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Alcohol-Induced Bone Loss: Driven by Dysregulated Spatial Distribution of Gut Microbiota and PGD2-IL17 Pathway-Mediated Osteoclast Activation

ABSTRACT:

Purpose: Alcohol-induced damage to bone microstructure leads to alcoholic osteopenia (AOP). While prior studies have demonstrated alcohol's negative impact on bone density, the mechanisms by which alcohol induces osteoporosis through immune pathways, gut microbiota dysbiosis, and metabolic alterations remain insufficiently characterized. Given that alcohol is primarily absorbed in the upper gastrointestinal tract, the research aims to elucidate the role of spatial distribution disorders in gut microbiota and metabolites in the pathogenesis of alcohol-induced osteoporosis and to evaluate the potential of microbiota supplementation and targeted immunosuppressants as therapeutic strategies for related bone diseases.

Methods: Eight-week-old male C57BL/6 mice were used to establish an osteoporosis model via the force-feeding method. Bone loss was validated using micro-computed tomography (micro-CT). Segmented intestinal samples and fecal samples were analyzed by 16S rRNA sequencing and metabolomics. Mechanistic studies were conducted by supplementing R. intestinalis, prostaglandin D2 (PGD2), and its specific immune inhibitor, Ramatroban. Analytical methods included tartrate-resistant acid phosphatase (TRAP) staining, flow cytometry, and enzyme-linked immunosorbent assay (ELISA). For statistical analysis, paired t-tests were used for comparisons between two groups, while one-way analysis of variance (ANOVA) followed by Tukey's post hoc test was employed for multiple group comparisons.

Results: Alcohol disrupts the spatial complexity of intestinal segments and fecal microbiota in mice, causing metabolic dysregulation and ultimately leading to elevated PGD2 levels. This, in turn, triggers Th17/Treg immune imbalance and osteoclast activation, resulting in bone loss. Supplementation with the probiotic R. intestinalis or inhibition of PGD2 can significantly improve bone density and alleviate inflammation.

Conclusion: Due to the complex spatial distribution of gut microbiota, fecal or colonic microbiota alone cannot fully represent the entire gut environment. The microbiota and metabolites in the lower gastrointestinal tract are better indicators of the host's systemic metabolic status, while the sensitive changes in microbial diversity in the upper gastrointestinal tract also play a significant role in disease progression. This study demonstrates that alcohol-induced elevation of prostaglandin D2 (PGD2) is a key pathogenic factor in alcohol-induced osteoporosis (AOP). PGD2 accelerates bone loss by promoting osteoclast formation through the activation of Th17 cells. Furthermore, this study highlights the importance of investigating the spatial distribution of gut microbiota and metabolites, providing potential targets and novel strategies for the precise treatment of AOP and other diseases associated with external stimuli.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS11887 | MetaboLights | 2025-03-28

REPOSITORIES: MetaboLights

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Project description:Neural control of visceral organ function is essential for homeostasis and health. Intestinal peristalsis is critical for digestive physiology and host defence and is often dysregulated in gastrointestinal (GI) disorders. Luminal factors, such as diet and microbiota regulate neurogenic programs of gut motility, but the underlying molecular mechanisms remain unclear. Here we show that the transcription factor Aryl hydrocarbon Receptor (AhR) functions as a biosensor in intestinal neural circuits linking their functional output to the microbial environment of the gut lumen. Using nuclear RNA sequencing of mouse enteric neurons representing distinct intestinal segments and microbiota states, we demonstrate that the intrinsic neural networks of the colon exhibit unique transcriptional profiles controlled by the combined effects of host genetic programmes and microbial colonisation. Microbiota-induced expression of AhR in neurons of the distal gastrointestinal tract enables them to respond to the luminal environment and induce expression of neuron-specific effector mechanisms. Neuron-specific deletion of Ahr or constitutive overexpression of its negative feedback regulator CYP1A1, results in reduced peristaltic activity of the colon, similar to that observed in microbiota-depleted mice. Finally, expression of Ahr in enteric neurons of antibiotic-treated mice partially restores intestinal motility. Taken together, our experiments identify AhR signalling in enteric neurons as a regulatory node that integrates the luminal environment with the physiological output of intestinal neural circuits towards gut homeostasis and health. The enteric nervous system (ENS) encompasses the intrinsic neural networks of the gastrointestinal (GI) tract, which regulate most aspects of intestinal physiology, including peristalsis. In addition to host-specific genetic programmes, microbiota and diet have emerged as critical regulators of gut tissue physiology and changes in the microbial composition of the lumen often accompany GI disorders. We found that gut environmental sensor Aryl hydrocarbon receptor (AhR) is induced in colonic neurons in response to microbiota colonisation and regulates intestinal peristalsis in an AhR ligand-dependent manner. In this experiment, we used RNA sequencing to identify genes regulated in mouse colonic neurons by AhR activation.

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Dataset Information

Alcohol-Induced Bone Loss: Driven by Dysregulated Spatial Distribution of Gut Microbiota and PGD2-IL17 Pathway-Mediated Osteoclast Activation

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