Reduced alcohol preference and intake after fecal transplant in patients with alcohol use disorder is transmissible to germ-free mice

Abstract

Alcohol use disorder is a major cause of morbidity, which requires newer treatment approaches. We previously showed in a randomized clinical trial that alcohol craving and consumption reduces after fecal transplantation. Here, to determine if this could be transmitted through microbial transfer, germ-free male C57BL/6 mice received stool or sterile supernatants collected from the trial participants pre-/post-fecal transplant. We found that mice colonized with post-fecal transplant stool but not supernatants reduced ethanol acceptance, intake and preference versus pre-fecal transplant colonized mice. Microbial taxa that were higher in post-fecal transplant humans were also associated with lower murine alcohol intake and preference. A majority of the differentially expressed genes (immune response, inflammation, oxidative stress response, and epithelial cell proliferation) occurred in the intestine rather than the liver and prefrontal cortex. These findings suggest a potential for therapeutically targeting gut microbiota and the microbial-intestinal interface to alter gut-liver-brain axis and reduce alcohol consumption in humans.

The Beneficial Effects of Lactobacillus GG Therapy on Liver and Drinking Assessments in Patients with Moderate Alcohol-Associated Hepatitis

“…Bajaj and associates performed a placebo-controlled randomized clinical trial in patients with cirrhosis and AUD in which FMT from a donor led to short-term lowered alcohol craving/consumption in the FMT group, but not placebo (14). They subsequently transplanted stool from these patients with cirrhosis into germ-free mice and showed that alcohol preference/intake was conferred through FMT (15). Cumulatively, these data suggest a role for dysbiosis and fecal metabolites in both ALD and AUD.…”

The Current and Future State of Microbiome Therapeutics in Liver Disease

“…In alcohol-related cirrhosis, FMT was found to be safe and demonstrated a reduction in short-term and long-term consequences of alcohol use (72). This was transferable to germ-free mice with similar changes in behavior focused on SCFA-producing microbiota but not with supernatants (73). In alcohol-associated hepatitis, open-label phase 1 and 2 trials have shown that nasojejunal tube FMT administration improved outcomes compared with standard-of-care groups and historical controls (74,75).…”

Keratin 18‐M65: A biomarker for early‐stage alcohol‐associated liver disease

“…This further links the gut: liver axis in the early pathogenesis of ALD. There are multiple lines of evidence from both humans and animal models that the microbiome and microbial metabolites play a role in both drinking behavior and alcohol‐related liver injury (Jiang et al, 2023; Kouno et al, 2023; Singhal et al, 2021; Smith et al, 2023; Vatsalya et al, 2023; Wolstenholme et al, 2022). There is also increasing interest in modulating the microbiome as a therapeutic intervention for both AUD and ALD.…”

“…There is also increasing interest in modulating the microbiome as a therapeutic intervention for both AUD and ALD. Indeed, there are recent animal and human studies to support this concept using both fecal transplantation and probiotic therapy (Jiang et al, 2023; Kouno et al, 2023; Singhal et al, 2021; Smith et al, 2023; Vatsalya et al, 2023; Wolstenholme et al, 2022).…”

“…Thus, measurement of K18 by ELISA can both quantify hepatocyte death and can differentiate necrosis from apoptosis (Vatsalya et al, 2020). Several groups have used K18-M65 as both a diagnostic and prognostic biomarker in severe alcohol-associated hepatitis (AH; Atkinson et al, 2020;Bissonnette et al, 2017;Vatsalya et al, 2020;Woolbright et al, 2017). Importantly, K18 more accurately measures the magnitude of cell death in alcohol-associated liver disease (ALD) than the regularly used AST and ALT levels (McClain et al, 2021).…”