.
Chemotherapy and targeted agents
The gut microbiota modulates the host response to chemotherapeutic drugs in two major domains: drug efficacy and toxicity [Table 1][67]. Jin et al. found that gut microbiota can enhance the chemosensitivity of HCC to 5-fluorouracil in vivo by increasing curcumin bioavailability[68]. On the other hand, gut microbiota alteration may also affect drug toxicity and treatment-related adverse events (AEs). Inukai et al. compared the gut microbiota in patients who developed diarrhea and those who did not after receiving Lenvatinib treatment for HCC[69]. The group with diarrhea showed a higher relative abundance of Parabacteroides and Prevotella[69]. Similarly, Yamamoto et al. also found an increased relative abundance of Butyricimonas, a butyric acid-producing bacteria, in the asymptomatic group than in the group with diarrhea[70]. Butyrate has a vital role in suppressing inflammatory and allergic responses[70]. Based on the above preliminary findings, chemotherapy combined with adjunctive microbiota modulation may be a promising therapeutic approach.
Gut microbiome alteration in antitumor therapies for liver cancer
| Reference | Models | Therapies | Diseases | Implicated microbiota | Sequencing method |
| Inukai et al. | Human | Chemotherapy | HCC (diarrhea and non-diarrhea) | ↑ Parabacteroides and Prevotella in the diarrhea group | 16S rRNA gene sequencing |
| Yamamoto et al.[70] | Human | Chemotherapy | HCC (diarrhea and non-diarrhea) | ↑ Butyricimonas, ↓ Citrobacter, Peptostreptococcus, and Staphylococcaceae in non-diarrhea group | 16S rRNA gene sequencing |
| Jin et al.[68] | Mice | Chemotherapy (curcumin combined with 5-fluorouracil) | HCC | ↑ Richness (Chao 1 index); curcumin treatment significantly ↑ Bifidobacterium and Lactobacillus in gut | 16S rDNA sequencing |
| Wu et al.[75] | Human | Immunotherapy (anti-PD-1) | HCC (R and NR) | ↑ α-diversity (Shannon and inverse Simpson indexes) in R; ↑ Faecalibacterium, Blautia, Lachnospiracea incertae Sedis, Megamonas, Ruminococcus, Coprococcus, Dorea and Haemophilus in R; ↑ Atopobium, Leptotrichia, Campylobacter, Allisonella, Methanobrevibacter, Parabacteroides, Bifidobacterium, and Lactobacillus in NR | 16S rRNA gene sequencing |
| Lee et al.[78] | Human | Immunotherapy (ICIs) | HCC (R and NR) | ↑ Prevotella 9 in NR, ↑ Lachnoclostridium, Lachnospiraceae, and Veillonella in R; ↑Lachnoclostridium and ↓ Prevotella 9 were associated with better overall survival | 16S rRNA gene sequencing |
| Chung et al. | Human | Immunotherapy (nivolumab) | HCC (R and NR) | NR: a skewed Firmicutes/Bacteroidetes ratio and a ↓ Prevotella/Bacteroides ratio; presence of Akkermansia species was associated with good response | 16S rRNA gene sequencing |
| Shen et al.[108] | Human | Immunotherapy (ICIs) | HCC (R and NR) | ↑Bifidobacterium, Coprococcus, and Acidaminococcus- in patients with disease control | 16S rRNA gene sequencing |
| Zheng et al. | Human | Immunotherapy (anti-PD-1 antibodies) | HCC | ↑ Four Lactobacillus species (L. oris, L. mucosae, L. gasseri, and L. vaginalis), Bifidobacterium dentium and Streptococcus thermophilus in R | Metagenomic sequencing |
| Mao et al.[109] | Human | Immunotherapy (anti-PD-1) | HCC or advanced biliary tract cancers | ↑ Ruminococcus calidus and Erysipelotichaceae bacterium-GAM147 in response. ↑ Veillonellaceae in NR | Metagenomic sequencing |
| Li et al.[84] | Human and mice | Radiotherapy | HCC (R and NR) | ↓ Diversity in NR; the distribution of the R group samples was closer to healthy control group samples; At the genus level, ↑ Faecalibacterium was observed in the healthy control and R group; ↑ order Clostridiales, family Ruminococcaceae, and genus Faecalibacterium in the R group; ↑ order Lactobacillales in the NR group | 16S rRNA sequencing |
| Bian et al.[86] | Rabbit | Transarterial chemoembolization | HCC | ↑Ruminococcus and Roseburia; ↓ Bacteroides; Parabacteroides and Escherichia after surgery | qPCR |
Immunotherapy
