Diffusion magnetic resonance spectroscopy captures microglial reactivity related to gut-derived systemic lipopolysaccharide: A preliminary study.

Neuroinflammation is a key component underlying multiple neurological disorders, yet non-invasive and cost-effective assessment of in vivo neuroinflammatory processes in the central nervous system remains challenging. Diffusion weighted magnetic resonance spectroscopy (dMRS) has shown promise in addressing these challenges by measuring diffusivity properties of different neurometabolites, which can reflect cell-specific morphologies. Prior work has demonstrated dMRS utility in capturing microglial reactivity in the context of lipopolysaccharide (LPS) challenges and serious neurological disorders, detected as changes of microglial metabolite diffusivity properties. However, the extent to which such dMRS metrics are capable of detecting subtler and more nuanced levels of neuroinflammation in populations without overt neuropathology is unknown. Here we examined the relationship between intrinsic, gut-derived levels of systemic LPS and dMRS-based apparent diffusion coefficients (ADC) of choline, creatine, and N-acetylaspartate (NAA) in two brain regions: the thalamus and the corona radiata. Higher plasma LPS concentrations were significantly associated with increased ADC of choline and NAA in the thalamic region, with no such relationships observed in the corona radiata for any of the metabolites examined. As such, dMRS may have the sensitivity to measure microglial reactivity across populations with highly variable levels of neuroinflammation, and holds promising potential for widespread applications in both research and clinical settings.

Gut-brain pathogenesis of post-acute COVID-19 neurocognitive symptoms.

Approximately one third of non-hospitalized coronavirus disease of 2019 (COVID-19) patients report chronic symptoms after recovering from the acute stage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Some of the most persistent and common complaints of this post-acute COVID-19 syndrome (PACS) are cognitive in nature, described subjectively as "brain fog" and also objectively measured as deficits in executive function, working memory, attention, and processing speed. The mechanisms of these chronic cognitive sequelae are currently not understood. SARS-CoV-2 inflicts damage to cerebral blood vessels and the intestinal wall by binding to angiotensin-converting enzyme 2 (ACE2) receptors and also by evoking production of high levels of systemic cytokines, compromising the brain's neurovascular unit, degrading the intestinal barrier, and potentially increasing the permeability of both to harmful substances. Such substances are hypothesized to be produced in the gut by pathogenic microbiota that, given the profound effects COVID-19 has on the gastrointestinal system, may fourish as a result of intestinal post-COVID-19 dysbiosis. COVID-19 may therefore create a scenario in which neurotoxic and neuroinflammatory substances readily proliferate from the gut lumen and encounter a weakened neurovascular unit, gaining access to the brain and subsequently producing cognitive deficits. Here, we review this proposed PACS pathogenesis along the gut-brain axis, while also identifying specific methodologies that are currently available to experimentally measure each individual component of the model.

Hydrogen Availability Is Dependent on the Actions of Both Hydrogen-Producing and Hydrogen-Consuming Microbes.

Hydrogen gas (H2) is produced by H2-producing microbes in the gut during polysaccharide fermentation. Gut microbiome also includes H2-consuming microbes utilizing H2 for metabolism: methanogens producing methane, CH4, and sulfate-reducing bacteria producing hydrogen sulfide, H2S. H2S is not measured in the evaluation of gaseous byproducts of microbial fermentation. We hypothesize that the availability of measured H2 depends on both hydrogen producers and hydrogen consumers by measuring H2 in vitro and in vivo. In the in vitro study, groups were Bacteroides thetaiotaomicron (B. theta, H2 producers), Desulfovibrio vulgaris (D. vulgaris, H2 consumers), and D. vulgaris + B. theta combined. Gas samples were collected at 2 h and 24 h after incubation and assayed for H2, CH4, and H2S. In the in vivo study Sprague-Dawley rats were gavaged with suspended bacteria in four groups: B. theta, D. vulgaris, combined, and control. Gas was analyzed for H2 at 60 min. In the in vitro experiment, H2 concentration was higher in the combined group (188 ± 93.3 ppm) compared with D. vulgaris (27.17 ± 9.6 ppm) and B. theta groups (34.2 ± 29.8 ppm; P < 0.05); H2S concentration was statistically higher in the combined group (10.32 ± 1.5 ppm) compared with B. theta (0.19 ± 0.03 ppm) and D. vulgaris group (3.46 ± 0.28 ppm; P < 0.05). In the in vivo study, H2 concentrations were significantly higher in the B. theta group (44.3 ± 6.0 ppm) compared with control (31.8 ± 4.3) and the combined group (34.2 ± 8.7, P < 0.05). This study shows that sulfate-reducing bacteria could convert available H2 to H2S, leading to measured hydrogen levels that are dependent on the actions of both H2 producers and H2 consumers.

Hydrogen Sulfide Actions in the Vasculature.

