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Correspondence to editorial on “Bacteroides eggerthii ameliorates metabolic dysfunction-associated steatotic liver disease through host-microbe signaling and highlights 2-hydroxyisocaproate as a potential effector”

Clinical and Molecular Hepatology 2026;32(3):e361-e364.
Published online: December 23, 2025

Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea

Corresponding author : Jung Woo Eun, Department of Gastroenterology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Korea Tel: +82-31-219-4681, Fax: +82-31-219-4680, E-mail: jetaimebin@gmail.com

Editor: Han Ah Lee, Chung-Ang University College of Medicine, Korea

• Received: December 13, 2025   • Accepted: December 17, 2025

Copyright © 2026 by The Korean Association for the Study of the Liver

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Dear Editor,
We sincerely appreciate Prof. Yu and colleagues for their thoughtful and insightful comments on our recent study investigating Bacteroides eggerthii as a potential therapeutic gut microbe in metabolic dysfunction-associated steatotic liver disease (MASLD) [1,2]. The Editorial effectively summarized the emerging landscape of next-generation probiotics (NGPs) and highlighted both the strengths of our findings and the challenges that must be addressed before clinical translation.
NGPs differ from traditional probiotics such as Lactobacillus or Bifidobacterium in that they target specific host–microbe signaling pathways and modulate key metabolic, inflammatory, gut-barrier, and bile-acid regulatory axes. This mechanistic precision aligns well with the multifactorial pathophysiology of MASLD. In our study, we identified a consistent depletion of B. eggerthii in both obese and Korean patients with MASLD and demonstrated in vivo that B. eggerthii administration ameliorated steatosis, inflammation, and fibrosis. Multi-omics analyses showed that B. eggerthii reshapes the gut microbiome and modulates bileacid–related pathways. It also downregulates hepatic genes involved in fatty-acid and bile-acid metabolism (e.g., FGF15, CYP8B1), ultimately enhancing FXR signaling. We further identified 2-hydroxyisocaproate (HICA) as a metabolite commonly elevated in both feces of B. eggerthii-treated mice and B. eggerthii culture, showing anti-steatotic activity in hepatocyte models. Collectively, these findings support B. eggerthii as a promising NGP candidate acting through host–microbe signaling [1].
As pointed out in the Editorial, however, several hurdles remain before B. eggerthii can advance toward clinical application. Human trials are essential to establish efficacy, safety, dose, and treatment duration. This in turn requires scalable manufacturing processes and extensive safety evaluation. Among NGP candidates reported in liver diseases, Akkermansia muciniphila currently appears to be the closest to clinical translation, supported by a more substantial body of human trial data than other species mentioned in the Editorial (Table 1) [3-8]. Because B. eggerthii is a strict anaerobe, industrial-scale cultivation presents an additional challenge. Nevertheless, a recent study demonstrated a feasible strategy for developing strict anaerobes as probiotics: the creation of an oxygen-tolerant variant of Faecalibacterium prausnitzii (DSM 32379) through stepwise oxidative-stress adaptation in an m-SHIRM bioreactor, while preserving key functional properties such as butyrate production and anti-inflammatory activity. Crossfeeding with Desulfovibrio piger further enabled biomass expansion, supporting scalable production [8]. These findings suggest that overcoming extreme oxygen sensitivity is technically achievable and could be applicable to B. eggerthii in the future.
Another potential therapeutic avenue is the use of HICA itself. As a leucine-derived branched-chain hydroxy acid, HICA has been reported to function as an anti-catabolic metabolite that enhances protein synthesis and muscle metabolism [9,10]. Recent work in a dietary model of obesity-linked type 2 diabetes showed that yogurt-derived branched-chain hydroxy acids, including HICA, help preserve glucose homeostasis and mitigate hepatic insulin resistance by acting as cell-autonomous metabolic regulators [11]. While these findings raise the possibility that HICA may contribute to the metabolic benefits of B. eggerthii, human data remain inconsistent. A recent study reported higher circulating HICA levels in moderate compared with mild MASLD, although this result requires cautious interpretation due to small sample size and cohort heterogeneity [12]. Further well-designed clinical studies are clearly needed to clarify whether HICA acts as a marker, mediator, or consequence of metabolic dysfunction in humans.
In conclusion, we thank Prof. Yu and colleagues for their constructive appraisal of our work. We fully agree that future research should focus on establishing scalable production systems, performing rigorous safety evaluations, and conducting human interventional studies to confirm the therapeutic potential of B. eggerthii and related metabolites. We hope that our findings contribute meaningfully to the growing field of microbiome-based therapeutics for MASLD, and we believe that continued collaborative efforts will be essential to advance next-generation probiotics from preclinical discovery to clinical application.

