Attention Deficit Hyperactivity Disorder (ADHD) and the gut microbiome: An ecological perspective.

Attention Deficit Hyperactivity Disorder (ADHD) is an increasingly prevalent neuropsychiatric disorder characterized by hyperactivity, inattention, and impulsivity. Symptoms emerge from underlying deficiencies in neurocircuitry, and recent research has suggested a role played by the gut microbiome. The gut microbiome is an ecosystem of interdependent taxa involved in an exponentially complex web of interactions, plus host gene and reaction pathways, some of which involve neurotransmitters with roles in ADHD neurocircuitry. Studies have analyzed the ADHD gut microbiome using macroscale metrics such as diversity and differential abundance, and have proposed several taxa as elevated or reduced in ADHD compared to Control. Few studies have delved into the complex underlying dynamics ultimately responsible for the emergence of such metrics, leaving a largely incomplete, sometimes contradictory, and ultimately inconclusive picture. We aim to help complete this picture by venturing beyond taxa abundances and into taxa relationships (i.e. cooperation and competition), using a publicly available gut microbiome dataset (targeted 16S, v3-4 region, qPCR) from an observational, case-control study of 30 Control (15 female, 15 male) and 28 ADHD (15 female, 13 male) undergraduate students. We first perform the same macroscale analyses prevalent in ADHD gut microbiome literature (diversity, differential abundance, and composition) to observe the degree of correspondence, or any new trends. We then estimate two-way ecological relationships by producing Control and ADHD Microbial Co-occurrence Networks (MCNs), using SparCC correlations (p ≤ 0.01). We perform community detection to find clusters of taxa estimated to mutually cooperate along with their centroids, and centrality calculations to estimate taxa most vital to overall gut ecology. We finally summarize our results, providing conjectures on how they can guide future experiments, some methods for improving our experiments, and general implications for the field.

70th Anniversary Collection for the Microbiology Society: Journal of Medical Microbiology.

In the last 70 years, we have seen a radical change in our perception and understanding of the microbial world. During this period, we learned from Woese and Fox there exists a third kingdom called 'Archea' based on the phylogenetic studies of the 16S rRNA that revolutionized microbiology (Woese & Fox, 1977; Woese et al., 1978). Furthermore, we were forced to reckon with the fact that Koch and Pasteur's way of growing cells in test-tubes or flasks planktonically does not necessarily translate to the real-life scenario of bacterial lifestyle, where they prefer to live and function as a closely knit microbial community called biofilm. Thanks are due to Costerton, who led the crusade on the concept of biofilms and expanded its scope of inquiry, which forced scientists and clinicians worldwide to rethink how we evaluate and apply the data. Then progressively, disbelief turned into belief, and now it is universally accepted that the micro-organisms hobnob with the members of their community to communicate and coordinate their behaviour, especially in regard to growth patterns and virulence traits via signalling molecules. Just when we thought that we were losing the battle against bacteria, antimicrobials were discovered. We then witnessed the rise and fall of antibiotics and the development of antibiotic resistance. Due to space and choice limitation, we will focus on the three areas that caused this major paradigm shift (i) antimicrobial resistance (AMR), (ii) biofilm and (iii) quorum sensing (QS), and how the Journal of Medical Microbiology played a major role in advancing the shift.

Pseudomonas aeruginosa MifS-MifR Two-Component System Is Specific for α-Ketoglutarate Utilization.

Pseudomonas aeruginosa is a Gram-negative, metabolically versatile opportunistic pathogen that elaborates a multitude of virulence factors, and is extraordinarily resistant to a gamut of clinically significant antibiotics. This ability, in part, is mediated by two-component regulatory systems (TCS) that play a crucial role in modulating virulence mechanisms and metabolism. MifS (PA5512) and MifR (PA5511) form one such TCS implicated in biofilm formation. MifS is a sensor kinase whereas MifR belongs to the NtrC superfamily of transcriptional regulators that interact with RpoN (σ54). In this study we demonstrate that the mifS and mifR genes form a two-gene operon. The close proximity of mifSR operon to poxB (PA5514) encoding a ß-lactamase hinted at the role of MifSR TCS in regulating antibiotic resistance. To better understand this TCS, clean in-frame deletions were made in P. aeruginosa PAO1 creating PAO∆mifS, PAO∆mifR and PAO∆mifSR. The loss of mifSR had no effect on the antibiotic resistance profile. Phenotypic microarray (BioLOG) analyses of PAO∆mifS and PAO∆mifR revealed that these mutants were unable to utilize C5-dicarboxylate α-ketoglutarate (α-KG), a key tricarboxylic acid cycle intermediate. This finding was confirmed using growth analyses, and the defect can be rescued by mifR or mifSR expressed in trans. These mifSR mutants were able to utilize all the other TCA cycle intermediates (citrate, succinate, fumarate, oxaloacetate or malate) and sugars (glucose or sucrose) except α-KG as the sole carbon source. We confirmed that the mifSR mutants have functional dehydrogenase complex suggesting a possible defect in α-KG transport. The inability of the mutants to utilize α-KG was rescued by expressing PA5530, encoding C5-dicarboxylate transporter, under a regulatable promoter. In addition, we demonstrate that besides MifSR and PA5530, α-KG utilization requires functional RpoN. These data clearly suggests that P. aeruginosa MifSR TCS is involved in sensing α-KG and regulating its transport and subsequent metabolism.