Immunotherapy is a promising oncological treatment by modulating the interaction between the host's immune system and cancer cells. Emerging evidence demonstrates the close crosstalk between the gut microbiota and patients’ response to ICIs [Table 1]. For example, the role of gut microbiota in modulating treatment response among patients on ICI targeting programmed cell death protein 1 (anti-PD-1) has garnered increasing attention in recent years[71,72]. Zheng et al. collected stool samples in HCC patients who received immunotherapy and revealed that responders had higher taxa richness and more gene counts than non-responders[73]. Responders were enriched with some beneficial species, such as Akkermansia muciniphila and Ruminococcaceae spp[73]. Similarly, Chung et al. proposed that a skewed Firmicutes/Bacteroidetes ratio and a low Prevotella/Bacteroides ratio could be predictive markers of non-responders among HCC patients receiving ICIs[74]. In contrast, the presence of Akkermansia species predicted a good response[74]. Wu et al. also found that responders had a higher level of α-diversity at baseline than non-responders[75]. They also profiled the serum metabolites and found that responders were enriched with Ruminococcus which was positively correlated with serum galactaric acid[75]. Furthermore, Routy et al. performed FMT on germ-free or antibiotic-treated mice using fecal samples from epithelial cancer patients who responded to ICIs and found that it could show the antitumor effects of PD-1 blockade, while FMT from non-responders could not restitute the same effect[76]. In a subgroup of patients with primary PD-1-refractory melanoma, FMT using a donor from the anti-PD1 responder could overcome drug resistance and re-capture anti-PD1 treatment response among 40% (6/15) of them by re-programming the gut microbiome and tumor microenvironment[77]. Metagenomics analysis revealed correlations between the relative abundance of A. muciniphila and clinical responses to ICIs[76]. Oral administration of A. muciniphila after FMT in non-responders has been shown to restore the efficacy of PD-1 blockade[76]. In addition, microbiota-derived metabolites also showed an association with clinical outcomes in patients with HCC receiving ICIs[78]. Responders had a significantly higher level of secondary bile acids[78]. If these findings can be replicated, modulating gut microbiota before immunotherapy by FMT from selected donors enriched in certain favorable species may potentially increase the clinical response rate of immunotherapy for liver cancer. In addition, subgroup analyses of survival outcomes according to clinical trials which evaluated the efficacy of ICIs revealed a discrepancy between viral HCC and non-viral HCC[79-82], implying a potential influence of tumor etiologies on treatment response[83]. Considering the variation in dysbiosis[29], more studies are needed to support the gut microbiome modulation before immunotherapy based on the etiologies of HCC.
Locoregional therapies
The role of gut microbiota in other locoregional treatments for liver cancer has also attracted considerable interest recently [Table 1]. Li et al. analyzed the fecal microbiota from HCC patients who received radiotherapy and found that the distribution of microbiota from responders was closer to that found in healthy controls[84]. Responders were enriched with specific bacteria at the genus level, such as Faecalibacteriu, while non-responders had a high abundance of members of the genus Streptococcus[84]. Further animal experiments demonstrated that gut dysbiosis induced by antibiotics significantly impaired radiotherapy-induced T-cell infiltration and that FMT could restore the antitumor effects of radiotherapy[84].
Another treatment option for intermediate and advanced liver cancer is transarterial chemoembolization (TACE), using localized high concentrations of chemotherapy agents and embolizing feeding vessels by oil iodide emulsion[85]. Bian et al. conducted TACE in rabbit HCC models and found that the procedure partially reversed the tumor-induced dysbiosis, improving the intestinal barrier and liver functions and decreasing the lipopolysaccharide (LPS) level in the blood[86]. Some key operational taxonomic units (OTUs) were closely associated with clinical factors, which provides a theoretical basis for the therapy combination of TACE with microbiota-targeted intervention in the future[86].
