Alleviation of Limosilactobacillus reuteri in polycystic ovary syndrome protects against circadian dysrhythmia-induced dyslipidemia via capric acid and GALR1 signaling Original paper

What was studied?

This study investigated the L. reuteri–capric acid–GALR1 axis in a rat model of circadian dysrhythmia–induced polycystic ovary syndrome (PCOS). The researchers used constant darkness to replicate circadian disruption and found that this dysregulation induced dyslipidemia, reproductive disturbances, and microbiome alterations characteristic of PCOS. They examined how Limosilactobacillus reuteri supplementation reshaped the gut microbiome, reduced microbiota-derived capric acid, and restored hepatic GALR1-NR1D1-SREBP1 signaling to protect against lipid abnormalities. This exploration of the gut–liver axis revealed microbial signatures—especially shifts in Lactobacillus, Clostridium sensu stricto 1, and Ruminococcaceae UCG-010—that are essential components of the focus keyphrase L. reuteri capric acid GALR1 axis.

Who was studied?

The study used female Sprague–Dawley rats exposed to eight weeks of constant darkness to induce PCOS-like phenotypes, including disrupted estrous cycles, elevated androgens, abnormal gonadotropins, and significant hepatic lipid accumulation. Rats received daily oral L. reuteri, and subsets were also treated with GALR1 agonists, antagonists, or capric acid to validate pathway involvement. Multi-omics profiling—16S rRNA sequencing, hepatic RNA-seq, fecal and serum metabolomics—was conducted across groups. This combination allowed identification of microbial taxa and metabolites mediating the observed physiologic effects.

Most important findings

The study demonstrated that circadian disruption increased hepatic GALR1 expression, which activated PI3K/AKT signaling, suppressing the circadian regulator NR1D1 and increasing SREBP1-driven lipogenesis. L. reuteri reversed this pattern by restructuring the gut microbiota. The probiotic sharply increased Lactobacillus abundance while reducing dysbiosis-associated taxa such as Clostridium sensu stricto 1 and Ruminococcaceae UCG-010. These shifts correlated with reduced levels of the microbial metabolite capric acid, which was strongly associated with hepatic GALR1 expression. Supplementation with capric acid negated the benefits of L. reuteri, confirming its mechanistic role. Multi-omics network analysis showed tightly linked microbial–metabolite–hepatic signaling interactions, where L. reuteri restored homeostasis across fecal microbiome, fecal metabolome, and serum metabolome. Histologic images verified reductions in hepatic steatosis after L. reuteri treatment.

Key implications

The findings suggest that targeting the L. reuteri–capric acid–GALR1 axis may offer a therapeutic approach for metabolic complications in PCOS, particularly those driven by circadian disruption. The microbiome signatures identified—especially reductions in Clostridium sensu stricto 1 and Ruminococcaceae UCG-010—could serve as biomarkers for stratifying PCOS subtypes or guiding probiotic therapy. By linking a specific microbial metabolite to hepatic lipid regulation, the study provides mechanistic clarity that could inform precision microbiome-based treatments. These insights deepen understanding of how environmental rhythm disturbances alter the gut–liver axis and promote metabolic disease.

Citation

Li S, Zhai J, Chu W, et al. Alleviation of Limosilactobacillus reuteri in polycystic ovary syndrome protects against circadian dysrhythmia-induced dyslipidemia via capric acid and GALR1 signaling. npj Biofilms and Microbiomes. 2023;9:47. doi:10.1038/s41522-023-00415-2