Molecular Mechanism of Microbiota Metabolites in Preterm Birth: Pathological and Therapeutic Insights

Abstract

Preterm birth (PTB) refers to the birth of infants before 37 weeks of gestation and is a challenging issue worldwide. Evidence reveals that PTB is a multifactorial dysregulation mediated by a complex molecular mechanism. Thus, a better understanding of the complex molecular mechanisms underlying PTB is a prerequisite to explore effective therapeutic approaches. During early pregnancy, various physiological and metabolic changes occur as a result of endocrine and immune metabolism. The microbiota controls the physiological and metabolic mechanism of the host homeostasis, and dysbiosis of maternal microbial homeostasis dysregulates the mechanistic of fetal developmental processes and directly affects the birth outcome. Accumulating evidence indicates that metabolic dysregulation in the maternal or fetal membranes stimulates the inflammatory cytokines, which may positively progress the PTB. Although labour is regarded as an inflammatory process, it is still unclear how microbial dysbiosis could regulate the molecular mechanism of PTB. In this review based on recent research, we focused on both the pathological and therapeutic contribution of microbiota-generated metabolites to PTB and the possible molecular mechanisms.

Keywords: metabolites; microbiota; molecular mechanism; postbiotics; preterm; probiotics.

Figure 1

Microbiota-metabolites and inflammatory markers in preterm birth. O: Oral; G: Gut; B: Blood; U: Urine; V: Vagina; C: Cervix; P: Placenta; A: Amniotic fluid. TMA: Trimethylamine, TMAO: Trimethylamine N-oxide; IL: Interleukin; TNF: Tumor necrosis factor; MMP: Matrix metalloproteinase; CCL: C-C motif chemokine ligand; CXCL: C-X-C motif chemokine; PTGDS2: Prostaglandin D2 synthase; OXTR: Oxytocin receptor; CX: Connexin; NFkB: Nuclear factor-kappa B; COX: Cyclooxygenase; PGDH: Prostaglandin dehydrogenase. Dashed lines indicate several steps, ↓ decreased, ↑ increased level. Location followed by color code.

Figure 2

Vaginal microbiota eubiosis and dysbiosis. Effect of beneficial and pathogenic microbiota in the vaginal environment. Pink = normal, while red = inflammation conditions.

Figure 3

Generation of microbiota metabolites. The blue color refers to carbohydrates, the red color refers to proteins, the yellow color refers to lipids, and the green color refers to vitamins. Colors indicate metabolites generated by their specific diatery molecules and microbiota. Colors from dark to light color shed indicate derivatives of metabolites conversion. VD: Vitamin D; 25D: 25-hydroxy vitamin D; 1,25(OH)2D3: 1α,25-dihydroxy vitamin D.

Figure 4

Molecular mechanism of microbiota-metabolites in preterm birth. Signaling of PAMPs and DAMPs derived from gut microbiota and dietary molecules have activated TLRs in PTB. The blue and gray colors refer to carbohydrates, the red color refers to proteins, the yellow color refers to lipids, and the green color refers to vitamins. From dark color to light color indicate metabolites forms and their generated inflammatory markers. PAMPs: Ppathogen-associated molecular patterns, DAMPs: Damage-associated molecular patterns; VD: Vitamin D; 25D: 25-hydroxy vitamin D; 1,25(OH)2D3: 1α,25-dihydroxy vitamin D. TMA: Trimethylamine, TMAO: Trimethylamine N-oxide; IL: Interleukin; TNF: Tumor necrosis factor; MMP: Matrix metalloproteinase; PGs: Prostaglandins. TLRs: Toll like receptors. Dashed lines indicate several steps, ↓ decreased, ↑ increased level.