FMT IN LIVER CANCERS AND RELATED COMPLICATIONS
Endoscopic procedures of FMT
FMT can be delivered into patients’ gastrointestinal tract via several routes, such as esophagogastroduodenoscopy (EGD), colonoscopy, feeding tubes, or rectal enemas[87]. Fresh or frozen fecal suspensions can be delivered into the duodenum or colon through the working channel of the flexible endoscope. Caution needs to be exercised when FMT is given by EGD in patients with a history of stomach or duodenal surgery to avoid adverse events such as aspiration[88]. FMT through colonoscopy allows for the concomitant diagnosis of colonic diseases and may be a preferable route in some situations[89,90].
Current evidence of FMT in liver cancers and related complications
To date, published data on FMT in liver cancer treatment is unavailable. Yet, it is worth noting that there is a recently registered clinical trial to investigate the effect of FMT in overcoming drug resistance to atezolizumab/bevacizumab among patients with liver cancers, which has been registered in ClinicalTrials.gov (NCT05690048) [Table 2]. Apart from atezolizumab and bevacizumab, the intervention group will receive three days of oral vancomycin followed by two rounds of FMT capsules, compared with placebo capsules in the control group. We eagerly await the results of this trial.
Application of FMT in liver cancer and related complications
| Reference | Model /study type | Disease | FMT details | Clinical outcome | Implicated microbiota |
| Clinicaltrial.gov: NCT05690048 | Human/phase II, single blind, RCT, | Liver cancer (unresectable HCC, BCLC stage C) | FMT via capsule (50 g of fecal matter) on day 0 and day 21 | The primary outcomes are differential tumoral CD8 T-cell infiltration and adverse event documentation of FMT | NA |
| Clinicaltrial.gov: NCT05170971 | Human/open label | Liver failure | Four times of FMT every 5 days, follow-up for 2 months | The primary outcomes are the change in liver function, coagulation function, MELD score, clinical manifestations, safety and adverse events and change of proinflammatory cytokine | The change in gut microbiota will be checked |
| Bloom et al.[91] | Human/open label (10 subjects) | HE | FMT capsules 5 times over 3 weeks, follow-up for 6 months | The PHES improved after three doses and five doses of FMT, and four weeks after the fifth dose of FMT. One SAE was extended‐spectrum beta‐lactamase Escherichia coli bacteremia | Responders had higher levels of Bifidobacterium and other beneficial species at baseline and throughout the study |
| Bajaj et al.[16] | Human/phase 1, RCT (20 subjects) | HE | 15 FMT capsules (universal donor with high Lachnospiraceae and Ruminococcaceae relative abundance), follow up for 5 months | All subjects tolerated the procedures (EGD, sigmoidoscopy and capsule); ↓ SAEs and number of patients with SAEs in the FMT group; ↑ improvement in brain function in the FMT group compared to baseline | In the duodenum, ↑ Ruminococcaceae and Bifidobacteriaceae and ↓ Veillonellaceae and Streptococcaceae post-FMT compared to pre-FMT |
| Bajaj et al.[15] | Human/RCT (20 subjects) | HE | Three frozen FMT units (90 mL total) were administered by enema and retained for 30 min, follow-up for five months | ↓SAE in FMT group compared to SOC group (8 vs. 2); Five SOC group and no FMT participants developed further HE. Cognition improved in FMT, but not SOC group | ↑ Lactobacillaceae, Bifidobacteriaceae post-FMT; patients in the FMT arm showed ↑ Lachnospiraceaeae and Ruminococcaceae after FMT |
| Sharma et al.[110] | Human/open label (13 subjects) | Alcohol-associated acute-on-chronic liver failure | FMT through nasojejunal tube from selected family members, follow up 3 months | Survival at 28 and 90 days was significantly better in the FMT arm (100% vs. 60%; 53.84% vs. 25%). More HE and ascites resolved in the FMT group compared to the SOC group (100% vs. 57.14%; 100% vs. 40%). Adverse events were similar in both groups | NA |
| Huang et al.[111] | Rats | portal hypertension and portosystemic collaterals | FMT by oral gavage | FMT ↓ portal pressure in cirrhotic rats | ↓Lachnospiraceae in cirrhotic rats. FMT ↑ Bifidobacterium |
