Bacteriophage targeting microbiota alleviates non-alcoholic fatty liver disease induced by high alcohol-producing Klebsiella pneumoniae

Abstract

Our previous studies have shown that high alcohol-producing Klebsiella pneumoniae (HiAlc Kpn) in the intestinal microbiome could be one of the causes of non-alcoholic fatty liver disease (NAFLD). Considering antimicrobial resistance of K. pneumoniae and dysbacteriosis caused by antibiotics, phage therapy might have potential in treatment of HiAlc Kpn-induced NAFLD, because of the specificity targeting the bacteria. Here, we clarified the effectiveness of phage therapy in male mice with HiAlc Kpn-induced steatohepatitis. Comprehensive investigations including transcriptomes and metabolomes revealed that treatment with HiAlc Kpn-specific phage was able to alleviate steatohepatitis caused by HiAlc Kpn, including hepatic dysfunction and expression of cytokines and lipogenic genes. In contrast, such treatment did not cause significantly pathological changes, either in functions of liver and kidney, or in components of gut microbiota. In addition to reducing alcohol attack, phage therapy also regulated inflammation, and lipid and carbohydrate metabolism. Our data suggest that phage therapy targeting gut microbiota is an alternative to antibiotics, with potential efficacy and safety, at least in HiAlc Kpn-caused NAFLD.

Increased fecal ethanol and enriched ethanol-producing gut bacteria Limosilactobacillus fermentum, Enterocloster bolteae, Mediterraneibacter gnavus and Streptococcus mutans in nonalcoholic steatohepatitis

“…Our results suggest the potential association of endogenous EtOH production by digestive microorganisms and NASH, and the use of new therapeutic avenues such as antibiotics ( E. bolteae is expected to be sensitive to rifaximin which is effective in NASH in some studies ( Abdel-Razik et al., 2018 2018 ; Boehme et al., 2023 2023 ), fecal transplantation or the use of phage therapy targeting E. bolteae as described by Yuan et al. with Klebsiella pneumoniae ( Gan et al., 2023 ). Future studies will determine ethanol production by the 12 species (81 strains) enriched in NASH patients.…”

Phage therapy: Targeting intestinal bacterial microbiota for the treatment of liver diseases

“… 85 Moreover, oral treatment with a single phage led to the alleviation of HiAlc Kpn-induced steatohepatitis in mice. 106 In a similar preclinical study targeting K. pneumoniae , Ichikawa et al. found that Th17 cell responses were induced by PSC-derived K. pneumoniae , which accelerated liver injury in hepatobiliary injury-prone mice.…”

What are the common downstream molecular events between alcoholic and nonalcoholic fatty liver?

“…Finally, selective elimination of the HiAlc Kpn strain before focal microbiome transplantation prevents NAFLD in recipient mice [ 123 ]. Other data suggest that phage therapy targeting the gut microbiota is an alternative to antibiotics, with potential efficacy and safety, at least in HiAlc Kpn -induced NAFLD [ 124 ]. In NASH patients, an increased abundance of alcohol-producing bacteria corresponds to an elevated blood ethanol concentration, suggesting a role for alcohol-producing microbiota in the pathogenesis of NASH [ 125 ].…”