Biology subjects

Martyniuk, C. J.

Publications and source records attributed to Martyniuk, C. J..

3 recordsLinked to original sources

bioRxiv2026

Loss of Bone Marrow β1/β2-Adrenergic Receptors Reprograms Host-Microbiota Interactions and Protects Against Diet-Induced Obesity

The gut ecosystem is shaped by multiple factors with the immune system being one of the major determinants in shaping its composition in health and disease. On the other hand, the immune system regulates its responses through the action of the sympathetic nervous system (SNS) in part through beta-adrenergic receptors 1/2 (ADRB1/2). In the past years, a clear link has been established between the immune system, SNS, and the modification of nutrient absorption by the gut microbiota in the development of diet-induced obesity. We have previously shown in male mice transplanted with bone marrow cells ADRB1/2 knock-out mice (KD) showed mild immunosuppression and microbiota changes. Post-recovery, mice were challenged with high-fat diet (HFD) for two weeks ad libitum. Our findings show that KD mice are protected against diet-induced adiposity and weight gain. Additionally, these mice showed an increase in residual calorific values and a decreased expression of the fatty acid transporter FAT/CD36. Suggesting a decreased absorption of lipids in the KD mice. Gut microbiota analysis showed that KD microbiota composition on a HFD remained stable with a significant enrichment in the Bacteroidetes phylum, which is depleted in obesity. This was associated with a switch from triglycerides to diglyceride fecal profile. Moreover, microbiome culture showed a decrease in triglycerides after an incubation with 0.1% of HFD lipid extract. Suggesting a potential role of the Bacteroidetes phylum in the metabolism of these lipids. Our findings demonstrate not only that the gut microbiota can modify nutrient absorption and susceptibility to diet-induced obesity but also that the immune system contributes to selective depletion of microbial members that would otherwise thrive on dietary lipids. Revealing a novel mechanism by which host immunity sculpts the gut ecosystem in ways that influence metabolic outcomes.

physiology↗

bioRxiv2025

Characterizing common loss-of-function genes and their potential utility in assessing population variability and chemical susceptibility

Inter-individual and population variability in susceptibility to chemical exposures confounds determination of threshold exposure levels to protect the most vulnerable. Current risk assessment frameworks, in the absence of empiric chemical-specific data, generally recommend default or probabilistic adjustment factors to account for such variability. We present an experimental approach to incorporate common genetic variants potentially impacting population-level differences in toxicant susceptibility into human cell-based models for any cellular apical endpoint of interest. We focus on the genes with the most common aggregate loss-of-function (LoF) alleles in the gnomAD v3.0 data which we designated as the PopVarLoF set. Unexpectedly, enrichment analysis of these genes found significant overrepresentation of gene products playing important functional roles in toxicology. Interrogation of GWAS and PheWAS databases found that these genes are associated with diverse metabolic phenotypes consistent with the relevance of the PopVarLoF set in studying variability of toxicant response in human populations. We further characterized the PopVarLoF set by developing custom lentiviral CRISPR knockout libraries targeting the PopVarLoF genes to assess their functional essentiality in the HepG2/C3A cell line. Functional disruption of 14 of the PopVarLoF genes ([~]1 %) without toxicant exposure resulted in significant growth defects in this cell line, consistent with the majority of PopVarLoF gene products having non-essential roles. The development of human cell-based toxicity assays or other NAMs which include the empiric assessment of common genetic sources of population variability in susceptibility to chemical exposure could contribute to more robust risk assessment which protects vulnerable populations while reducing uncertainty. Impact statementWe characterize common loss of function genetic variants which could impact toxicant susceptibility and describe an approach to incorporate them into NAMs to enable empiric estimates of the contribution of genetic variability to diverse toxicity endpoints.

pharmacology and toxicology↗

bioRxiv2024

Intestinal serotonergic vagal signaling as a mediator of microbiota-induced hypertension

Hypertension is a pervasive global health challenge, impacting over a billion individuals worldwide. Despite strides in therapeutic strategies, a significant proportion of patients remain resistant to the currently available therapies. While conventional treatments predominantly focus on cardiac, renal, and cerebral targets, emerging research underscores the pivotal role of the gut and its microbiota. Yet, the precise mechanisms governing interactions between the gut microbiota and the host blood pressure remain unclear. Here we describe a neural host-microbiota interaction that is mediated by the intestinal serotonin (5-HT) signaling via vagal 5HT3a receptors and which is crucial for maintenance of blood pressure homeostasis. Notably, a marked decrease in both intestinal 5-HT and vagal 5HT3aR signaling is observed in hypertensive rats, and in rats subjected to fecal microbiota transplantation from hypertensive rats. Leveraging an intersectional genetic strategy in a Cre rat line, we demonstrate that intestinal 5HT3aR vagal signaling is a crucial link between the gut microbiota and blood pressure homeostasis and that recovery of 5-HT signaling in colon innervating vagal neurons can alleviate hypertension. This paradigm-shifting finding enhances our comprehension of hypertensive pathophysiology and unveils a promising new therapeutic target for combating resistant hypertension associated with gut dysbiosis.

physiology↗