The maternal vaginal microbiome partially mediates the effects of prenatal stress on offspring gut and hypothalamus

Jašarević, Eldin; Howard, Christopher D.; Morrison, Kathleen E.; Misic, Ana M.; Weinkopff, Tiffany; Scott, Phillip; Hunter, Christopher A.; Beiting, Daniel P.; Bale, Tracy L.

doi:10.1038/s41593-018-0182-5

Cited by 154 publications

(135 citation statements)

References 57 publications

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“…9 In addition, increasing evidence suggests that vertically transmitted maternal microbiota-which can be perturbed in response to stress-can also influence a number of offspring characteristics. [12][13][14][15] Such mechanisms support the major role that mothers can have on offspring outcomes. This review is an effort to synthesize these evolutionary and proximate approaches toward understanding developmental plasticity and early-life adversity.…”

mentioning

confidence: 81%

“…Thus far, however, successful reversals have primarily involved prenatal programming effects reversed by early postnatal intervention. Furthermore, some prenatal effects appear irreversible, 12 suggesting that plastic responses during the earliest periods of life are likely to be canalized. developmental responses are likely to yield positive fitness returns.…”

Section: Offspring-centric Models: Developmental Constraints and Parmentioning

confidence: 99%

“…GCs can influence offspring phenotype both directly, by reaching the offspring via the placenta and through milk, and indirectly, by altering maternal physiology and behavior . In addition, increasing evidence suggests that vertically transmitted maternal microbiota—which can be perturbed in response to stress—can also influence a number of offspring characteristics . Such mechanisms support the major role that mothers can have on offspring outcomes.…”

Section: Introductionmentioning

confidence: 99%

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Developmental responses to early‐life adversity: Evolutionary and mechanistic perspectives

Petrullo

Carrera

et al. 2019

Evolutionary Anthropology

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Adverse ecological and social conditions during early life are known to influence development, with rippling effects that may explain variation in adult health and fitness. The adaptive function of such developmental plasticity, however, remains relatively untested in long‐lived animals, resulting in much debate over which evolutionary models are most applicable. Furthermore, despite the promise of clinical interventions that might alleviate the health consequences of early‐life adversity, research on the proximate mechanisms governing phenotypic responses to adversity have been largely limited to studies on glucocorticoids. Here, we synthesize the current state of research on developmental plasticity, discussing both ultimate and proximate mechanisms. First, we evaluate the utility of adaptive models proposed to explain developmental responses to early‐life adversity, particularly for long‐lived mammals such as humans. In doing so, we highlight how parent‐offspring conflict complicates our understanding of whether mothers or offspring benefit from these responses. Second, we discuss the role of glucocorticoids and a second physiological system—the gut microbiome—that has emerged as an additional, clinically relevant mechanism by which early‐life adversity can influence development. Finally, we suggest ways in which nonhuman primates can serve as models to study the effects of early‐life adversity, both from evolutionary and clinical perspectives.

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mentioning

confidence: 81%

Section: Offspring-centric Models: Developmental Constraints and Parmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Developmental responses to early‐life adversity: Evolutionary and mechanistic perspectives

Petrullo

Carrera

et al. 2019

Evolutionary Anthropology

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“…Extraction and PCR blanks were used to control for environmental contamination and mock communities were used to control for contamination across wells. The V4 region of the 16S rRNA gene was amplified using barcoded primers for use on the Illumina platform (26). The concentration of each PCR product was determined using a PicoGreen assay, and samples were normalized to equal amounts and pooled.…”

Section: Methodsmentioning

confidence: 99%

Gut microbiome features associated withClostridium difficilecolonization in puppies