Authors’ contributions

S.S.K. drafted the manuscript, while J.Y.C. and J.W.E. supervised and approved the final version of the manuscript.

Acknowledgements

This work was supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (grant number HR21C1003), and by the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT (MSIT), Republic of Korea (grant numbers RS-2022-NR070489, RS-2024-00422549, RS-2025-00521818, and RS-2025-00562556).

Conflicts of Interest

The authors have no conflicts to disclose.

Table 1.
Overview of human trial evidence for candidate next-generation probiotics and their potential relevance to MASLD
Table 1.
Strain Human clinical trial Population/Indication Study phase & design Main outcomes Relevance to MASLD
Akkermansia muciniphila Yes Overweight/obese adults with insulin resistance [3] Proof-of-concept RCT; double-blind; 3 months (live vs. pasteurized vs. placebo) (NCT02637115) Pasteurized form improved insulin sensitivity; reduced fasting insulin, cholesterol, body weight, fat mass, and hip circumference; improvements in AST, ALT, and GGT; well tolerated Demonstrated metabolic and liver enzyme improvements, suggesting potential relevance for MASLD
Adults with overweight/obese type 2 diabetes [4] Early Phase 2 RCT; double-blind; 12 weeks (NCT04797442) Reduction in body weight, fat mass, and HbA1c among participants with low baseline A. muciniphila levels Confirms metabolic benefits; MASLD-specific efficacy not yet evaluated
Clostridium butyricum (synbiotic with lactulose + Bifidobacterium longum infantis) Yes Liver cirrhosis with BMI <25 kg/m² [5] RCT; 12 weeks (NCT05687409) Reduction of pathogenic taxa; increase in SCFA-producing bacteria; improvement in metabolic milieu No MASLD-specific trial; mechanistically relevant via SCFA production
Bacteroides thetaiotaomicron Yes Adolescents with Crohn’s disease [6] Randomized, double-blind, placebo-controlled, dose-escalation trial (NCT02704728) Well tolerated; evidence of colonization; clinical efficacy not assessed No metabolic or MASLD trials to date
Bacteroides ovatus No Only preclinical data; no human safety or efficacy studies
Bacteroides eggerthii No Only preclinical data; strong MASLD-related efficacy in animal models but no human data
Bacteroides uniformis No direct strain-administration trials Healthy male adults [7] Randomized, double-blind, placebo-controlled; 9 weeks (placebo vs. flaxseed lignans vs. α-cyclodextrin) Endogenous B. uniformis increased; improved endurance exercise performance with α-cyclodextrin No direct supplementation trial; metabolic associations suggest potential MASLD relevance
Faecalibacterium prausnitzii Yes (oxygen-tolerant formulation with Desulfovibrio piger) Healthy adults [8] Randomized, double-blind, placebo-controlled (NCT03728868) Safe; partial engraftment observed Anti-inflammatory properties support MASLD relevance, but no efficacy trials
Coprococcus species No Observed in metabolic association studies; no human intervention trials

This table summarizes only the probiotic strains referenced in the accompanying Editorial, with a focus on their available human clinical evidence and potential relevance to MASLD.[2]

MASLD, metabolic dysfunction-associated steatotic liver disease; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; GGT, gamma-glutamyl transferase; HbA1c, hemoglobin A1c; SCFA, short-chain fatty acid; RCT, randomized controlled trial.

