Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, affecting 25% of the global population [
1]. MASLD involves a spectrum of liver pathologies. About 20% of patients with simple steatosis develop metabolic dysfunction-associated steatohepatitis (MASH), which may further advance to fibrosis, cirrhosis, and eventually liver malignancy. While MASLD is the consequence of intricate interplay among host genetic/epigenetic and environmental factors [
2], recent evidence has highlighted the pivotal roles of gut microbiota in MASLD. In MASLD, the crosstalk between human intestines and liver is greatly interrupted by gut microbial dysbiosis, causing impaired intestinal barrier, endotoxaemia, and dysregulated microbes-mediated metabolism, together contributing to disease development and progression [
3].
Numerous studies have profiled dysbiotic microbial alterations in the development and progression of MASLD. Of note, while certain species such as
Faecalibacterium prausnitzii, Eubacterium, and
Coprococcus are consistently associated with MASLD, the changes of many other species (e.g.,
Bacteroides, Ruminococcus) are greatly varied across studies [
3]. This discrepancy is most likely due to the gut microbiota, which is readily influenced by environmental factors including diets, geographical region, and ethnicity [
4]. To evaluate microbial alterations specific to Koreans, a recent study by Choi et al. [
5] compared the gut microbiota between 148 patients with MASLD and 50 healthy individuals. The abundance of
Blautia and
Ruminococcus gnavus is increased in patients with MASLD, in contrast to the depletion of
Bacteroides and
Alistipes. Choi et al. [
5] further classified the 148 patients with MASLD into obese and non-obese subgroups based on body mass index. In general, about 3–30% of global MASLD cases occur in individuals without obesity, while microbiota composition is markedly different between patients with obese MASLD and non-obese MASLD [
6]. Through multiple pairwise comparisons, Choi et al. [
5] identified bacterial species that are consistently altered in disease conditions, highlighting the depletion of
Bacteroides eggerthii (B. eggerthii) in both obese MASLD and non-obese MASLD.
B. eggerthii is an anaerobic Gram-negative bacterium resident in the human gut microbiota. Its effects on humans have been controversial, while
B. eggerthii protects against chemotherapy-induced diarrhoea [
7], other studies reported its immunostimulatory role and association with colitis [
8,
9]. To validate
in silico sequencing findings, Choi et al. [
5] established a mouse model of MASLD by Western diet feeding, concomitant with
B. eggerthii administration. Indeed,
B. eggerthii treatment not only improves MASLD by reducing liver damage and lipid accumulation, but also alleviates fibrosis severity in mice.
B. eggerthii is able to colonise in mouse colon, where it exhibits protective function against MASLD by restoring the gut microbiota and boosting the activity of bile salt hydrolase. Through transcriptomic analysis, Choi et al. [
5] demonstrated that
B. eggerthii downregulates hepatic genes related to fatty acid and bile acid metabolism (e.g., FGF15, CYP8B1) and promotes farnesoid X receptor signalling, thereby normalising lipid and bile acid metabolic regulators. Mechanistically,
B. eggerthii secretes 2-hydroxyisocaproic acid (HICA) to reduce lipid accumulation and alleviate MASLD. HICA is a metabolite mainly produced by lactic acid bacteria [
10], capable of inhibiting the growth of microbial pathogens including
Enterococcus faecalis, Candida albicans, and
Aspergillus [
11,
12]. In addition to its antimicrobial activity, Choi et al. [
5] reported the anti-steatotic function of HICA, collectively showing that
B. eggerthii generates HICA to attenuate MASLD development by mediating lipid and bile acid metabolism.
Traditional probiotics, particularly
Lactobacillus and
Bifidobacterium, can treat MASLD by improving liver function and reducing blood glucose levels in patients [
13]. Meanwhile, recent advance in microbial profiling technology has facilitated the identification of potentially beneficial bacteria that reside and are depleted in the gut microbiota of patients with MASLD. Once their beneficial roles and mechanism-of-action are comprehensively understood, these gut commensals can be utilised as so-called “next-generation probiotics” (e.g.,
Akkermansia muciniphila [
14,
15] and
Clostridium butyricum [
16]). In general, the sequencing-based next-generation probiotics are natural inhabitants of the human gut microbiota, thus they have safer profile, easier colonisation, and greater disease-targeting precision than traditional probiotics. Several gut commensal
Bacteroides species have shown potential to treat MASLD (
Table 1). For example,
Bacteroides uniformis is depleted in patients with MASH, and it can mitigate diet-induced MASH development in mice by restoring the function of hepatic natural killer cells [
17].
