Microbiome changes associated with acute and chronic pancreatitis: A systematic review.

BACKGROUND: Altered intestinal microbiota has been reported in pancreatic disorders, however, it remains unclear whether these changes alter the course of disease in patients with acute (AP) and chronic pancreatitis (CP), or whether these disease states alter the environment to enable pathogenic microbial composition changes to occur. We undertook a systematic review to characterize the gut microbiome in pancreatitis patients. METHODS: MEDLINE and EMBASE were searched for studies on microbiota in pancreatitis published from January 1, 2000 to June 5, 2020. Animal studies, reviews, case reports, and non-English articles were excluded. A frequency analysis was performed for outcomes reported in ≥2 studies and studies were analyzed for risk of bias and quality of evidence. RESULTS: 22 papers met inclusion criteria; 15 included AP, 7 included CP. No studies were appropriately designed to assess whether alterations in the gut microbiome exacerbate pancreatitis or develop as a result of pancreatitis. We did identify several patterns of microbiome changes that are associated with pancreatitis. The gut microbiome demonstrated decreased alpha diversity in 3/3 A P studies and 3/3 C P studies. Beta diversity analysis revealed differences in bacterial community composition in the gut microbiome in 2/2 A P studies and 3/3 C P studies. Functionally, gut microbiome changes were associated with infectious pathways in AP and CP. Several studies suffered from high risk of bias and inadequate quality. CONCLUSIONS: Detecting differences in microbial composition associated with AP and CP may represent a diagnostic tool. Appropriately controlled longitudinal studies are needed to determine whether microbiome changes are causative or reactive in pancreatitis.

Correction: Therapeutic targeting of Id2 reduces growth of human colorectal carcinoma in the murine liver.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Therapeutic targeting of Id2 reduces growth of human colorectal carcinoma in the murine liver.

During development inhibitor of DNA-bind-2 (Id2) regulates proliferation and differentiation. Id2 expression has been detected in cancer cells, yet its cellular function and validity as a therapeutic target remains largely unknown. Immunohistochemical analysis of colorectal cancer (CRC) specimens revealed that Id2 was undetectable in normal colonic mucosa, but occurs in 40% of primary tumors and in most CRC liver metastases (P<0.0001). Additionally, Id2 was expressed in all CRC cell lines assayed. CRC cells with reduced Id2 expression demonstrated reduced proliferation. Analysis of CRC cell cycle regulatory proteins showed that reducing Id2 levels reduces cyclin D1 levels and increased p21 levels. Reduction of Id2 expression also enhanced tumor cell apoptosis, increasing levels of the pro-apoptotic protein Bim/Bod, and cleavage of caspase-7 and poly (ADP-ribose) polymerase. In vivo studies show tumors derived from cells with decreased Id2 levels formed smaller tumors with fewer metastases compared with tumors with normal levels (P<0.05). Furthermore, intraperitoneal administration of Id2 small interfering RNA (siRNA) conjugated with the neutral liposome 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine decreased tumor burden in mice compared with control treatment (P=0.006). We conclude that Id2 is upregulated in CRC, and is important in promoting cell survival. In vivo targeting of Id2 by siRNA establishes that it is a valid therapeutic target where its expression occurs.

Estrogen-induced uterine vasodilatation is antagonized by L-nitroarginine methyl ester, an inhibitor of nitric oxide synthesis.

OBJECTIVES: Our study was designed to determine whether nitric oxide mediates estrogen-induced increases in uterine blood flow. STUDY DESIGN: Six nonpregnant oophorectomized ewes were instrumented with uterine artery flow probes and catheters. Ewes received estradiol-17 beta 1 microgram/kg, which maximally increased uterine blood flow by 120 minutes. Each animal then received local bolus injections of the nitric oxide synthetase inhibitor L-nitroarginine methyl ester. RESULTS: Estradiol-17 beta increased uterine blood flow from 16 +/- 6 to 139 +/- 32 ml/min by 120 minutes. Local uterine artery administration of L-nitroarginine methyl ester (1 to 30 mg) caused a dose-related decrease in uterine blood flow, which reached a maximum of 59% +/- 6% inhibition. Higher doses of L-nitroarginine methyl ester less than or equal to 10 mg/kg (330 to 460 mg) given locally led to a maximum inhibition of 79% +/- 3% but showed systemic responses. CONCLUSION: Estradiol-17 beta-induced increases in uterine blood flow are mediated mainly by nitric oxide; the observed vasodilation can be antagonized by the intraaterial administration of nitric oxide synthetase inhibitor L-nitroarginine methyl ester.

Effect of calcitonin gene-related peptide on the uterine vasculature of the nonpregnant ewe.

OBJECTIVES: The current study was designed to evaluate the uterine vascular effects of calcitonin gene-related peptide on the uterine vasculature of nonpregnant sheep and compare them with the effects of prostacyclin. STUDY DESIGN: Five nonpregnant oophorectomized ewes were instrumented with uterine and pulmonary artery flow probes and catheters. Dose-response curves were constructed according to increasing doses of calcitonin gene-related peptide (0.01, 0.03, 0.1, 0.3, 1, and 3, micrograms/min) and prostacyclin (0.03, 0.1, 0.3, 1, 3, and 10 micrograms/min) via 10-minute uterine artery infusions. RESULTS: Both calcitonin gene-related peptide and prostacyclin produced a significant increase in uterine blood flow and a decrease in uterine vascular resistance. Calcitonin gene-related peptide was found to be approximately 17 times more potent than prostacyclin as a vasodilator. Local uterine artery infusions of calcitonin gene-related peptide led to significant increases in heart rate but did not alter blood pressure, cardiac output, or total peripheral resistance at the doses tested. In contrast, at doses of prostacyclin that produced similar uterine vasodilatation, prostacyclin led to significant decreases in systemic arterial blood pressure and total peripheral resistance and increases in heart rate and cardiac output. CONCLUSION: These data strongly suggest that calcitonin gene-related peptide, an endogenously occurring vasoactive peptide, could play an important role in regulating uterine and systemic hemodynamics.

Comparison of the urinary bladder base and detrusor to cholinergic and histaminergic receptor activation in the rabbit.

The effects of cholinergic and histaminergic agonists and antagonists on the receptor responsiveness of the bladder as well as the fundus were compared. Carbachol and histamine were more potent and generated a greater force of contraction in the detrusor muscle than in the neck region. Histamine characteristically produced a rapid twitch-like contraction followed by an increase in motility in the neck smooth muscle while it produced an increased sustained contraction similarly induced by carbachol in the detrusor preparation. Pyrilamine was equally effective in competitively blocking histamine response in both the detrusor and neck preparations. We conclude that the bladder neck, like the detrusor regions, has cholinergic and H1 histaminergic receptors.