Biology subjects

Williams, B. M.

Publications and source records attributed to Williams, B. M..

3 recordsLinked to original sources

bioRxiv2025

Fetal sex is associated with the maternal gut microbiota composition and its metabolic function

BackgroundPregnancy affects almost every organ and system, including the microorganisms that resides in the gastrointestinal track, the gut microbiota. Pregnancy hormones, such as progesterone and estradiol, alter the composition of the maternal gut microbiota, directly and indirectly, and in turn, the gastrointestinal microorganism can modify the activity of reproductive hormones. While the levels of pregnancy hormones depend on the fetal sex, the role of fetal sex in the maternal gut microbiota composition and function has not been explored yet. MethodsUsing publicly available microbial sequencing data from a cohort of 485 pregnant women in Guangzhou, China, we identified taxonomical and predicted metabolic signatures associated with fetal sex and gestational age using zero-inflated Gaussian models and linear models, respectively, correcting for pre-pregnancy BMI, maternal age, parity, and residency status. Further, we determined sex-specific co-abundance microbial networks using SPIEC-EASI. ResultsWe observed higher diversity levels in male than in female pregnancies and identified multiple microbial species and predicted microbial enzymes that were differentially abundant between the fetal sex groups, such as increased levels of Tyzerrella and {beta}-glucuronidase in female pregnancies, respectively. {beta}-glucuronidase deconjugates glucuronide-bound estrogens into free estrogens and glucuronic acid. Further, the microbial co-abundance networks between the male and female pregnancies were distinct, with efficient information transfer being representative of the female network while the male network was characterized by a larger number of competitive or exclusion interactions between microbial species. While the two networks had similar core communities, there were distinct connections between hormone metabolizing microbes, with {beta}-glucuronidase expressing microbes being more highly connected in the female network. ConclusionsOur study suggests that differences in the maternal-fetal interactions, such as fetus/placenta-produced hormone levels, may affect and be affected by the composition of the gut microbiota of pregnant individuals in a sex-specific manner. A better understanding of the relationship between fetal sex and the maternal gut microbiota may improve maternal health and fetal outcomes. Plain English SummaryThe adequate functioning of the microbial communities that reside in the maternal gastrointestinal tract is essential for normal fetal development and their abnormal behavior has been associated with multiple conditions such as preterm birth, gestational diabetes, or depression. Yet, male and female fetuses interact differently with the maternal systems, in part due to the differences in fetal/placental-produced sex hormones. As studies outside pregnancy have shown that estrogen and progesterone metabolites can affect and be affected by the gut microbiota, fetal sex may have direct and indirect effects on maternal outcomes. Understanding these differences could enable better tailoring of prenatal care. HighlightsO_LIFetal/placental-produced sex hormones may affect and be affected by the maternal gut microbiota composition and its metabolic functions. C_LIO_LIGut microbiota diversity and composition during pregnancy is linked to the fetal sex. C_LIO_LIBacterially produced beta-glucuronidase (GUS), an enzyme that can deconjugate glucuronide-bound estrogens into free glucuronic acid and free estrogen, is increased in pregnancies with female fetuses, plausibly due higher levels of glucuronide-bound estrogens in female pregnancies that benefit GUS-expressing bacterial species that consume glucuronic acid C_LIO_LIThe maternal co-abundance gut microbial communities (networks) are distinct in pregnancies with female versus male fetuses specially among taxa that could produce GUS. C_LI

bioinformatics↗

bioRxiv2025

A stress-activated mid-insula to BNST pathway regulates susceptibility to abstinence-induced negative affect in female mice

Stress is central to many neuropsychiatric conditions, including alcohol use disorder (AUD). Stress influences the initiation and continued use of alcohol, the progression to AUD, and relapse. Identifying the neurocircuits activated during stress, and individual variability in these responses is critical for developing new treatment targets for AUD, particularly to mitigate stress-induced relapse. Using a longitudinal approach, this study examined the relationship between sub-chronic stress exposure and negative affect during protracted abstinence following chronic ethanol exposure. Sub-chronic restraint stress heightened negative affect-like behavior in protracted abstinence. Interestingly, this was driven by a subset of "stress-susceptible" female mice. We examined the mid-insula, a hub in the brains salience network, as a driver of this effect, given its role in emotional regulation and links to alcohol craving, consumption, and abstinence-induced negative affect. Mid-insula GCaMP fiber photometry revealed that GCaMP activity during stress exposure was positively correlated with activity during the novelty-suppressed feeding test (NSFT) two weeks into abstinence. A distinct subset of mice exhibited increasing activity during the consummatory phase, implicating the mid-insula as a neural basis for heightened negative affect in abstinence. Chemogenetic inhibition of mid-insula neurons projecting to the dorsal BNST during stress disrupted the emergence of stress susceptibility, highlighting this circuit as a key determinant of susceptibility to abstinence-induced negative affect. These outcomes were female-specific, addressing a critical gap in understanding AUD risk in women. Furthermore, female mice exhibited higher struggling behavior during stress than males. However, this effect was blocked by chemogenetic inhibition of the insula-BNST pathway during stress. By linking pre-alcohol stress response with abstinence outcomes, this work positions the insula-BNST pathway as a potential AUD circuit activity biomarker and therapeutic target.

neuroscience↗

bioRxiv2023

A mechanistically novel peptide agonist of the IL-7 receptor that addresses limitations of IL-7 cytokine therapy

Interleukin (IL)-7 is broadly active on T-cell populations, and modified versions have been clinically evaluated for a variety of therapeutic applications, including cancer, lymphopenia and infectious diseases; and found to be relatively well-tolerated and biologically active. Here we describe novel IL-7R agonists that are unrelated in structure to IL-7, bind to the receptor subunits differently from IL-7, but closely emulate IL-7 biology. The small size, low structural complexity, and the natural amino acid composition of the pharmacologically active peptide MDK1472 allows facile incorporation into protein structures, such as the IgG2-Fc fusion MDK-703. This molecule possesses properties potentially better suited to therapeutic applications than native IL-7 or its derivatives. We compared these compounds with IL-7 for immune cell selectivity, induction of IL-7R signaling, receptor-mediated internalization, proliferation, and generation of immune cell phenotypes in human and non-human primate (NHP) peripheral blood cells in vitro; and found them to be similar in biological activity to IL-7. In cynomolgus macaques, MDK-703 exhibits a circulating half-life of 46 hr, and produces sustained T-cell expansion characteristic of IL-7 treatment. In the huCD34+-engrafted NSG mouse model of the human immune system, MDK-703 induces an immune cell profile very similar to that generated by IL-7-derived compounds; including the pronounced expansion of memory T-cells, particularly the population of stem-like memory T-cells (Tscm), which may be important for anti-tumor activities reported with IL-7 treatment. Clinical administration of IL-7 and modified variants has been reported to induce anti-drug antibodies (ADAs), including IL-7 neutralizing antibodies. The novel peptide agonist reported here scores very low in predicted immunogenicity, and because the peptide lacks sequence similarity with IL-7, the problematic immunogenic neutralization of endogenous cytokine should not occur.

immunology↗