On the other hand, more published data are available to demonstrate the efficacy and safety of FMT in liver cancer-related complications [Table 2]. FMT is now a potential therapeutic option for HE. Bajaj et al. conducted a randomized controlled trial (RCT) investigating the safety and efficacy of FMT from donors with high levels of Lachnospiraceae and Ruminococcaceae[15]. The results showed that patients receiving a single FMT enema developed less severe adverse events (SAE) (20% vs. 80%) and less recurrent HE (0% vs. 50%) compared with the control group (who were given the standard of care)[15]. Two SAEs (i.e., hospitalization) in the FMT group were considered unrelated to the FMT by the independent Data Safety Monitoring Board[15]. Furthermore, FMT group showed improved cognition, but the control group did not[15]. Microbiome analysis indicated that, after FMT, a significant increase was found in the relative abundance of Lachnospiraceaeae and Ruminococcaceaen[15]. Based on these findings, Bajaj et al. conducted another RCT treating patients with HE by FMT capsules from a single donor who had enriched Lachnospiraceaeae and Ruminococcaceae, demonstrating that oral FMT capsules were safe and well-tolerated even in patients with cirrhosis and recurrent HE[16]. This trial also confirmed the efficacy of FMT in improving duodenal mucosal diversity, dysbiosis, and resolution of HE. Similarly, a recent study investigated the efficacy and safety of FMT capsules from different donors in HE[91]. They found that the levels of Bifidobacterium and other known beneficial bacteria at baseline and throughout the study were higher in responders[91]. Moreover, the fecal SCFAs levels from donors were the lowest among recipients with worse cognitive outcomes[91]. These data suggested that the efficacy of FMT can be affected by recipient and donor effects. More data exploring the crosstalk between the microbiome of donor and recipient are needed before more definitive conclusions can be drawn.
LIMITATIONS AND FUTURE PERSPECTIVE
Although the safety of FMT has been demonstrated in patients with CDI[90,92,93], inflammatory bowel diseases (IBD)[94-98], other types of cancers[77,99,100], graft versus host disease (GVHD)[101,102], and critically ill patients hospitalized in the intensive care unit (ICU)[103], safety issues relating to FMT in patients with liver cirrhosis and liver cancer should be taken into consideration. One SAE of extended-spectrum beta-lactamase (ESBL) Escherichia coli bacteremia has been reported previously[91]. Portal hypertension, which results in increased intestinal permeability and impaired barrier function, may induce additional risks to bacterial translocation, leading to an excessive risk of bacteremia. Recently, a new methodology based on an automatic purification system of FMT, known as washed microbiota transplantation (WMT), showed lower AE rates than traditional manual methods[97,104], WMT was regarded as a safer and cleaner type of FMT[105,106], which could be an alternative option in high-risk patients with liver cancers and related complications. In addition to the safety issues, cost-effectiveness is another critical area worth further study. A multidisciplinary team, including endoscopists, hepatologists, oncologists, microbiologists, pharmacists, and other related healthcare professionals, can work together to develop an appropriate and pragmatic strategy to help these patients. The primary diagnosis, cancer stage, complications, microbiota profiles, and oncological therapies should be considered on an individualized basis to determine the optimal delivery route, dose, and frequency of FMT. Selective microbiota transplantation (SMT) by matching selected donors could be considered to reduce the potential infective risks further. Under the premise of ensuring safety, FMT and other microbiome modulation modalities can be considered adjunctive therapy for liver cancer and related complications[107].
CONCLUSION
In conclusion, the role of gut microbiota modulation in patients with liver cancer and related complications is biologically plausible and supported by a growing body of literature. More studies on efficacy and safety are needed if FMT is to be incorporated into mainstream clinical applications.
DECLARATIONS
Authors’ contributionsDid literature review, drafted and revised the manuscript: Dai M
Revised the manuscript: Lau LHS, Lui RN
Availability of data and materialsNot applicable.
Financial support and sponsorshipNone.
Conflicts of interestLau LHS has received research grant support from GenieBiome Ltd. Lau LHS has served as a lecture speaker for Olympus, Boston Scientific, Pfizer, and GenieBiome Ltd. Lui NR has served as an advisory board member for Gilead Sciences and as a speaker for GenieBiome, Gilead Sciences, and Pierre Fabre, and owns equity in Pfizer.
Ethical approval and consent to participateNot applicable.
Consent for publicationNot applicable.
Copyright© The Author(s) 2023.
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Dai, M.; Lui R. N.; Lau L. H. S. The role of gut microbiome and fecal microbiota transplantation in liver cancer and related complications: mechanisms and therapeutic potentials. Hepatoma. Res. 2023, 9, 39. http://dx.doi.org/10.20517/2394-5079.2023.33
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