Hydrogen sulfide (H2 S) is a small, gaseous molecule with poor solubility in water that is generated by multiple pathways in many species including humans. It acts as a signaling molecule in many tissues with both beneficial and pathological effects. This article discusses its many actions in the vascular system and the growing evidence of its role to regulate vascular tone, angiogenesis, endothelial barrier function, redox, and inflammation. Alterations in some disease states are also discussed including potential roles in promoting tumor growth and contributions to the development of metabolic disease. © 2021 American Physiological Society. Compr Physiol 11:1-22, 2021.

Portal Venous Flow Is Increased by Jejunal but Not Colonic Hydrogen Sulfide in a Nitric Oxide-Dependent Fashion in Rats.

Hydrogen sulfide (H2S) is a recently discerned endogenous signaling molecule that modulates the vascular system. Endogenous hydrogen sulfide has been shown to dilate both the mesenteric and portal vasculature. Gut microbiome, via sulfur reducing bacteria, is another source of H2S production within the gut lumen; this source of H2S is primarily produced and detoxified in the colon under physiologic conditions. Nitric oxide (NO), a major endogenous vasodilator in the portal circulation, participates in H2S-induced vasodilation in some vascular beds. We hypothesize that jejunal but not colonic H2S increases portal vein flow in a NO-dependent fashion. To evaluate the effects of luminal H2S, venous blood flow, portal venous pressure, and systemic venous pressure were measured in rats after administration of either vehicle or an H2S donor (NaHS) into the jejunum or the colon. We found that portal venous pressure and systemic pressure did not change and were similar between the three study groups. However, portal venous blood flow significantly increased following jejunal administration of NaHS but not in response to colonic NaHS or vehicle administration. To test the contribution of NO production to this response, another group of animals was treated with either an NO synthase inhibitor (N-Ω-nitro-L-arginine, L-NNA) or saline prior to jejunal NaHS infusion. After L-NNA pretreatment, NaHS caused a significant fall rather than increase in portal venous flow compared to saline pretreatment. These data demonstrate that H2S within the small intestine significantly increases portal venous blood flow in a NO-dependent fashion.

Reevaluating our understanding of lactulose breath tests by incorporating hydrogen sulfide measurements.

BACKGROUND AND AIM: Breath testing has become a commonly used tool in gastroenterology to evaluate changes in the fermentation pattern of the gut microbiome. Currently, hydrogen and methane gas concentrations are measured in breath testing and evaluated against specific cut-off values for interpretation as normal or abnormal. However, microbial gas kinetics is a complex process that is not currently fully considered when interpreting breath gas results. Gas exchange between hydrogen producers and hydrogen consumers (methanogens and sulfate-reducing bacteria) is a process whereby hydrogen availability is determined by both its production and removal. Hydrogen sulfide is a crucial gas involved in this process as it is a major hydrogen-consumptive pathway involved in energy exchange. METHODS: This is a cross-sectional study evaluating lactulose breath testing with the inclusion of hydrogen sulfide measurements in patients referred for breath testing for gastrointestinal symptoms of bloating, excessive gas, and/or abdominal pain. RESULTS: A total of 159 patients were analyzed between October 2016 and June 2017. Mean hydrogen concentrations with a positive trend through a 3-h period (R 2 = 0.97), mean methane concentrations with a positive trend (R 2 = 0.69), and mean hydrogen sulfide concentrations with a negative trend (R 2 = -0.71) were observed. CONCLUSION: By incorporating energy exchange in the interpretation of the lactulose breath test, we reevaluated specific breath gas profiles, including those commonly described as "hydrogen nonproducers" and the "double-peak" phenomenon.

Malignant biliary obstruction: From palliation to treatment.

Malignant obstruction of the bile duct from cholangiocarcinoma, pancreatic adenocarcinoma, or other tumors is a common problem which may cause debilitating symptoms and increase the risk of subsequent surgery. The optimal treatment - including the decision whether to treat prior to resection - depends on the type of malignancy, as well as the stage of disease. Preoperative biliary drainage is generally discouraged due to the risk of infectious complications, though some situations may benefit. Patients who require neoadjuvant therapy will require decompression for the prolonged period until attempted surgical cure. For pancreatic cancer patients, self-expanding metallic stents are superior to plastic stents for achieving lasting decompression without stent occlusion. For cholangiocarcinoma patients, treatment with percutaneous methods or nasobiliary drainage may be superior to endoscopic stent placement, with less risk of infectious complications or failure. For patients of either malignancy who have advanced disease with palliative goals only, the choice of stent for endoscopic decompression depends on estimated survival, with plastic stents favored for survival of < 4 mo. New endoscopic techniques may actually extend stent patency and patient survival for these patients by achieving local control of the obstructing tumor. Both photodynamic therapy and radiofrequency ablation may play a role in extending survival of patients with malignant biliary obstruction.