Fatty acids are good energy sources (9 kcal per gram) that aerobic tissues can use except for the brain (glucose is an alternative source). Apart from the energy source, fatty acids are necessary for cell signaling, learning-related memory, modulating gene expression, and functioning as cytokine precursors. Short-chain fatty acids (SCFAs) are saturated fatty acids arranged as a straight chain consisting minimum of 6 carbon atoms. SCFAs possess various beneficial effects like improving metabolic function, inhibiting insulin resistance, and ameliorating immune dysfunction. In this review, we discussed the biogenesis, absorption, and transport of SCFA. SCFAs can act as signaling molecules by stimulating G protein-coupled receptors (GPCRs) and suppressing histone deacetylases (HDACs). The role of SCFA on glucose metabolism, fatty acid metabolism, and its effect on the immune system is also reviewed with updated details. SCFA possess anticancer, anti-diabetic, and hepatoprotective effects. Additionally, the association of protective effects of SCFA against brain-related diseases, kidney diseases, cardiovascular damage, and inflammatory bowel diseases were also reviewed. Nanotherapy is a branch of nanotechnology that employs nanoparticles at the nanoscale level to treat various ailments with enhanced drug stability, solubility, and minimal side effects. The SCFA functions as drug carriers, and nanoparticles were also discussed. Still, much research was not focused on this area. SCFA functions in host gene expression through inhibition of HDAC inhibition. However, the study has to be focused on the molecular mechanism of SCFA against various diseases that still need to be investigated.

Short-chain fatty acid: An updated review on signaling, metabolism, and therapeutic effects.

Short-chain fatty acids (SCFAs) derived from the fermentation of carbohydrates by gut microbiota play a crucial role in regulating host physiology. Among them, acetate, propionate, and butyrate are key players in various biological processes. Recent research has revealed their significant functions in immune and inflammatory responses. For instance, butyrate reduces the development of interferon-gamma (IFN-γ) generating cells while promoting the development of regulatory T (Treg) cells. Propionate inhibits the initiation of a Th2 immune response by dendritic cells (DCs). Notably, SCFAs have an inhibitory impact on the polarization of M2 macrophages, emphasizing their immunomodulatory properties and potential for therapeutics. In animal models of asthma, both butyrate and propionate suppress the M2 polarization pathway, thus reducing allergic airway inflammation. Moreover, dysbiosis of gut microbiota leading to altered SCFA production has been implicated in prostate cancer progression. SCFAs trigger autophagy in cancer cells and promote M2 polarization in macrophages, accelerating tumor advancement. Manipulating microbiota- producing SCFAs holds promise for cancer treatment. Additionally, SCFAs enhance the expression of hypoxia-inducible factor 1 (HIF-1) by blocking histone deacetylase, resulting in increased production of antibacterial effectors and improved macrophage-mediated elimination of microorganisms. This highlights the antimicrobial potential of SCFAs and their role in host defense mechanisms. This comprehensive review provides an in-depth analysis of the latest research on the functional aspects and underlying mechanisms of SCFAs in relation to macrophage activities in a wide range of diseases, including infectious diseases and cancers. By elucidating the intricate interplay between SCFAs and macrophage functions, this review aims to contribute to the understanding of their therapeutic potential and pave the way for future interventions targeting SCFAs in disease management. 

The impact of microbiota-derived short-chain fatty acids on macrophage activities in disease: Mechanisms and therapeutic potentials.

Abstract The relationship between microbiota, short chain fatty acids (SCFAs), and obesity remains enigmatic. We employ amplicon sequencing and targeted metabolomics in a large ( n = 1904) African origin cohort from Ghana, South Africa, Jamaica, Seychelles, and the US. Microbiota diversity and fecal SCFAs are greatest in Ghanaians, and lowest in Americans, representing each end of the urbanization spectrum. Obesity is significantly associated with a reduction in SCFA concentration, microbial diversity, and SCFA synthesizing bacteria, with country of origin being the strongest explanatory factor. Diabetes, glucose state, hypertension, obesity, and sex can be accurately predicted from the global microbiota, but when analyzed at the level of country, predictive accuracy is only universally maintained for sex. Diabetes, glucose, and hypertension are only predictive in certain low-income countries. Our findings suggest that adiposity-related microbiota differences differ between low-to-middle-income compared to high-income countries. Further investigation is needed to determine the factors driving this association. 