Berry

Barnhart

Kelly

et al. 2019

Preprint

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27In people, colonization with Clostridium difficile, the leading cause of antibiotic-associated diarrhea, has been shown to be 28 associated with distinct gut microbial features, including reduced bacterial community diversity and depletion of key taxa. In dogs, 29 the gut microbiome features that define C. difficile colonization are less well understood. We sought to define the gut microbiome 30 features associated with C. difficile colonization in puppies, a population where the prevalence of C. difficile has been shown to be 31 elevated, and to define the effect of puppy age and litter upon these features and C. difficile risk. We collected fecal samples from 32 weaned (n=27) and unweaned (n=74) puppies from 13 litters and analyzed the effects of colonization status, age and litter on 33 microbial diversity using linear mixed effects models. 34 Colonization with C. difficile was significantly associated with younger age, and colonized puppies had significantly decreased 35 bacterial community diversity and differentially abundant taxa compared to non-colonized puppies, even when adjusting for age. C. 36 difficile colonization remained associated with decreased bacterial community diversity, but the association did not reach statistical 37 significance in a mixed effects model incorporating litter as a random effect. 38 Even though litter explained a greater proportion (67%) of the variability in microbial diversity than colonization status, we 39 nevertheless observed heterogeneity in gut microbial community diversity and colonization status within more than half of the 40 litters, suggesting that the gut microbiome contributes to colonization resistance against C. difficile. The colonization of puppies with 3 41 C. difficile has important implications for the potential zoonotic transfer of this organism to people. The identified associations point 42 to mechanisms by which C. difficile colonization may be reduced. 43 44 45 46

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“…Genomic DNA was extracted from fecal pellets of mice using Qiagen DNeasy PowerSoil Kit. The V4 region of the 16S rRNA gene was amplified using barcoded primers for use on the Illumina platform (32, 33). Sequencing was performed using 250-base paired-end chemistry on an Illumina MiSeq instrument.…”

Section: Methodsmentioning

confidence: 99%

LINGO3 interacts with Trefoil factor 2 to enforce mucosal barrier integrity and drive tissue repair during colitis

Wang

et al. 2018

Preprint

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Mucosal epithelia are constantly exposed to damaging stimuli from mechanical, chemical, or biologic entities, and depend on rapid repair mechanisms to maintain tissue homeostasis and immunological quiescence. The reparative cytokine Trefoil factor 2 (TFF2) serves to enforce mucosal barrier integrity, but whether TFF2 receptor(s) exist is controversial. Herein, we demonstrate leucine rich repeat and immunoglobulin like domain containing nogo receptor interacting protein 3 (LINGO3) is a necessary transmembrane component for TFF2-mediated ERK signaling, proliferation, and recovery of trans-epithelial resistance of primary epithelia during wound healing. Human respiratory and intestinal epithelia express LINGO3 and mice lacking Lingo3 have impaired intestinal barrier function and fail to recover from DSSinduced colitis. Compared to wild-type controls, LINGO3 deficiency impairs both crypt regeneration and expression of the intestinal stem cell marker Lgr5. Importantly, Lingo3 -/mice display a phenotype similar to that previously reported for Tff2 deficiency, with increased paracellular permeability, and significant accumulation of mucosal CD4 + T H 1 cells expressing IFNγ + TNF + even under steady-state conditions. Combined, these data reveal a previously unrecognized role for LINGO3 as a putative TFF2 receptor that regulates mucosal barrier integrity and GI inflammation. Significance:Intestinal epithelial cells (IEC) are necessary for maintenance of homeostasis, resistance to infectious organisms, and overall organismal health. When injured the IEC and the underlying stroma and progenitor cell pool undergo restitutive and regenerative processes driven by the reparative cytokine Trefoil factor 2 (TFF2).This report identifies a novel receptor component for TFF2 signaling expressed on both human and mouse epithelial cells that is necessary for barrier integrity at the steady state and during colitic disease. The discovery of a novel TFF2-LINGO3 axis sheds new light on the processes controlling tissue repair, restitution, and regeneration at the mucosal interface.

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The maternal vaginal microbiome partially mediates the effects of prenatal stress on offspring gut and hypothalamus

Cited by 154 publications

References 57 publications

Developmental responses to early‐life adversity: Evolutionary and mechanistic perspectives

Developmental responses to early‐life adversity: Evolutionary and mechanistic perspectives

Gut microbiome features associated withClostridium difficilecolonization in puppies

LINGO3 interacts with Trefoil factor 2 to enforce mucosal barrier integrity and drive tissue repair during colitis

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