Letter to the Editor: Circadian and microbial misalignment in metabolic dysfunction-associated steatotic liver disease - mechanistic insights and chronotherapeutic potential

Abstract

We read with interest the article by Rusman et al published in World Journal of Experimental Medicine. Beyond microbial composition, the gut–liver axis is a rhythmic system regulated by a bidirectional interaction between host clocks and the gut microbiota. Social jetlag induces “temporal dysbiosis”, disrupting the timing of metabolites and compromising the intestinal barrier, which exacerbates metabolic injury in metabolic dysfunction-associated steatotic liver disease. Restoration of these rhythms through chronotherapeutic approaches provides an effective method to restore alignment and improve clinical outcomes. Specifically, social jetlag desynchronizes hepatic clocks and disrupts microbially-modified bile acid signaling, promoting fat accumulation. Chronotherapeutic strategies like time-restricted eating can effectively mitigate disease progression by “reprogramming” the liver transcriptome and reducing hepatic triglycerides.

Key Words: Circadian disruption; Steatotic liver disease; Time-restricted eating; Melatonin; Chronotherapy

Core Tip: The gut-liver axis is a rhythmic system regulated by a bidirectional interaction between host clocks and the gut microbiota. Social jetlag disrupts the timing of metabolites and compromises the intestinal barrier, exacerbating metabolic injury in metabolic dysfunction-associated steatotic liver disease. Restoration of these rhythms through chronotherapeutic approaches provides an effective method to restore alignment and improve clinical outcomes.

TO THE EDITOR

We read with interest the article published in World Journal of Experimental Medicine by Rusman et al[1] regarding the gut microbiota’s role in metabolic dysfunction-associated steatotic liver disease (MASLD). The authors provide a comprehensive synthesis of how dysbiosis, increased intestinal permeability, and endotoxemia drive hepatic inflammation. MASLD currently affects more than 25% of the global population. Hepatocellular carcinoma, which accounts for 85%-90% of primary liver cancers, is increasingly attributed to MASLD. Liver cancer remains a leading cause of cancer-related mortality worldwide[2,3]. Given that obesity and insulin resistance are primary etiologies, understanding the molecular pathways of disease progression is critical[4]. In this context, we propose that current disease models must account for social jetlag (SJL), the discrepancy between internal biological time and social demands, which acts as a persistent chronobiological disruptor, impairing the temporal homeostasis of the gut-liver axis[5]. Recognizing circadian timing as a determinant of therapeutic responsiveness is essential for optimizing intervention strategies and improving clinical outcomes[5].

BARRIER RHYTHMS: FROM CONTINUOUS LEAKAGE TO TIMING DYSREGULATION

In their discussion of increased intestinal permeability, Rusman et al[1] identify lipopolysaccharide translocation as a key pathogenic mediator of hepatic inflammation[1]. Research indicates that the intestinal barrier is subject to circadian regulation rather than constant function[6]. Expression of the tight junction proteins occludin and claudin-1 exhibits specific daily variations[7], with mRNA levels reaching a nadir at ZT12 (zeitgeber time, a standardized way to measure time in circadian rhythm research, where ZT0 is typically lights-on and ZT12 is lights-off) and protein nadirs at ZT16 (late day/early night in zeitgeber time)[6]. Epigenetically, this rhythm is driven by histone deacetylase 3 (HDAC3), which represses claudin expression via timely histone deacetylation; loss of epithelial HDAC3 leads to increased intestinal permeability and dampened diurnal rhythms[8]. This epigenetic failure is particularly pathological because the loss of HDAC3 does not simply increase leakage but specifically abolishes the diurnal rhythm of intestinal permeability[8]. Consequently, the liver is deprived of its rhythmic period of protection, remaining continuously vulnerable to a constant flux of endotoxins that fuels chronic inflammation and disease progression[1].

Circadian disruption via SJL or shift work disrupts these junctions, leading to barrier dysfunction and endotoxemia[7]. This disruption is further exacerbated under obesogenic dietary conditions, wherein circadian misalignment exacerbates metabolic disturbances by diminishing microbial diversity and compositional stability[9]. Furthermore, recognition of microbial products through toll-like receptors follows a circadian pattern, indicating that an intact host clock is essential for preserving immune-microbial homeostasis[10].

METABOLIC DIALOGUE: FROM CONTENT DEFICIENCY TO SIGNAL DESYNCHRONIZATION

A critical limitation in current research is that it focuses solely on the absolute abundance of metabolites. Rusman et al[1] discuss the depletion of short-chain fatty acids (SCFAs) like butyrate and acetate; their physiological function is inherently linked to timing and diurnal oscillation[11]. More in detail, SCFAs oscillate diurnally and synchronize hepatic peripheral clocks[12]. Mechanistically, butyrate synchronizes epithelial rhythms via histone deacetylase inhibition, modulating core clock genes like Per2[13]. Similarly, unconjugated bile acids, generated by microbial bile salt hydrolase activity, serve as signaling molecules that enhance the expression of hepatic regulators such as Dbp[14]. In MASLD, SJL-induced circadian misalignment leads to arrhythmic metabolite signaling and is characterized by “nighttime metabolic dysfunction”[13,15], which attenuates the hepatoprotective effects normally mediated by temporally coordinated metabolic pathways[16].

