Introduction

Updated nomenclature for steatotic liver disease (SLD) uses moderate-to-heavy alcohol drinking to classify metabolic dysfunction-associated steatotic liver disease (MASLD) and with increased alcohol intake (MetALD). However, the association between light-to-moderate alcohol drinking (≤14 g/d for females and ≤28 g/d for males) and the risk of SLD, particularly MASLD, remains unclear, with this knowledge gap being especially pronounced in Chinese populations where prospective cohort evidence remains scarce. In this study, we conducted a cohort study of 2942 Chinese adult participants using data from the Anhui Liver Disease Study (ALDS), where SLD and its subtypes were defined based on vibration-controlled transient elastography (VCTE).We examined the relationship between light-to-moderate alcohol drinking and the risk of SLD and MASLD.We further investigated gut microbiome changes linked to light-to-moderate drinking, and assessed the association between light-to-moderate alcohol-associated microbiota and SLD in a subset of the ALDS.

Aims & Methods

We aimed to investigate the association between light-to-moderate drinking and the risk of incident SLD/MASLD, assess the 1-year gut microbiome changes linked to light-to-moderate drinking, and examine the association between light-to-moderate alcohol-associated microbiota and SLD.In a cohort of 2942 Chinese adults from the Anhui Liver Disease Study (ALDS), alcohol intake was measured via a validated food frequency questionnaire, while SLD were diagnosed by vibration-controlled transient elastography. In a subset of ALDS (n=330), dietary information and fecal samples for 16S rRNA sequencing were collected twice, 1 year apart. Cox regression and logistic regression were used to calculate multivariable-adjusted hazard ratios (aHRs) and odds ratios (aORs) with 95%CIs, respectively.

Results

Upon 4 years of follow-up, 513 SLD (473 MASLD) were newly identified among participants without pre-existing SLD. Light-to-moderate alcohol drinkers exhibited higher risks of SLD (aHR=1.27, 95%CI: 1.03-1.58) and MASLD (aHR=1.27, 95%CI: 1.01-1.59) versus abstainers. Such positive association persisted in subgroups by age, sex, the number of cardiometabolic risk factors, physical activity, and diet quality. Beverage-specific analysis revealed positive associations with SLD risk for liquor (aHR=1.29, 95%CI:1.01-1.65) and beer (aHR=1.38, 95%CI: 0.96-1.99), but not wine. Longitudinal microbiome analysis identified 16 genera with altered abundance in light-to-moderate alcohol drinkers: 8 increased (including Actinomyces) and 8 decreased (all P_FDR<0.05). Among these genera, Actinomyces abundance correlated with SLD risk (aOR=1.19, 95%CI: 1.03-1.41).

Conclusion

Our findings support that light-to-moderate alcohol drinking was associated with higher risks of SLD and MASLD, which might be partly via modulation of gut microbial composition.

References

[1] Israelsen M, Francque S, Tsochatzis EA, Krag A. Steatotic liver disease. Lancet. 2024;404(10464):1761-78. https://doi.org/10.1016/S0140-6736(24)01811-7.
[2] Younossi ZM, Stepanova M, Ong J, Trimble G, AlQahtani S, Younossi I, Ahmed A, Racila A, Henry L. Nonalcoholic Steatohepatitis Is the Most Rapidly Increasing Indication for Liver Transplantation in the United States. Clin Gastroenterol Hepatol. 2021;19(3):580-9 e5. https://doi.org/10.1016/j.cgh.2020.05.064.
[3] Wong VWS, Ratziu V, Bugianesi E, Francque S, Zelber-Sagi S, Valenti L, Roden M, Schick F, Yki-Järvinen H, Gastaldelli A, Vettor R, Frühbeck G, Dicker D, Easl, Easl, Easd, Easo. EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol. 2024;81(3):492-542. https://doi.org/10.1016/j.jhep.2024.04.031.
[4] Mak LY, Liu K, Chirapongsathorn S, Yew KC, Tamaki N, Rajaram RB, Panlilio MT, Lui R, Lee HW, Lai JC, Kulkarni AV, Premkumar M, Lesmana CRA, Hsu YC, Huang DQ. Liver diseases and hepatocellular carcinoma in the Asia-Pacific region: burden, trends, challenges and future directions. Nat Rev Gastroenterol Hepatol. 2024;21(12):834-51. https://doi.org/10.1038/s41575-024-00967-4.

