Microbiota-related Changes in Bile Acid & Tryptophan Metabolism are Associated with Gastrointestinal Dysfunction in a Mouse Model of Autism

peer-reviewedAutism spectrum disorder (ASD) is one of the most prevalent neurodevelopmental conditions worldwide. There is growing awareness that ASD is highly comorbid with gastrointestinal distress and altered intestinal microbiome, and that host-microbiome interactions may contribute to the disease symptoms. However, the paucity of knowledge on gut-brain axis signaling in autism constitutes an obstacle to the development of precision microbiota-based therapeutics in ASD. To this end, we explored the interactions between intestinal microbiota, gut physiology and social behavior in a BTBR T+ Itpr3tf/J mouse model of ASD. Here we show that a reduction in the relative abundance of very particular bacterial taxa in the BTBR gut – namely, bile-metabolizing Bifidobacterium and Blautia species, - is associated with deficient bile acid and tryptophan metabolism in the intestine, marked gastrointestinal dysfunction, as well as impaired social interactions in BTBR mice. Together these data support the concept of targeted manipulation of the gut microbiota for reversing gastrointestinal and behavioral symptomatology in ASD, and offer specific plausible targets in this endeavor.The APC Microbiome Institute is a research institute funded by Science Foundation Ireland (SFI) through the Irish Government's National Development Plan. J.F·C, T.G.D, C.S., S.A.J. and C.G.M.G. are supported by SFI (Grant Nos. SFI/12/RC/2273). S.A.J is also funded by SFI-EU 16/ERA-HDHL/3358. J.F·C, C.S. and T.G.D have research support from Mead Johnson, Cremo, 4D Pharma, Suntory Wellness, and Nutricia. J.F.C, C.S., T.G.D and G.C. have spoken at meetings sponsored by food and pharmaceutical companies

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Efficacy and Mechanism of Angiotensin II Receptor Blocker Treatment in Experimental Abdominal Aortic Aneurysms

<div><h3>Background</h3><p>Despite the importance of the renin-angiotensin (Ang) system in abdominal aortic aneurysm (AAA) pathogenesis, strategies targeting this system to prevent clinical aneurysm progression remain controversial and unproven. We compared the relative efficacy of two Ang II type 1 receptor blockers, telmisartan and irbesartan, in limiting experimental AAAs in distinct mouse models of aneurysm disease.</p> <h3>Methodology/Principal Findings</h3><p>AAAs were induced using either 1) Ang II subcutaneous infusion (1000 ng/kg/min) for 28 days in male ApoE^−/− mice, or 2) transient intra-aortic porcine pancreatic elastase infusion in male C57BL/6 mice. One week prior to AAA creation, mice started to daily receive irbesartan (50 mg/kg), telmisartan (10 mg/kg), fluvastatin (40 mg/kg), bosentan (100 mg/kg), doxycycline (100 mg/kg) or vehicle alone. Efficacy was determined via serial <em>in vivo</em> aortic diameter measurements, histopathology and gene expression analysis at sacrifice. Aortic aneurysms developed in 67% of Ang II-infused ApoE^−/− mice fed with standard chow and water alone (n = 15), and 40% died of rupture. Strikingly, no telmisartan-treated mouse developed an AAA (n = 14). Both telmisartan and irbesartan limited aneurysm enlargement, medial elastolysis, smooth muscle attenuation, macrophage infiltration, adventitial neocapillary formation, and the expression of proteinases and proinflammatory mediators. Doxycycline, fluvastatin and bosentan did not influence aneurysm progression. Telmisartan was also highly effective in intra-aortic porcine pancreatic elastase infusion-induced AAAs, a second AAA model that did not require exogenous Ang II infusion.</p> <h3>Conclusion/Significance</h3><p>Telmisartan suppresses experimental aneurysms in a model-independent manner and may prove valuable in limiting clinical disease progression.</p> </div

Effect of drug treatment on systolic blood pressure.