Gut microbiota and fecal short chain fatty acids differ with adiposity and country of origin: the METS-microbiome study

The gut microbiome influences host physiology and pathophysiology through several pathways, one of which is microbial production of chemical metabolites which interact with host signaling pathways. Short-chain fatty acids (SCFAs) are a class of gut microbial metabolites known to activate multiple signaling pathways in the host. Growing evidence indicates that the gut microbiome is linked to blood pressure, that SCFAs modulate blood pressure regulation, and that delivery of exogenous SCFAs lowers blood pressure. Given that hypertension is a key risk factor for cardiovascular disease, the examination of novel contributors to blood pressure regulation has the potential to lead to novel approaches or treatments. Thus, this review will discuss SCFAs with a focus on their host G protein-coupled receptors including GPR41 (G protein-coupled receptor 41), GPR43, and GPR109A, as well as OLFR78 (olfactory receptor 78) and OLFR558. This includes a discussion of the ligand profiles, G protein coupling, and tissue distribution of each receptor. We will also review phenotypes relevant to blood pressure regulation which have been reported to date for Gpr41, Gpr43, Gpr109a , and Olfr78 knockout mice. In addition, we will consider how SCFA signaling influences physiology at baseline, and, how SCFA signaling may contribute to blood pressure regulation in settings of hypertension. In sum, this review will integrate current knowledge regarding how SCFAs and their receptors regulate blood pressure. 

Short-Chain Fatty Acid Receptors and Blood Pressure Regulation: Council on Hypertension Mid-Career Award for Research Excellence 2021

Animal Models of Neointimal Hyperplasia and Restenosis: Species-Specific Differences and Implications for Translational Research

Background The potential role of the gut microbiome in cardiovascular diseases is increasingly evident. Arterial restenosis attributable to neointimal hyperplasia after cardiovascular procedures such as balloon angioplasty, stenting, and bypass surgery is a common cause of treatment failure, yet whether gut microbiota participate in the development of neointimal hyperplasia remains largely unknown. Methods and Results We performed fecal microbial transplantation from conventionally raised male C57BL/6 mice to age-, sex-, and strain-matched germ-free mice. Five weeks after inoculation, all mice underwent unilateral carotid ligation. Neointimal hyperplasia development was quantified after 4 weeks. Conventionally raised and germ-free cohorts served as comparison groups. Conclusions Germ-free mice have significantly attenuated neointimal hyperplasia development compared with conventionally raised mice. The arterial remodeling response is restored by fecal transplantation. Our results describe a causative role of gut microbiota in contributing to the pathogenesis of neointimal hyperplasia.

/pdf/microbial-colonization-of-germ-free-mice-restores-neointimal-y7lj6665zb.pdf

Microbial Colonization of Germ-Free Mice Restores Neointimal Hyperplasia Development After Arterial Injury.

Association between smoking history and response to anti-arrhythmic therapy in atrial fibrillation patients across race-ethnicity


 BACKGROUND:
 Smoking is associated with increased risk of developing atrial fibrillation (AF) and stroke. Yet, it remains unclear if it also predicts response to rhythm control therapy across race-ethnicity. We sought to determine if response to rhythm control therapy for AF is modulated by smoking across race-ethnicity.
 
 
 Methods:
 529 patients treated with a rhythm control strategy were prospectively enrolled in the Chicagoland area. Patients were classified into White, Black or Hispanic\Latino based on race\ethnicity and ancestry markers. Rhythm control included antiarrhythmic drugs (AADs) and/or catheter ablation. Successful response was defined as continuation of the same AAD for at least 6 months and/or successful catheter ablation without recurrence of AF for 12 months.
 
 
 Results:
 235 (44%) were Black, 192 (36%) were White, and 102 (19%) were Hispanic. 299 (57%) were treated with AADs and 230 (44%) with catheter ablation. One-hundred sixty-eight (35%) patients had a history of smoking. Baseline co-morbidities were similar across responders and non-responders. In multivariate regression analysis (Table 1), patients with a smoking history were more likely to have a recurrence of AF when treated with a rhythm control strategy (odds ratio [OR] 1.51, 95% confidence interval [CI] 1.03-2.21,
 P
 =0.03). Stratified multivariate regression analysis showed that smokers were more likely to have a recurrence of AF after ablation therapy as compared to AADs (OR 1.49, 95% CI 1.03-2.17,
 P
 = 0.03). Multivariate logistic regression showed that patients that smoked for >20 years were twice as likely to have a recurrence of AF with a rhythm control therapy than those who smoked for <20 years (OR 1.88, 95% CI 1.20- 2.93,
 P
 = 0.01).
 
 
 Conclusions:
 A smoking history modulates response to rhythm control therapy for AF across race-ethnicity. Our study highlights the importance of smoking cessation before initiation of rhythm control agents in patients with AF.
 
 
 


Abstract 11171: Smoking Modulates Response to Anti-Arrhythmic Therapy for Atrial Fibrillation Patients Across Race-Ethnicity

Clinical predictors of rate control therapy in patients with atrial fibrillation across race-ethnicity

Abstract 462: Microbial Colonization Restores Neointimal Hyperplasia Development After Arterial Injury in Germ-Free Mice

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