Introduction

Obesity, characterized by low-grade systemic inflammation, is associated with numerous chronic inflammatory conditions including inflammatory bowel diseases (IBD). While accumulating body fat has direct influence on IBD progression, creeping fat (CF) in Crohn’s disease (CD) manifests independently of body weight. As a response of mesenteric adipose tissue (AT) to intestinal inflammation, preadipocytes migrate towards affected intestinal segments to form a distinct immunophenotypic AT comprising hyperplastic adipocytes, preadipocytes and immune cells which exert complex immunologic and metabolic interactions with the adjacent intestine. However, associations between the cellular architecture of CF and CD progression remain unclear.

Aims & Methods

We aim to study gut-AT interactions in the context of IBD, focusing on the role of preadipocytes in CF as well as relevance of metabolic integrity of mesenteric adipocytes for intestinal homeostasis. Ex vivo co-cultures of wild-type murine intestinal organoids and mesenteric mature adipocytes or preadipocytes using a novel 3D culture system allowed us to study direct effects on transcriptional profiles and growth capacity, distinguishably between adipogenic cells of distinct differentiation states. Furthermore, we generated a mouse model of adipocyte-specific mitochondrial dysfunction by genetic deletion of heat shock protein 60 (Hsp60) to investigate mechanisms of metabolic and inflammatory phenotype transmission between mesenteric AT and intestinal epithelium. In addition, we used human mesenteric and CF explants from CD patients undergoing surgical resection to isolate preadipocytes and perform ex vivo proliferation and differentiation studies.

Results

In intestinal organoids from mice, the presence of both, mature adipocytes and preadipocytes induces downregulation of Hsp60 accompanied by induction of mitochondrial stress markers (Trb3, Chop). However, solely preadipocytes were sufficient to induce intestinal epithelial gene signatures involved in oxidative stress (Ido1, Nos2, Duox2) and reduced stemness (Lgr5) as attributable to metabolic impairment and injury phenotypes. Conversely, in response to presence of intestinal organoids, mesenteric adipocytes show upregulated expression of browning markers (Ucp1, Cidea, Cox7a1) accompanied by reduced inflammatory and mitochondrial stress signaling. In mice, genetically induced mitochondrial dysfunction in adipocytes leads to phenotypic AT remodeling of specifically the mesenteric depot, resulting in extensive immune cell infiltration and crown-like structure formation in anatomic relation to the intestinal epithelium. Human CF-derived preadipocytes in comparison to equivalent cells from healthy mesentery of the same patient exhibit distinct morphological features and diminished lipid incorporation after adipogenic differentiation ex vivo.

Conclusion

We demonstrate that exclusively preadipocytes condition the intestinal epithelium to injury-related phenotypic features, suggesting a novel and crucial relevance for IBD research and management. Vice versa, intestinal epithelial cells can stimulate mesenteric adipocytes to recruit thermogenic capacity, which is associated with anti-inflammatory effects, suggesting a protective role of mesenteric AT browning capacity. Disturbing adipocyte mitochondrial function is sufficient to remodel mesenteric AT architecture and induce propagating inflammation. Consequent effects on the adjacent intestine we address in our ongoing studies considering adipocyte mitochondria as target for therapeutic interventions in CD.

Introduction

A reduction of bowel wall thickness (BWT) on intestinal ultrasound (IUS) is an early predictor of endoscopic response in ulcerative colitis (UC).¹ Shear-wave elastography (SWE) may offer additional prognostic information.

