Page 78 - Read Online

Tian et al. Microbiome Res Rep 2024;3:49 https://dx.doi.org/10.20517/mrr.2024.33 Page 11 of 14

be activated by specific metabolites and bacterial cell wall components such as lipopolysaccharides (LPS),
[36]
peptidoglycans, and lipoteichoic acids, subsequently activating the immune system . This activation
initiates innate and adaptive immune responses as well as inflammation [37,38] . A recent study found that
compared to non-inflammatory depression or control groups, patients with inflammatory depression
exhibit an increase in the abundance of Proteobacteria and a decrease in butyrate-producing bacteria like
[39]
Faecalibacterium in their gut microbiota . Transplanting fecal microbiota from individuals with
inflammatory depression into mice has been shown to induce depressive and anxiety-like behaviors,
accompanied by increased peripheral and central inflammatory markers and intestinal permeability.
Mechanistically, the TLR-4/NF-κB and NLRP3 inflammasome signaling pathways partially mediate this
interaction, highlighting the intricate relationship between gut microbiota, inflammation, and mood
[39]
disorders .

In previous research, we found that administering CCFM6432 could reduce the abundance of pathogenic
[40]
microorganisms, such as Escherichia-shigella, in the guts of chronically stressed mice . In vitro antibacterial
tests revealed that this strain inhibits the growth of Escherichia coli, Staphylococcus aureus subsp. aureus,
Listeria monocytogenes, and Salmonella typhimurium through the production of lactic acid rather than
bacteriocins . Additionally, in animal models, CCFM6432 administration helped reverse the abnormal
[41]
increase in gut barrier permeability and serum LPS levels caused by chronic stress. This intervention further
inhibited the expression of receptor proteins and pro-inflammatory cytokines in the TLR4/NF-κB signaling
[41]
pathway in the brain, thereby reducing the overactivation of microglia in the hippocampus . The
observations from this human study are logically consistent with previous results, suggesting that
CCFM6432 may alleviate immune activation associated with depression through lactic acid production,
thereby improving the host’s emotional state. In contrast to the results observed in mice, the probiotic did
not significantly alter the overall structure of the gut microbiota in the human cohort. This outcome aligns
with the intrinsic definition of probiotics, which emphasizes their gentle and non-invasive mode of action.
Many classic probiotics have been isolated from the early-life gut microbiota of infants, indirectly
highlighting their low immunogenicity and minimal host stimulation. Moreover, there has been no
consistent evidence to suggest that gut microbiota diversity is significantly altered in patients with
depression, nor that such alterations are a direct consequence of the disorder . Therefore, the theoretical
[42]
basis for developing probiotic therapies aimed at improving gut microbiota structure remains insufficiently
substantiated. This further underscores the need for future development of psychiatric probiotics to focus
more on the effective substances that mediate their therapeutic effects.

Clinical depression patients often experience various gastrointestinal dysfunctions and sleep disorders .
[10]
Our research has shown that intervention with Pediococcus acidilactici CCFM6432 significantly alleviated
these symptoms, which aligns with clinical findings of other psychobiotics [43,44] . However, unlike most
probiotics, the intake of this strain did not significantly alter the overall structure of the patients’ gut
microbiota. Its mechanism may involve increasing the levels of its metabolic product, lactic acid, in the gut,
reducing the abundance of pathogenic bacteria and associated inflammation, thereby improving depressive
symptoms. Nevertheless, the specific interactions between gut metabolites (such as lactic acid), circulating
inflammatory factors, and brain immune status require further investigation.

There are, however, some limitations in our study that future research should address. Firstly, due to the
small sample size and short intervention period, we cannot resolve the individual differences in symptoms
and responses to probiotic intervention caused by different living environments, genetic backgrounds, and
medication interventions in depressed patients. Future studies should increase sample sizes and
intervention durations, and controlling or stratifying participants’ diets, medications, and living