There are existing pieces of compelling evidences

The gap

Evidence profile

Sourced from the future work of the source papers, classified as general, drawn from work published between 2024 and 2026, spanning 3 journals. Those papers have been cited 100 times in total.

Supporting evidence — 4 representative gaps

• Gut-brain-immune interactions in neonatal hypoxic–ischemic brain injury (2026) · Molecular and Cellular Pediatrics · doi

  The gut–brain-immune axis in neonatal HI is a young but evolving field positioned to move from descriptive corre- lation towards mechanistic causality and clinical transla- tion. To summarize the previous sections, main findings are graded by the strength of evidence in Table 1, distin- guishing four levels: human association (correlational, typically confounded by clinical care), animal causality (interventional, e.g. faecal microbiota transplantation), extrapolation from adult stroke or non-HI inflammatory models, and therapeutic speculation. From this overview, two research priorities can be defined: unaddressed mechanistic links and conceptual gaps in preclinical and clinical study designs (Table 2). At the conceptual level, two questions remain. First, sex differences are well documented separately for the developing brain, immune system and gut micro- biota [86–88]. HI itself produces sex-specific patterns of lesion size, microglial activation, cell-death path- ways and peripheral immune cell function [47, 89–92]. Whether sex-specific gut dysbiosis contributes to these dimorphic brain and immune responses has not been examined. Sex-stratified designs in both preclinical and clinical studies will be essential to avoid missing biologi- cally relevant effects. Second, the developmental memory of perinatal microbial perturbations and its potential impact on lifelong immunity and neurological function remain poorly defined. Clinical and preclinical data are sparse and inconsistent. After caesarean section, over- all microbiome structure normalizes as the gut matures although selected genera differ at five years [93]. Rodent prebiotic supplementation from P5 to P14/15 produces a community that is no longer detectable in adulthood [74], whereas perinatal fructo-oligosaccharides in pigs persistently modulate the adult faecal microbiota at nine months [73]. A large population-based study did not find a consistent association between adult microbi- ome composition and early-life events [94]. The absence Herz et al. Molecular and Cellular Pediatrics (2026) 13:39 Table 1 Levels of evidence underlying the principal claims of this review Page 9 of 14 A Animal causality, H Human association, E Extrapolation from adult stroke or non-HI models, T Therapeutic speculation of an enduring microbial signature does, however, not exclude a "developmental priming", by which transient perturbations during critical windows shape immune programming with lifelong consequences. This is, for example, illustrated by maternal fiber deprivation, which alters offspring microbiota and predisposes to low-grade inflammation and obesity [95]. HI insults superimposed on antibiotic exposure may therefore unmask or amplify Herz et al. Molecular and Cellular Pediatrics (2026) 13:39 Page 10 of 14 Table 2 Research priorities

  generalfuture work
  Keywords: immune clinical adult brain causality association microbiota preclinical mechanistic evidence levels human animal faecal extrapolation
• Gut microbiota-gonadal axis: the impact of gut microbiota on reproductive functions (2024) · Frontiers in Immunology · cited 96× · doi

  There are existing pieces of compelling evidences, however little, which prove beyond reasonable doubts the link between the gut microbiota and reproduction. Most studies agree that gut microbiota influences gonadal functions by modulation steroid sex hormones, insulin sensitivity, immune system, and gonadal microbiota. Also, ingestion of probiotics and prebiotics also modifies gonadal functions by modulating the gut and gonadal microbiota. Although the mechanisms involved in gut microbiota- gonadal cross talk are complex and yet to be fully explored, the roles of gut microbiota, as well as probiotics and prebiotics that promote gut microbiota, should not be downplayed. Human studies validating the findings in animal models are important to curtail the reported global decline in fertility, especially for couples seeking conception. Also, to investigate the gut is important microorganisms that may have a significant impact on gonadal metatranscriptomics profile. In addition, the role of gut virome and epididymal microbiota in reproduction should be explored. it

  generalfuture work
  Keywords: microbiota gonadal reproduction functions probiotics prebiotics explored important there existing pieces compelling evidences little prove
• The Maternal Microbiome in Pregnancy: From Physiological Changes to Dysbiosis and Obstetrical Complications—Therapeutic Perspectives (2026) · Life · cited 2× · doi

  Despite the growing evidence linking maternal microbiota to pregnancy outcomes, many questions remain regarding the mechanisms through which microbial communities influence maternal–fetal health. Future research will likely focus on several key areas. One important direction involves longitudinal cohort studies that follow women throughout pregnancy, allowing researchers to monitor microbial changes across differ- ent trimesters and to correlate these changes with pregnancy outcomes. Such studies have shown that the maternal microbiota undergoes dynamic shifts during pregnancy and that these alterations may be associated with complications such as GDM or preterm birth [3]. Another promising research area is the integration of multi-omics approaches, in- cluding metagenomics, metabolomics, and transcriptomics. These technologies enable a more comprehensive analysis of microbial composition and function, as well as the met- abolic pathways through which microbial communities interact with the host. Recent studies suggest that microbial metabolites, including SCFAs, may influence immune reg- ulation, placental function, and fetal metabolic development [190]. Future studies should focus on the translation of microbiome research into clinical practice. Advances in high-throughput sequencing and multi-omics technologies are ex- pected to improve the identification of microbial biomarkers predictive of obstetrical com- plications. Integrating microbiome sequencing with metabolomic and immune profiling may enable earlier identification of women at risk for complications such as PTB or GDM [191]. Identifying microbial biomarkers associated with pregnancy complications may al- low for earlier risk assessment and the development of targeted preventive strategies. In addition, microbiome-based interventions such as dietary modifications, probiotics, and other microbiota-modulating therapies are being explored as potential approaches to im- prove pregnancy outcomes [21] Another promising area of research involves the development of microbiome-tar- geted interventions. Strategies such as probiotic supplementation, dietary modulation, and microbiota transplantation are being investigated as potential methods for restoring microbial balance during pregnancy. Understanding the physiological dynamics of the vaginal microbiota during pregnancy may therefore provide new opportunities for im- proving maternal and neonatal outcomes [61]. However, additional clinical trials are re- quired to determine the safety and effectiveness of these approaches in pregnant popula- tions [192]. https://doi.org/10.3390/life16061033 Life 2026, 16, 1033 35 of 47 Advances in microbiome research have opened new perspectives for the develop- ment of microbiome-based therapeutic strategies aimed at improving maternal and fetal health during pregnancy. Increasing evidence suggests that maternal microbial