Aims & Methods

We aimed to identify early IUS parameters predicting treatment response to filgotinib, a selective JAK-1 inhibitor. This prospective observational study included UC patients with endoscopically active disease starting on filgotinib 200 mg daily. IUS parameters, including SWE, were assessed at baseline (T0), week 4 (T1) and at second endoscopy (T2). The endoscopic Mayo score (EMS) was assessed at T0 and at T2 in both the most-affected segment and the sigmoid. Endoscopic response was defined as a decrease in EMS of at least 1 point.

Results

A total of 23 patients were included. 10 patients were female (10/23, 44%), the mean disease duration was 14.4 years (SD±10.4), and 14 patients (14/23, 61%) had failed 2 or more biologics. Endoscopic response was observed in 6 of the 21 patients (29%) who underwent a second endoscopy after a median of 14 weeks (IQR 12-17). The submucosal thickness in the sigmoid decreased significantly more between T0 and T1 in endoscopic responders compared to non-responders (-40±23.9% vs -11.5±24.5%, p=0.022). At T1, a BWT decrease of ≥1.33 mm or ≥24.7% (OR 32.5 [2.38-443.15], p=0.009 and OR: 13.8 [1.21-156.6], p=0.035) and a submucosal thickness decrease of ≥20.8% (OR: 13.8 [1.21-156.6], p=0.035) predicted endoscopic response at T2. Additionally, improvement in Colour Doppler Signal (CDS) at T1 predicted endoscopic response (OR: 20.0 [1.66-241.7], p=0.018). SWE values in the sigmoid at T0, T1 and T2 were not significantly different between endoscopic responders and non-responders in the sigmoid. While the change in SWE values at T2 compared to baseline was significantly different between the two groups (9.9± 11.5 kPa vs. -8.1 ± 11.4 kPa, p=0.002), the difference at T1 was not significant and did not predict endoscopic response in the sigmoid (OR: 1.07 [0.99-1.16], p=0.088).

Conclusion

On IUS, BWT, submucosal thickness and CDS predict endoscopic response after four weeks of filgotinib treatment. SWE values in the sigmoid changed differently among endoscopic responders and non-responders, but did not predict treatment response.

References

1. de Voogd FA et al. Early Intestinal Ultrasound Predicts Clinical and Endoscopic Treatment Response and Demonstrates Drug-Specific Kinetics in Moderate-to-Severe Ulcerative Colitis. Inflamm Bowel Dis 2023. DOI: 10.1093/ibd/izad274.

Disclosure

MP: none;
CT: none;
FV: received speaker’s fees from AbbVie, Pfizer and Takeda;
RJ: none,
ML: Consultancy/lecture fees from Abbvie, Bristol Myers Squibb, Eli Lilly, Galapagos, Janssen-Cilag, Johnson & Johnson, Medtronic, Pfizer, Takeda, Tillotts. Grants received from Alfasigma, NFU transformation deal, ZonMW and TKI.
RG: received speakers free from Janssen-Cilag BV and Pfizer Inc.
GD: has served as advisor for AbbVie, Abivax, Alimentiv,, Astrazeneca, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, , GlaxoSmithKline, Johnson and Johnson, Merck Sharp Dome, Pfizer, Polpharm, Sanofi, Takeda, Tillotts, and received speaker fees from AbbVie, Eli Lilly, Johnson and Johnson, Merck Sharp Dome, , Pfizer, Takeda, Tillotts,.
KG: KB Gecse has received grants from AbbVie, Pfizer Inc, Celltrion and Galapagos; consultancy fees from AbbVie, Arena Pharmaceuticals, ImmunicTherapeutics, Janssen Pharmaceuticals, Novartis, Pfizer Inc., and Takeda and speaker’s honoraria from Abbvie, Celltrion, Eli Lilly, Ferring, Janssen Pharmaceuticals, Pfizer Inc, Takeda and Tillotts.