<p><b>A:</b> Dot plot graphs show plasma drug levels in individual Ang II-infused ApoE^−/− mice receiving each drug treatment. Horizontal line in each graph indicates mean drug concentration from 10–14 mice in each group. <b>B:</b> Effect of telmisartan, irbesartan, doxycycline and fluvastatin on systolic blood pressure in ApoE^−/− mice 14 and 28 days after Ang II infusion. <b>C:</b> Effect of bosentan on systolic blood pressure in ApoE^−/− mice 7, 14, 21 and 28 days after Ang II infusion. <b>D:</b> Effect of telmisartan on systolic blood pressure in C57BL/6J mice 7 and 14 days after PPE infusion. Data in B–D are given as mean ± standard derivation for each group. Data in B and C were obtained from separate experiments, each with its own control group. In all experiments, two-way ANOVA followed by Newman-Keuls post-test, *<i>P</i><0.05 or <i>**P</i><0.01 compared to control group at same time points. n = 10–15 (A–C) or 7–9 (D) mice in each group.</p

Effect of telmisartan, irbesartan, fluvastatin and doxycycline on aortic diameters of Ang II-infused ApoE^−/− mice.

<p>Noninvasive transabdominal ultrasonography was used to measure suprarenal aortic diameters in individual mice prior to drug treatment (day -7), on the Ang II infusion day (day 0), and 3, 7, 14, 21 and 28 days after Ang II infusion. Data are given as mean ± standard derivation of the aortic diameters for all groups, with all dimensions listed in units of mm. Number of mice in each group is shown in the parenthesis. Two-way ANOVA analysis followed by Newman-Keuls post-test, <i>*P</i><0.05 and <i>**P</i><0.01 compared to the control group at same measurement day.</p

Influence of drug treatment on inflammatory gene expression.

<p>Aortic mRNA expression levels (fold expression) as a function of Ang II infusion (left column) and drug treatment status. Nonparametric Mann-Whiteny test, <i>*P</i><0.05 and <i>**P</i><0.01.</p

Antihypertension-independent effect of telmisartan on AAAs. A–C:

<p>Effect of bosentan on AAA incidence (A), mortality (B) and suprarenal aortic diameters (C) in Ang II-infused ApoE^−/− mice. <b>D:</b> Effect of telmisartan on infrarenal aortic diameters in C57BL/6J mice after PPE infusion. Data in B and D are given as mean ± standard derivation for each group. Two-way ANOVA followed by Newman-Keuls post-test, *<i>P</i><0.05 or <i>**P</i><0.01 compared to the control group at corresponding time points. n = 10–15 (A–C) or 7–9 (D) mice in each group.</p

Influence of drug treatment on AAA incidence and mortality.

<p><b>A–C:</b> Ultrasound images representing an intact aorta (A), an aneurysmal aorta without dissection (B) and an aneurysmal aorta with medial dissection (C). <b>D, E:</b> AAA incidence (D) and mortality (E) in Ang II-infused mice treated with telmisartan, irbesartan, fluvastatin or doxycycline. Kaplan-Meier analysis, <i>*P</i><0.05 and <i>**P</i><0.01 compared to control group, n = 14–15 mice in each group.</p

Microbiota-related Changes in Bile Acid & Tryptophan Metabolism are Associated with Gastrointestinal Dysfunction in a Mouse Model of Autism

Autism spectrum disorder (ASD) is one of the most prevalent neurodevelopmental conditions worldwide. There is growing awareness that ASD is highly comorbid with gastrointestinal distress and altered intestinal microbiome, and that host-microbiome interactions may contribute to the disease symptoms. However, the paucity of knowledge on gut-brain axis signaling in autism constitutes an obstacle to the development of precision microbiota-based therapeutics in ASD. To this end, we explored the interactions between intestinal microbiota, gut physiology and social behavior in a BTBR T+ Itpr3tf/J mouse model of ASD. Here we show that a reduction in the relative abundance of very particular bacterial taxa in the BTBR gut – namely, bile-metabolizing Bifidobacterium and Blautia species, - is associated with deficient bile acid and tryptophan metabolism in the intestine, marked gastrointestinal dysfunction, as well as impaired social interactions in BTBR mice. Together these data support the concept of targeted manipulation of the gut microbiota for reversing gastrointestinal and behavioral symptomatology in ASD, and offer specific plausible targets in this endeavor