  generalfuture work
  Keywords: pregnancy microbial maternal microbiome microbiota outcomes fetal complications approaches development strategies evidence communities uence health
• The Maternal Microbiome in Pregnancy: From Physiological Changes to Dysbiosis and Obstetrical Complications—Therapeutic Perspectives (2026) · Life · cited 2× · doi

  in pathogenesis. Front. Cell. Infect. Microbiol. 2025, 15, 1697739. https://doi.org/10.3389/fcimb.2025.1697739. https://doi.org/10.3390/life16061033 Life 2026, 16, 1033 42 of 47 97. Faas, M.M.; Smink, A.M. Shaping immunity: Influence of maternal gut bacteria on fetal immune development. Semin. Immuno- pathol. 2025, 47, 13. https://doi.org/10.1007/s00281-025-01039-8. 98. Siddiqui, R.; Makhlouf, Z.; Alharbi, A.M.; Alfahemi, H.; Khan, N.A. The gut microbiome and female health. Biology 2022, 11, 1683. https://doi.org/10.3390/biology11111683. 99. Rowland, I.; Gibson, G.; Heinken, A.; Scott, K.; Swann, J.; Thiele, I.; Tuohy, K. Gut microbiota functions: Metabolism of nutrients and other food components. Eur. J. Nutr. 2018, 57, 1–24. https://doi.org/10.1007/s00394-017-1445-8. 100. LeBlanc, J.G.; Milani, C.; de Giori, G.S.; Sesma, F.; van Sinderen, D.; Ventura, M. Bacteria as vitamin suppliers to their host: A gut microbiota perspective. Curr. Opin. Biotechnol. 2013, 24, 160–168. https://doi.org/10.1016/j.copbio.2012.08.005. 101. Hill, M.J. Intestinal flora and endogenous vitamin synthesis. Eur. J. Cancer Prev. 1997, 6, S43-5. https://doi.org/10.1097/00008469- 199703001-00009. 102. Rossi, M.; Amaretti, A.; Raimondi, S. Folate production by probiotic bacteria. Nutrients 2011, 3, 118–134. https://doi.org/10.3390/nu3010118. 103. Zelante, T.; Iannitti, R.G.; Cunha, C.; De Luca, A.; Giovannini, G.; Pieraccini, G.; Zecchi, R.; D(cid:31)Angelo, C.; Massi-Benedetti, C.; Fallarino, F.; et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 2013, 39, 372–385. https://doi.org/10.1016/j.immuni.2013.08.003. 104. Ruiz-Triviño, J.; Álvarez, D.; Cadavid, J.Á.P.; Alvarez, A.M. From gut to placenta: Understanding how the maternal microbiome models life-long conditions. Front. Endocrinol. 2023, 14, 1304727. https://doi.org/10.3389/fendo.2023.1304727. 105. Du, X.; Elsabagh, M.; He, F.; Wu, H.; Zhang, B.; Fan, K.; Wang, M.; Zhang, H. gut microbiota and its metabolites modulate pregnancy outcomes by regulating placental autophagy and ferroptosis. Antioxidants 2025, 14, 970. https://doi.org/10.3390/antiox14080970. 106. Husso, A.; Pessa-Morikawa, T.; Koistinen, V.M.; Kärkkäinen, O.; Kwon, H.N.; Lahti, L.; Iivanainen, A.; Hanhineva, K.; Niku, M. Impacts of maternal microbiota and microbial metabolites on fetal intestine, brain, and placenta. BMC Biol. 2023, 21, 207. https://doi.org/10.1186/s12915-023-01709-9. 107. Calatayud, M.; Koren, O.; Collado, M.C. Maternal microbiome and metabolic health program microbiome development and health of the offspring. Trends Endocrinol. Metab. 2019, 30, 735–744. https://doi.org/10.1016/j.tem.2019.07.021. 108. Sun, G.; Wang, Z.; Guo, X.; Sun, H.; Teng, T.; Shi, B. From maternal microbes to offspring development: Gut microbiota-derived thiamine regulates the gut microbiota and drives the placental Notch pathway to coordinate angiogenesis and nutrient transport. Microbiome 2026, 14, 52. https://doi.org/10.1186/s40168-025-02317-1. 109. Feil, R.; Fraga, M.F. Epigenetics and the environment: Emerging patterns and implications. Nat. Rev. Genet. 2012, 13, 97–109. https://doi.org/10.1038/nrg3142. 110. Davie, J.R.

  generalfuture work
  Keywords: https microbiota maternal microbiome life bacteria development health front immunity fetal biology nutrients vitamin placenta

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