Saturday, April 30, 2022

Precision medicine for IBD

Precision medicine, also known as personalized medicine, is a key clinical goal for the effective treatment of heterogeneous, complex diseases such as inflammatory bowel disease (IBD), cancer, autoimmune diseases and COVID-19. 

Recent paper published in the journal Nature Communications describes a precision medicine approach - the integrated SNP (Single Nucleotide Polymorphism) Network Pipeline (iSNP). 

The iSNP tool will help to identify subtype of IBD for every patient based on their specific genetics. It could help to describe the individual pathogenesis story and find the best treatment.

Patients with Inflammatory Bowel Disease (IBD) develop the condition due to distinct and different mechanisms, determined by their genetics. The causes of IBD aren't understood but are linked to dysfunction of the immune system and how it reacts to food and the gut microbiome, including virome

For IBD, less than 10% of the identified SNPs are in coding regions of genes and over 90% of SNPs are in areas once thought to just be junk DNA, controlling and regulating the activity of the genes. The immune system functions by taking a wide range of different inputs that trigger different signaling networks within the cell, integrating these to produce a balanced, appropriate response, so a combination of even subtlest SNPs could disequilibrate the system. Understanding how they combine to influence intricately interlinked signals would fill in major gaps enabling personalized treatment. 

The iSNP workflow identifies patient clusters with distinct pathomechanisms. 

Patient data is layered with population-wide genomics and transcriptomics using. To achieve this, hidden proteins contributing to pathogenesis and key pathogenic pathways are identified and aligned with pathological processes in disease development. 

High-quality individual patient genetic information was used along with preprocessed and quality-controlled immunochip datamiRNA-TS identification algorithm MIRANDA was included in the pipeline along with other genetic analysis tools. A computer simulation of interactions, pathways and networks used databases of known and predicted interactions between proteins in the network.

There was not enough granularity in the clinical data to link all pathways with phenotypes and remove confounders such as recurrent corticosteroid therapy. Further work will need to be done on larger cohorts and with multi-omics datasets to confirm the potential for iSNP to be used for precision therapy based on patient-specific genetics.

REFERENCE

Johanne Brooks-Warburton et al, A systems genomics approach to uncover patient-specific pathogenic pathways and proteins in ulcerative colitis, Nature Communications (2022). DOI: 10.1038/s41467-022-29998-8

Monday, March 21, 2022

Passive sensors for health monitoring

Ubiquitous sensing with the use of passive sensors is on the rise - transforming work, healthcare, leisure and everyday life. 

We would love to collect data relevant to our health without extra effort on our part. Carriable and wearable sensors require some effort - for example, they have to be periodically charged. They should be small, light and forgettable to be more convenient, but this increases the chance that you can forget or even lose them.

Ten years ago, wearables were predicted to evolve into insideables. The road was longer than expected. The rise and fall of Proteus Digital Health teaches us about the dangers of complexity and excessive costs in remote health. Besides inconveniencing the patients - that had to wear a patch to collect the signals from ingested pills - their technology also required commitment from insurers and doctors and changing the healthcare system's model of funding drugs. 

But the ingestible sensors keep evolving. One of the latest proposals is a dissolvable biodegradable sensor that monitors gut bacteria.  

Diagnosing and screening for digestive conditions is challenging and time-consuming. And so is monitoring and managing it. Assessment still heavily relies on self-report mechanisms and great opportunities exist for novel, transformational tools - but they should be sufficiently accurate, frequently updated and integrated with rapidly evolving knowledge, detailed, ethical, easy and fun to use (and maintain/calibrate), defending user privacy and developers' intellectual property while providing monetization opportunities

Some sensors are more successful than others. Pfizer was able to monitor patients’ eczema-related scratching at night by providing them a wearable motion tracker. But there is a luck of fun tools for monitoring digestive disorders. The compliance to IBD-Home, for example, was very low (29%). Still, home monitoring was determined to be feasible and a fully digital Virtual IBD clinic is picking up steam. 


REFERENCES

Inami A, Kan T, Onoe H. Ingestible Wireless Capsule Sensor Made from Edible Materials for Gut Bacteria Monitoring. In2022 IEEE 35th International Conference on Micro Electro Mechanical Systems Conference (MEMS) 2022 Jan 9 (pp. 110-113). IEEE.

Das SK, Miki AJ, Blanchard CM, Sazonov E, Gilhooly CH, Dey S, Wolk CB, Khoo CS, Hill JO, Shook RP. Perspective: opportunities and challenges of technology tools in dietary and activity assessment: bridging stakeholder viewpoints. Advances in Nutrition. 2022 Jan;13(1):1-5.

Puolanne AM, Kolho KL, Alfthan H, Färkkilä M. Is home monitoring of inflammatory bowel disease feasible? A randomized controlled study. Scandinavian Journal of Gastroenterology. 2019 Jul 3;54(7):849-54.

Taylor NS. Utilising new technologies and supported self-management to enhance the inflammatory bowel disease patient pathway: pilot, feasibility and development studies (Doctoral dissertation, University of Southampton).