HICA

2-hydroxyisocaproate

MASLD

metabolic dysfunction-associated steatotic liver disease

NGPs

next-generation probiotics
  • 1. Choi J, Yoon MG, Jang SH, Baek GO, Jung HS, Lee NR, et al. Bacteroides eggerthii ameliorates metabolic dysfunction-associated steatotic liver disease through host-microbe signaling and highlights 2-hydroxyisocaproate as a potential effector. Clin Mol Hepatol 2026;32:239-257.
  • 2. Lau HC, Yu J. Bacteroides eggerthii: a new human gut probiotic against metabolic dysfunction-associated steatotic liver disease: Editorial on “Bacteroides eggerthii ameliorates metabolic dysfunction-associated steatotic liver disease through host–microbe signaling and highlights 2-hydroxyisocaproate as a potential effector”. Clin Mol Hepatol 2026;32:1400-1404.
  • 3. Depommier C, Everard A, Druart C, Plovier H, Van Hul M, Vieira-Silva S, et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nat Med 2019;25:1096-1103.
  • 4. Zhang Y, Liu R, Chen Y, Cao Z, Liu C, Bao R, et al. Akkermansia muciniphila supplementation in patients with overweight/obese type 2 diabetes: Efficacy depends on its baseline levels in the gut. Cell Metab 2025;37:592-605.e6.
  • 5. Lu H, Zhu X, Wu L, Lou X, Pan X, Liu B, et al. Alterations in the intestinal microbiome and metabolic profile of patients with cirrhosis supplemented with lactulose, Clostridium butyricum, and Bifidobacterium longum infantis: a randomized placebo-controlled trial. Front Microbiol 2023;14:1169811.
  • 6. Hansen R, Sanderson IR, Muhammed R, Allen S, Tzivinikos C, Henderson P, et al. A double-blind, placebo-controlled trial to assess safety and tolerability of (Thetanix) Bacteroides thetaiotaomicron in adolescent Crohn’s disease. Clin Transl Gastroenterol 2020;12:e00287.
  • 7. Morita H, Kano C, Ishii C, Kagata N, Ishikawa T, Hirayama A, et al. Bacteroides uniformis and its preferred substrate, α-cyclodextrin, enhance endurance exercise performance in mice and human males. Sci Adv 2023;9:eadd2120.
  • 8. Khan MT, Dwibedi C, Sundh D, Pradhan M, Kraft JD, Caesar R, et al. Synergy and oxygen adaptation for development of next-generation probiotics. Nature 2023;620:381-385.
  • 9. Mero AA, Ojala T, Hulmi JJ, Puurtinen R, Karila TA, Seppälä T. Effects of alfa-hydroxy-isocaproic acid on body composition, DOMS and performance in athletes. J Int Soc Sports Nutr 2010;7:1.
  • 10. Sumi K, Sakuda M, Munakata K, Nakamura K, Ashida K. α-Hydroxyisocaproic acid decreases protein synthesis but attenuates TNFα/IFNγ co-exposure-induced protein degradation and myotube atrophy via suppression of iNOS and IL-6 in murine C2C12 myotube. Nutrients 2021;13:2391.
  • 11. Daniel N, Nachbar RT, Tran TTT, Ouellette A, Varin TV, Cotillard A, et al. Gut microbiota and fermentation-derived branched chain hydroxy acids mediate health benefits of yogurt consumption in obese mice. Nat Commun 2022;13:1343.
  • 12. Chen Y, Wang Y, Shen T, Wang N, Bai X, Li Q, et al. Serum metabolic signatures and MetalnFF diagnostic score for mild and moderate metabolic dysfunction-associated steatotic liver disease. J Pharm Biomed Anal 2025;260:116772.