Bacteroides thetaiotaomicron, an emerging next-generation probiotic strain, also significantly inhibits diet-induced MASLD in mice by decreasing serum glutamate levels and modulating unsaturated fatty acid metabolism to reduce liver damage and lipid accumulation [
18,
19]. Concordantly, the latest study by Choi et al. [
5] provides solid evidence of
B. eggerthii depletion in human MASLD and its anti-steatotic effects in mice, showcasing that
B. eggerthii is a novel member in the reservoir of MASLD-targeting probiotics.
On the other hand, it is noteworthy that there is currently insufficient evidence reporting the efficacy of next-generation probiotics in clinical settings. Compared to traditional probiotics, which display robust therapeutic potential in clinical trials [
13], the utilisation of
Bacteroides as probiotics is mainly based on preclinical animal models (
Table 1). Hence, although Choi et al. [
5] provides strong proof of the anti-steatotic effects of
B. eggerthii in mice, human trials are necessary to confirm its efficacy, safety, treatment duration, and dosage prior to clinical application. Inter-individual variability is another critical concern for next-generation probiotics. Given that these probiotic strains were identified based on the gut microbiota, they might be less effective in individuals with higher baseline abundance of these species. For instance, while Choi et al. [
5] identified the decreased
Bacteroides abundance in Korean patients with MASLD, other studies revealed that
Bacteroides is in turn enriched in American or European patients [
20,
21]. It is therefore reasonable to speculate that
Bacteroides would be less effective in individuals or populations with affluent
Bacteroides colonised in their intestines. To this end, large-cohort and/or multi-centre clinical investigations are definitely needed to evaluate the inter-individual variability of
B. eggerthii as well as other next-generation probiotics to treat MASLD in humans.
In summary, Choi et al. [
5] demonstrate that
B. eggerthii can serve as an anti-steatotic probiotic to alleviate MASLD in mice. To date, MASLD is managed by lifestyle intervention, whilst there are only two approved drugs (thyroid hormone receptor-beta agonist resmetirom and glucagon-like peptide-1 receptor agonist semaglutide) for treating the more severe MASH. Given the close link between MASLD and the gut microbiota, recent studies have invested great efforts to identify novel probiotic strains and utilise them to prevent and inhibit the development and progression of MASH [
22]. These newly discovered probiotics, including
B. eggerthii, yield promising potential to treat MASLD by reducing liver damage and lipid accumulation in preclinical models. Nevertheless, extensive human studies are warranted, which would facilitate the application of
B. eggerthii and other next-generation probiotics for clinical management of MASLD.
FOOTNOTES
-
Authors’ contribution
HCHL researched the data and drafted the manuscript. JY supervised the study and revised the manuscript.
-
Acknowledgements
This study is supported by Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0500200).
-
Conflicts of Interest
The authors have no conflicts to disclose.
Table 1.Probiotic strains for treating MASLD, identified by human microbiota profiling
*,†
Table 1.
|
Species |
Country |
Observational sequencing cohort |
Change in MASLD |
Mouse model |
Phenotypes |
Clinical trial validation |
Reference |
|
Bacteroides eggerthii
|
Korea |
148 MASLD, 50 healthy |
Decreased |
Diet-induced MASLD |
Inhibit MASLD |
No |
[5] |
|
Reduced hepatic steatosis, lipid accumulation, damage, fibrosis |
|
Bacteroides uniformis
|
China |
20 MASH, 20 healthy |
Decreased |
Diet-induced MASLD |
Inhibit MASLD |
No |
[17] |
|
Reduced hepatic steatosis, lipid accumulation, inflammation, fibrosis |
|
Faecalibacterium prausnitzii
|
Korea |
45 MASH, 99 healthy |
Decreased |
Diet-induced MASLD |
Inhibit MASLD |
No |
[23] |
|
Reduced hepatic steatosis, lipid accumulation, inflammation, fibrosis |
|
Coprococcus
|
China |
44 MASLD, 41 healthy |
Decreased |
Diet-induced MASLD |
Inhibit MASLD |
No |
[24] |
|
Reduced hepatic lipid accumulation, inflammation, fibrosis |
Abbreviations
metabolic dysfunction-associated steatohepatitis
metabolic dysfunction-associated steatotic liver disease
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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”
Soon Sun Kim, Jae Youn Cheong, Jung Woo Eun
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