Sunday, January 2, 2022

Lipid dysregulation

Compared to control subjects, patients with IBS show significantly higher lipid levels in their blood. Elevated levels of certain lipids, such as arachidonic acid, in plasma may even serve as putative biological markers in this condition. Lipids have been shown to sensitize mechanoreceptor response and increase perception of gut distention. Some of probiotics beneficial to irritable bowel - such as Lactobacillus or Bifidobacterium - are related to the lipid metabolism displaying lipid-lowering effects.

Dysregulation of lipid metabolism has been a hallmark of many other diseases and conditions including cancer and COVID-19.


Lipids play a crucial role throughout the viral life cycle, and viruses are known to exploit lipid pathways to affect host metabolism. Numerous observational studies have shown potential beneficial effects of lipid-lowering treatment on the course of COVID-19 with significant improved prognosis and reduced mortality. On the other hand, bioactive lipids have been proposed as potential drugs helping to combat COVID-19.  

Here is what we know.

Glycerolipids and glycerophospholipids are markers of severe COVID-19, increased in ARDS (acute respiratory distress syndrome). Lipid storm can be self-destructive enhancing peptide-mediated cytokine storms. Dysregulation of lipid metabolism may be a defining feature of the severity of COVID-19. 

Shorter chain lipids were found at increased levels after successful COVID vaccination.

Sphingolipids, especially Sphingomyelin (SM) that associates with cholesterol to form lipid rafts that promote Coronavirus entry on the cellular surface (help viral S-protein to bind the cellular receptor ACE2) are decreased in asymptomatic patients. Other ether lipids [including PC O-35:4 (i), LPC O-18:1 (i) and LPE O-18:2], sphingomyelin (SM34:1; O2), and fatty acids (including FA 18:1 and FA 20:0) are also decreased in asymptomatic COVID.

Lysophospholipids including lysophosphatidylserine (LPS) 18:1, lysophosphatidic acid (LPA) 18:1 and LPA 18:0, lysophosphatidylcholine (LPC) 22:1, and lysophosphatidylinositol (LPI) 18:1 are generally decreased in asymptomatic COVID-19 patients. - Diacylglycerol (DG) 30:0 (14:0_16:0), DG 36:5 (18:2_18:3), phosphatidylcholine (PC) 36:5 (18:2_18:3), and phosphatidylethanolamine (PE) 36:2 (18:0_18:2) are increased. These lipids seem to have a protective effect in COVID-19.

Bioactive lipids - phospholipids including Plasmalogens and PAFs, gamma-linolenic acid (GLA), dihomo-GLA (DGLA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) help cells of the innate immune system - macrophages - with phagocytosis. Targeting membrane sphingolipids and interfering with the virus lipid metabolism could represent a promising path to follow towards the development of COVID-19 treatments. 


REFERENCES

Lee SH, Kim KN, Kim KM, Joo NS. Irritable bowel syndrome may be associated with elevated alanine aminotransferase and metabolic syndrome. Yonsei medical journal. 2016 Jan 1;57(1):146-52.

Serra J, Salvioli B, Azpiroz F, Malagelada JR. Lipid-induced intestinal gas retention in irritable bowel syndrome. Gastroenterology. 2002 Sep 1;123(3):700-6.

Schwarz B, Sharma L, Roberts L, Peng X, Bermejo S, Leighton I, Casanovas-Massana A, Minasyan M, Farhadian S, Ko AI, Cruz CS. Cutting edge: Severe SARS-CoV-2 infection in humans is defined by a shift in the serum lipidome, resulting in dysregulation of eicosanoid immune mediators. The Journal of Immunology. 2021 Jan 15;206(2):329-34.

Hao Y, Zhang Z, Feng G, Chen M, Wan Q, Lin J, Wu L, Nie W, Chen S. Distinct lipid metabolic dysregulation in asymptomatic COVID-19. Iscience. 2021 Sep 24;24(9):102974.

Surma S, Banach M, Lewek J. COVID-19 and lipids. The role of lipid disorders and statin use in the prognosis of patients with SARS-CoV-2 infection. Lipids in Health and Disease. 2021 Dec;20(1):1-4.

Casari I, Manfredi M, Metharom P, Falasca M. Dissecting lipid metabolism alterations in SARS-CoV-2. Progress in Lipid Research. 2021 Feb 8:101092.

Demopoulos CA. Is Platelet-Activating Factor (PAF) a missing link for elucidating the mechanism of action of the coronavirus SARS-CoV-2 and explaining the side effects-complications of Covid-19 disease?.

Deng Y, Angelova A. Coronavirus-Induced Host Cubic Membranes and Lipid-Related Antiviral Therapies: A Focus on Bioactive Plasmalogens. Frontiers in Cell and Developmental Biology. 2021 Mar 12;9:551.

Martín-Fernández M, Aller R, Heredia-Rodríguez M, Gómez-Sánchez E, Martínez-Paz P, Gonzalo-Benito H, Sánchez-de Prada L, Gorgojo Ó, Carnicero-Frutos I, Tamayo E, Tamayo-Velasco Á. Lipid peroxidation as a hallmark of severity in COVID-19 patients. Redox biology. 2021 Dec 1;48:102181.

Das UN. Bioactive lipids-based therapeutic approach to COVID-19 and other similar infections. Archives of Medical Science. 2021.