Biomedical subjects

Anthony A Fodor

Publications and source records attributed to Anthony A Fodor.

8 recordsLinked to original sources

PubMed2026

Defined human Clostridia consortia reverse colitis via dual effects of tryptophan metabolites on microbiota and immunity.

Microbial dysbiosis and disrupted mucosal immune homeostasis are integrally involved in the pathogenesis of inflammatory bowel diseases (IBDs). Live biotherapeutic products (LBPs) offer a potential therapeutic strategy to restore beneficial microbes and mitigate disease. We investigated the therapeutic efficacy of 2 LBPs, human Clostridia consortia 17-mix and 11-mix, by treating established colitis in murine models. Both LBPs exhibited therapeutic effects in T cell-mediated chronic colitis models induced by human microbiota and in pathobiont-driven gnotobiotic colitis models established with combinations of IBD-relevant human-derived strains. Metagenomic and metabolomic analyses elucidated mechanisms that go beyond established functions driven by short-chain fatty acids (SCFAs) and interleukin (IL)-10-producing regulatory T cells. Notably, LBPs exerted therapeutic effects by directly inhibiting resident pathobionts and through IL-10-independent activation of host anti-inflammatory aryl hydrocarbon receptor (AhR) pathways by bacterial tryptophan metabolites. These results elucidate SCFA- and IL-10-independent protective mechanisms exerted by defined resident bacterial strains that are depleted in IBD dysbiosis.

Animals↗

PubMed2025

Duration of Hospitalization is Associated with the Gut Microbiome in Patients Undergoing Hematopoietic Stem Cell Transplantation: Early Results from a Randomized Trial of Home Versus Hospital Transplantation.

Home-based hematopoietic stem cell transplantation (HCT) is an innovative care model with growing interest, but its impact on the gut microbiome remains unexplored in a randomized setting. We present interim results from the first randomized controlled trials (RCT) evaluating the effect of HCT location-home versus hospital-on gut microbial diversity and antimicrobial resistance (AMR) gene carriage. We hypothesize that patients randomized to undergo home HCT would have higher gut taxonomic diversity and lower AMR gene abundance compared to those undergoing standard hospital HCT. We analyzed stool samples from the first 28 patients enrolled in ongoing Phase II RCTs comparing home (n = 16) and hospital (n = 12) HCT at Duke University using shotgun metagenomic sequencing to compare taxa and AMR gene composition between groups. We also performed a secondary analysis comparing patients who received transplants at outpatient infusion clinics versus inpatient standard HCT to evaluate the influence of hospitalization duration. In the primary RCT analysis, taxonomic and AMR gene α- and β-diversity were comparable between home and hospital groups, reflecting similar durations of hospitalization despite group allocation. In contrast, secondary analyses demonstrated that patients transplanted in outpatient infusion clinics who experienced significantly reduced hospitalization had higher gut taxonomic α-diversity and differential β-diversity, although AMR gene diversity remained unchanged. In summary, randomization by transplant location did not impact the gut microbiota to the same extent as the duration of hospitalization, although secondary analyses were heavily confounded. Even when taxonomic differences were observed, AMR genes were similar between groups. This RCT represents a novel investigation into how care setting influences the gut microbiome during HCT. Our findings suggest that hospital duration, rather than randomization allocation alone, is the primary driver of microbial disruption. These results underscore the potential for reducing hospital duration to mitigate microbiome injury, thereby informing future interventions to reduce infection risk and improve patient outcomes.

Microbiome↗

PubMed2019

Dietary iron variably modulates assembly of the intestinal microbiota in colitis-resistant and colitis-susceptible mice.

Iron deficiency, a common comorbidity of gastrointestinal inflammatory disorders such as inflammatory bowel diseases (IBD), is often treated with oral iron supplementation. However, the safety of oral iron supplementation remains controversial because of its association with exacerbated disease activity in a subset of IBD patients. Because iron modulates bacterial growth and function, one possible mechanism by which iron may exacerbate inflammation in susceptible hosts is by modulating the intestinal microbiota. We, therefore, investigated the impact of dietary iron on the intestinal microbiota, utilizing the conventionalization of germ-free mice as a model of a microbial community in compositional flux to recapitulate the instability of the IBD-associated intestinal microbiota. Our findings demonstrate that altering intestinal iron availability during community assembly modulated the microbiota in non-inflamed wild type (WT) and colitis-susceptible interleukin-10-deficient (Il10-/-) mice. Depletion of luminal iron availability promoted luminal compositional changes associated with dysbiotic states irrespective of host genotype, including an expansion of Enterobacteriaceae such as Escherichia coli. Mechanistic in vitro growth competitions confirmed that high-affinity iron acquisition systems in E. coli enhance its abundance over other bacteria in iron-restricted conditions, thereby enabling pathobiont iron scavenging during dietary iron restriction. In contrast, distinct luminal community assembly was observed with dietary iron supplementation in WT versus Il10-/- mice, suggesting that the effects of increased iron on the microbiota differ with host inflammation status. Taken together, shifts in dietary iron intake during community assembly modulate the ecological structure of the intestinal microbiota and is dependent on host genotype and inflammation status.