Patients with MASLD exhibit exaggerated nocturnal insulin resistance and reduced insulin availability at night[15]. This is compounded by the depletion of commensals like Dysosmobacter welbionis, which ferments dietary myo-inositol into butyrate to promote liver health[17]. Additionally, deregulated bile acid signaling contributes to a suppressive tumor immune microenvironment[18]. Restoration of Bacteroides eggerthii has been shown to reactivate the farnesoid X receptor (FXR)-FGF15 axis, while UDCA acts as an FXR agonist to bind directly to the TLR4 promoter, suppressing downstream MAPK and NF-κB inflammatory pathways[19,20].

CHRONOTHERAPY: RESTORING RHYTHMS AS A NOVEL THERAPEUTIC TARGET

In models of nonalcoholic steatohepatitis, fecal microbiota transplantation (FMT) was effective in restoring microbial rhythmicity only when derived from the feeding phase of the donor, but not the fasting phase[18]. Furthermore, time-restricted eating, which restricts intake to a consistent 8-10 hours window, improves insulin sensitivity and reduces hepatic steatosis in humans by modulating hepatic gene expression and re-establishing microbial circadian rhythmicity[21]. These interventions stimulate sirtuin-1 activity, which is positively associated with gut microbiome richness and circadian stability[22]. Additionally, supplemental melatonin can function as a chronobiotic to restore microbial temporal alignment and attenuate systemic endotoxin burden caused by sleep restriction[22]. Regarding clinical translation, a meta-analysis of 8 randomized clinical trials confirms that FMT significantly reduces alanine transaminase, aspartate transaminase, and liver fat content in MASLD patients[23]. Clinical feasibility is further enhanced by the United States Food and Drug Administration’s approval of live biotherapeutic products such as Rebyota and Vowst, which facilitate standardized application[24,25]. Standardized safety is ensured through rigorous donor screening and testing protocols designed to exclude asymptomatic pathogen carriers and avoid infection transmission, as established by European guidelines for human tissue transplantation[24,26]. Finally, these circadian mechanisms extend beyond the liver; circadian disruption enhances cardiovascular risk by 40%-63% and significantly promotes diabetes through hyperinsulinemia and impaired glucose tolerance[27,28].

CONCLUSION

Circadian disruption and SJL can act as modifiers in the pathogenesis of MASLD and its management (Table 1). We commend Rusman et al[1] for their synthesis and propose that the integration of host–microbial circadian synchrony - through chrono-nutrition and chronobiotics - is necessary to break the self-sustaining loop of metabolic injury across the gut–liver axis.

Table 1 Circadian disruption and social jet lag as modifiers of associated steatotic liver disease pathogenesis and management.

Domain	Circadian/SJL-related factor	MASLD-relevant mechanism	Ref.
Disease framework	Circadian regulation of metabolic homeostasis	Hepatic lipid handling, glucose metabolism, and inflammatory pathways are under circadian control; disruption amplifies insulin resistance and steatosis	[15,16]
Lifestyle modifiers	SJL	Persistent misalignment between endogenous clocks and behavioural schedules promotes metabolic inflammation independent of caloric excess	[5,7]
Gut-liver axis	Rhythmic intestinal barrier function	Tight junction proteins (occludin, claudin-1) show circadian oscillation; disruption increases permeability and endotoxin flux	[6,8]
Innate immunity	Circadian gating of immune responses	Toll-like receptor signalling varies by time of day; circadian disruption exaggerates inflammatory responses to microbial products	[10]
Gut microbiota	Temporal dysbiosis	Circadian disruption blunts microbial diurnal oscillations, impairing host–microbe metabolic signalling	[5,12]
Metabolite signalling	SCFAs as clock synchronisers	SCFAs (e.g., butyrate) entrain epithelial and hepatic clocks via HDAC inhibition; arrhythmic delivery weakens metabolic homeostasis	[11,13]
Bile acid metabolism	Circadian bile acid-FXR axis	Diurnal bile acid oscillations regulate hepatic lipid and glucose metabolism; disruption impairs FXR signalling	[14,18]
Human phenotype	Nocturnal metabolic vulnerability	MASLD associated with exaggerated nocturnal insulin resistance and reduced nighttime insulin availability	[15]
Dietary intervention	Time-restricted eating	Consistent eating windows restore hepatic and microbial rhythmicity, improving insulin sensitivity and reducing liver fat	[21,29]
Microbiota-targeted therapy	Circadian dependence of efficacy	FMT efficacy correlates with restoration of microbial rhythmicity	[23,29]
Adjunctive strategies	Chronobiotics (e.g., melatonin)	Chronobiotics can re-entrain host–microbial rhythms under circadian disruption	[22]
Research considerations	Timing as a biological confounder	Ignoring circadian timing may obscure biomarker interpretation and treatment effects	[5]

SJL: Social jet lag; MASLD: Associated steatotic liver disease; SCFAs: Short-chain fatty acids; HDAC: Histone deacetylase; FXR: Farnesoid X receptor; FMT: Fecal microbiota transplantation.