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Correspondence to editorial on “Bacteroides eggerthii ameliorates metabolic dysfunction-associated steatotic liver disease through host-microbe signaling and highlights 2-hydroxyisocaproate as a potential effector”
Clin Mol Hepatol. 2026;32(3):e361-e364.   Published online December 23, 2025
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Correspondence to editorial on “Bacteroides eggerthii ameliorates metabolic dysfunction-associated steatotic liver disease through host-microbe signaling and highlights 2-hydroxyisocaproate as a potential effector”
Clin Mol Hepatol. 2026;32(3):e361-e364.   Published online December 23, 2025
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Correspondence to editorial on “Bacteroides eggerthii ameliorates metabolic dysfunction-associated steatotic liver disease through host-microbe signaling and highlights 2-hydroxyisocaproate as a potential effector”
Correspondence to editorial on “Bacteroides eggerthii ameliorates metabolic dysfunction-associated steatotic liver disease through host-microbe signaling and highlights 2-hydroxyisocaproate as a potential effector”
Strain Human clinical trial Population/Indication Study phase & design Main outcomes Relevance to MASLD
Akkermansia muciniphila Yes Overweight/obese adults with insulin resistance [3] Proof-of-concept RCT; double-blind; 3 months (live vs. pasteurized vs. placebo) (NCT02637115) Pasteurized form improved insulin sensitivity; reduced fasting insulin, cholesterol, body weight, fat mass, and hip circumference; improvements in AST, ALT, and GGT; well tolerated Demonstrated metabolic and liver enzyme improvements, suggesting potential relevance for MASLD
Adults with overweight/obese type 2 diabetes [4] Early Phase 2 RCT; double-blind; 12 weeks (NCT04797442) Reduction in body weight, fat mass, and HbA1c among participants with low baseline A. muciniphila levels Confirms metabolic benefits; MASLD-specific efficacy not yet evaluated
Clostridium butyricum (synbiotic with lactulose + Bifidobacterium longum infantis) Yes Liver cirrhosis with BMI <25 kg/m² [5] RCT; 12 weeks (NCT05687409) Reduction of pathogenic taxa; increase in SCFA-producing bacteria; improvement in metabolic milieu No MASLD-specific trial; mechanistically relevant via SCFA production
Bacteroides thetaiotaomicron Yes Adolescents with Crohn’s disease [6] Randomized, double-blind, placebo-controlled, dose-escalation trial (NCT02704728) Well tolerated; evidence of colonization; clinical efficacy not assessed No metabolic or MASLD trials to date
Bacteroides ovatus No Only preclinical data; no human safety or efficacy studies
Bacteroides eggerthii No Only preclinical data; strong MASLD-related efficacy in animal models but no human data
Bacteroides uniformis No direct strain-administration trials Healthy male adults [7] Randomized, double-blind, placebo-controlled; 9 weeks (placebo vs. flaxseed lignans vs. α-cyclodextrin) Endogenous B. uniformis increased; improved endurance exercise performance with α-cyclodextrin No direct supplementation trial; metabolic associations suggest potential MASLD relevance
Faecalibacterium prausnitzii Yes (oxygen-tolerant formulation with Desulfovibrio piger) Healthy adults [8] Randomized, double-blind, placebo-controlled (NCT03728868) Safe; partial engraftment observed Anti-inflammatory properties support MASLD relevance, but no efficacy trials
Coprococcus species No Observed in metabolic association studies; no human intervention trials
Table 1. Overview of human trial evidence for candidate next-generation probiotics and their potential relevance to MASLD

This table summarizes only the probiotic strains referenced in the accompanying Editorial, with a focus on their available human clinical evidence and potential relevance to MASLD.[2]

MASLD, metabolic dysfunction-associated steatotic liver disease; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; GGT, gamma-glutamyl transferase; HbA1c, hemoglobin A1c; SCFA, short-chain fatty acid; RCT, randomized controlled trial.