Animals↗

PubMed2006

Cochlear function in mice lacking the BK channel alpha, beta1, or beta4 subunits.

Large conductance voltage- and calcium-activated potassium (BK) channels are important for regulating many essential cellular functions, from neuronal action potential shape and firing rate to smooth muscle contractility. In amphibians, reptiles, and birds, BK channels mediate the intrinsic frequency tuning of the cochlear hair cell by an electrical resonance mechanism. In contrast, inner hair cells of the mammalian cochlea are extrinsically tuned by accessory structures of the cochlea. Nevertheless, BK channels are present in inner hair cells and encode a fast activating outward current. To understand the role of the BK channel alpha and beta subunits in mammalian inner hair cells, we analyzed the morphology, physiology, and function of these cells from mice lacking the BK channel alpha (Slo-/-) and also the beta1 and beta4 subunits (beta1/4-/-). Beta1/4-/- mice showed normal subcellular localization, developmental acquisition, and expression of BK channels. Beta1/4-/- mice showed normal cochlear function as indicated by normal auditory brainstem responses and distortion product otoacoustic emissions. Slo-/- mice also showed normal cochlear function despite the absence of the BKalpha subunit and the absence of fast activating outward current from the inner hair cells. Moreover, microarray analyses revealed no compensatory changes in transcripts encoding ion channels or transporters in the cochlea from Slo-/- mice. Slo-/- mice did, however, show increased resistance to noise-induced hearing loss. These findings reveal the fundamentally different contribution of BK channels to nonmammalian and mammalian hearing and suggest that BK channels should be considered a target in the prevention of noise-induced hearing loss.

Animals↗

PubMed2006

BK calcium-activated potassium channels regulate circadian behavioral rhythms and pacemaker output.

Spontaneous action potentials in the suprachiasmatic nucleus (SCN) are necessary for normal circadian timing of behavior in mammals. The SCN exhibits a daily oscillation in spontaneous firing rate (SFR), but the ionic conductances controlling SFR and the relationship of SFR to subsequent circadian behavioral rhythms are not understood. We show that daily expression of the large conductance Ca(2+)-activated K(+) channel (BK) in the SCN is controlled by the intrinsic circadian clock. BK channel-null mice (Kcnma1(-/-)) have increased SFRs in SCN neurons selectively at night and weak circadian amplitudes in multiple behaviors timed by the SCN. Kcnma1(-/-) mice show normal expression of clock genes such as Arntl (Bmal1), indicating a role for BK channels in SCN pacemaker output, rather than in intrinsic time-keeping. Our findings implicate BK channels as important regulators of the SFR and suggest that the SCN pacemaker governs the expression of circadian behavioral rhythms through SFR modulation.

Animals↗

PubMed2006

Statistical limits to the identification of ion channel domains by sequence similarity.

The study of ion channel function is constrained by the availability of structures for only a small number of channels. A commonly used bioinformatics technique is to assert, based on sequence similarity, that a domain within a channel of interest has the same structure as a reference domain for which the structure is known. This technique, while useful, is often employed when there is only a slight similarity between the channel of interest and the domain of known structure. In this study, we exploit recent advances in structural genomics to calculate the sequence-based probability of the presence of putative domains in a number of ion channels. We find strong support for the presence of many domains that have been proposed in the literature. For example, eukaryotic and prokaryotic CLC proteins almost certainly share a common structure. A number of proposed domains, however, are not as well supported. In particular, for the COOH terminus of the BK channel we find a number of literature proposed domains for which the assertion of common structure based on common sequence has a nontrivial probability of error.

Animals↗

PubMed2004

Influence of conservation on calculations of amino acid covariance in multiple sequence alignments.

It has long been argued that algorithms that find correlated mutations in multiple sequence alignments can be used to find structurally or functionally important residues in proteins. We examined the properties of four different methods for detecting these correlated mutations. On both simple, artificial alignments and real alignments from the Pfam database, we found a surprising lack of agreement between the four correlated mutation methods. We argue that these differences are caused in part by differing sensitivities to background conservation. Correlated mutation algorithms can be envisioned as "filters" of background conservation with each algorithm searching for correlated mutations that occur at a different background conservation frequency.

Algorithms↗

PubMed2004

On evolutionary conservation of thermodynamic coupling in proteins.

The inherent complexity of thermodynamic coupling in proteins presents a major challenge in understanding and engineering protein function. Recent work has argued that the study of proteins can be simplified by the use of correlated mutations in the evolutionary record to locate a small subset of thermodynamically coupled residues that participate in functionally important, evolutionarily conserved energetic pathways. To test this hypothesis, we examined the predictions of correlated mutation algorithms for a number of proteins for which coupling between residues has been determined by analysis of double mutant cycles. We find that correlated mutation algorithms can find residue pairs that are physically close and that physically close residue pairs tend to be thermodynamically coupled. We find little evidence, however, for the hypothesis that thermodynamic coupling is limited to the subset of evolutionarily constrained residue positions.

Algorithms↗