Reactive oxidant species (ROS) accumulation is key to osteoclast differentiation,a phenomenon related to bone reabsorption and the onset of osteoporosis. Plant-derived polyphenols that have reduced ROS production have been widely studied for the treatment of osteoporosis. However, these compounds are rarely absorbed in the small intestine and are instead converted to phenolic acids by the microbiota in the colon. These large quantities of low-molecular-weight phenolic acids, instead, can then be absorbed by the body. 4-Hydroxy-phenylacetic acid (4-HPA) is an important metabolite of these polyphenols that is generated by the human intestinal microbiota. A study of last December 2024 elucidated the role of 4-HPA on osteoclastogenesis, by showing that 4-HPA inhibited osteoclast differentiation and function and downregulated osteoclast-specific genes, including NFATc1, c-Fos, CTSK, Acp5 and MMP9.
As for further mechanism exploration, 4-HPA reduced ROS accumulation by regulating nuclear factor erythroid 2-related factor (Nrf2), a well known transcription factor that upregulates protective and antioxidant proteins (SOD2, HO-1, Trx-1, GSR1, GSTp and others) while inhibited the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. It has been demonstrated that Nrf2 expression can inhibit osteoclastogenesis in vitro and in vivo, and Nrf2 deletion promotes this process. To evaluate the in vivo effect of 4-HPA on postmenopausal osteoporosis, scientist employed an ovariectomized (OVX) mouse model where Micro-CT and histomorphometry analyses showed that 4-HPA effectively prevents bone loss. Encouragingly, 4-HPA demonstrated efficacy in treating osteoporosis induced by OVX in rats.
Microbial short chain fatty acids (SCFAs) have been shown to modulate the entrainment of peripheral clock genes within tissues such as the liver and kidney in mice. The timing of SCFA exposure is crucial for the effect, meaning that the microbiome communicates with host tissues to synchronize peripheral clocks. While the exact mechanisms linking microbial rhythms and host circadian processes remain to be fully established, emerging evidence suggests that microbial metabolites are key mediators in this interaction. In addition to SCFAs, the microbiome also regulates circadian rhythms through the production of other metabolites, such as polyamines and bile acids. Polyamines can influence the interactions between clock proteins by acting on the casein kinase-2 (CK-2 alpha), which phosphorylates clock proteins at several residues.
Research has also linked microbial metabolites to regular social behavior and in the context of developmental disorders. For instance, an assessment of fecal metabolites from infants found an association between variations in the levels of microbial metabolites, especially higher lactate and lower SCFAs levels, and fewer autism-related behaviors, depicted by a lower score on the social responsiveness scale. Juvenile social isolation in mice was found to increase propionic acid in the gut. Administration of ergothioneine, a metabolite produced by Lactobacillus reuteri, reduced social avoidance behavior in rats. Transplantation of specific bacteria Ruminococcacea, Lachnospiraceae and Clostridiales to germ-free mice also induced social avoidance behavior in the recipient mice, an effect associated with high production of the microbial metabolite cresol.
Several receptors, such as G protein-coupled receptors (GPCRs), IL-10 receptor, aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR-alpha) and peroxisome proliferator-activated receptor gamma (PPAR-γ) have been linked to microbial modulation of host behaviors, but scientists deem there might be most likely others. However, epigenetic mechanisms such as DNA methylation, histone modification and chromatin modeling are emerging as modulators of neuroplasticity and behavior. Indeed, SCFAs like butyrate work as modulators of the host epigenetics. Microbiome-mediated choline metabolism may also affect DNA methylation and anxiety behavior in mice. The effects of SCFAs on immune responses are well-known and also connected to neurochemistry and thus with the human behavior.
With what science already knows and what is going furtherly to discover on the gut microbiota, one wonders who the guest and the host really are.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Miao Y, Wang M, Sun H et al. Inflammation. 2024 Dec 11.
Jiang Y, Luo W et al. Life Science 2020 Apr; 246:117422.
Hoskisson PA, Seipke RF et al. mBio. 2020; 11(5):1110.
Postler TS, Ghosh S. Cell Metab. 2017; 26(1):110–130.
Hyeon S et al. Free Radic Biol Med. 2013; 65:789-799.
