Although previous studies have found the functional relevance of gut microbiome and CRP with the development of anxiety and depression(30, 31), the biological mechanism underlying the effects of interaction between gut microbiome and CRP on the risks of anxiety and depression remains to be elucidated(32). In this study, we explored the interaction between CRP and 114 gut microbiome-related traits and observed a significant interaction between them for depression and anxiety.
Intestinal permeability defects are believed to be the basis for the chronic low-grade inflammation observed in stress-related psychiatric disorders(20). Inflammation takes an indirect role in modulating brain function. For example, gut microbiome could influence inflammation by beneficial nutrients (e.g. short-chain fatty acids (SCFAs)). It is clear that SCFAs could promote the expression of anti-inflammatory IL‐10 in macrophages and intestinal dendritic cells(33). Furthermore, complex polysaccharides can be converted into SCFAs by Ruminococcaceae which could degrade mucin, enhance systemic and antitumor immune responses (34, 35). Ruminococcaceae was associated with disorders of the central nervous system (35, 36). There were higher levels of Ruminococcaceae in APOE2/E3 genotype carriers, compared with APOE4 carriers, one of the strongest prevalent risk factors for neuropathology and Alzheimer’s disease(36). It is clear that Ruminococcaceae distributed differently in bipolar disorder (BD) and Major depressive disorder (MDD)(37). In our study, Ruminococcaceae is the most significant taxon associated with PHQ-9 score. In addition, the gut microbiome serves as a barrier to enteropathogen infection. This barrier function may be disrupted by inflammatory substances(38). However, its exact mechanism remains unclear now. Further explorations are needed to draw a definitive conclusion.
In this study, we found 11 significant taxons associated with PHQ-9 score, such as Akkermansia, Lactobacillales and Coprococcus. Akkermansia muciniphila (Akk bacteria) can also degrade mucin, which is negatively related to inflammation and metabolic disorders(39, 40). It is demonstrated that genus Akkermansia and family Akkermansiaceae were consistently changed in both idiopathic rapid-eye-movement sleep behavior disorder and Parkinson’s disease(41). In addition, microbial community profiling revealed reduction (e.g. Akkermansia, Lactobacillus) in the Adrenocorticotrophic hormone induced depression rat model(42). Anti-inflammatory properties have been displayed in several strains of Lactobacillus in vitro in human intestinal epithelial cells(43). Lactobacillus was implicated in gut-brain communication and had positive effects on stress and cognition(44). Coprococcus was related to the activity of the dopamine pathway, and also led to the production of butyrate (6). Loss of bacteria that produce the anti-inflammatory, barrier-strengthening molecule butyrate, could lead to a loss of protection against epithelial inflammation and gut barrier disruption(45). Furthermore, Coprococcus was associated with higher quality of life indicators and was also depleted in depression(46).
We also found 16 significant taxons associated with GAD-7 score. Bacteroidales is the most common microbial category in the human gut. It takes significant roles in metabolic pathways and immune system(47). Previous studies reported that acquired inter bacterial defense gene clusters in Bacteroidales species reside in the human gut microbiome. In a mouse model, taking oral human commensal Bacteroides fragilis corrected gut permeability, altered gut microbiome composition, and ameliorated defects in communicative, stereotypic, anxiety-like, and sensorimotor behaviors(48). Individuals with MDD showed enriched species for Bacteroides and depleted species for Blautia(47). Furthermore, Blautia can mediate beneficial anti-inflammatory effects(47).
We observed 4 gut microbiome PRS interacting with CRP were associated with both PHQ-9 score and GAD-7 score in our study, which may be related to pathophysiology of anxiety and depression through the communication of peripheral inflammation to the brain. For example, 3-hydroxyoctadecaenoic acid (C18-3OH) is an agonist of peroxisome proliferator activated receptor gamma. The production of it by bacteria could be one of the mechanisms implicated in the anti-inflammatory properties of probiotics. In addition, C18-3OH correlated with an increase in the abundance in Holdemanella(49). In a previous animal study, higher loading of Holdemanella and Desulfovermiculus were found in Obsessive-compulsive patients(50). The over-representation of Desulfovibrio is associated with gut mucosal injury and inflammatory pathology through releasing hydrogen sulfide(50). In addition, Desulfovibrio competes with butyrate-producing bacteria for the lactate which results in the production of higher amounts of propionic acid(51). This phenomenon led to autism-like manifestations in animals(51). Moreover, previous studies also observed higher abundance of Desulfovibrio in MDD(52).
To the best of our knowledge, this is a novel study to explore the relationship between psychiatric disorders and the interaction of gut microbiome and CRP. Our study is based on a large cohort study with a long follow-up as well as representative samples. However, several limitations should be pointed out. First, owing to all samples in this study are from European ancestry, the findings should be inferred to other races with caution. Second, the key elements that influence the accuracy of PRS for a specific trait are SNP heritability, genetic architecture, sample size of the discovery GWAS including insufficiently powered GWAS sample sizes for most complex traits, potential confounding in causal inference, and a lack of ancestral diversity. Due to the related loci relied on previous published GWAS, the results may be affected.
In summary, our results support the significant effect of interaction between CRP and gut microbiome on the risks of anxiety and depression, and identified several candidate gut microbiome for them. These findings may provide novel therapeutic targets for psychiatric disorders, and give insights into the mechanism of anxiety and depression. Further studies are eager to confirm our findings and clarify the more detailed mechanism of gut microbiome × CRP interaction in psychiatric disorders.