**1. Introduction**

The human intestinal tract hosts different microbial communities playing a pivotal role in maintaining health conditions. Gut microbiota imbalance can also exacerbate some actions promoting a cascade of metabolic abnormalities and vice versa. In numerous diseases, such as obesity, type 2 diabetes, as well as cardiovascular and auto-immune diseases, a marked alteration in microbiota composition and functions occurs [1,2]. Moreover, in Chronic Kidney Disease (CKD) patients, the gut microbiota is quantitatively and qualitatively changed with respect to healthy subjects contributing to uremic syndrome and CKD-related complications [3–5]. In CKD patients, microbiota metabolite changes exert major consequences. In fact, metabolites generally proven to promote health—particularly short-chain fatty acids (SCFAs)—are reduced while uremic toxins, such as indoles, ammonia, and trimethylamine N-oxide, produced by gut microbiota, accumulate—both for their overproduction and for the reduced excretion by impaired kidney function—thus enhancing CKD development and progression [6–9]. Lowered SCFAs production results in impaired CKD due to gut dysbiosis and also a decreased consumption of dietary fibre that, on the one hand, reduces SCFAs production and, on the other are, involved in increased amino nitrogen, which can be transformed into uremic toxins by gut microbiota [10]. The accumulation of these gut-derived compounds correlates with systemic inflammation and protein wasting and enhances cardiovascular complications in these patients [11]. The dysbiotic gut microbiome in CKD is associated with immune dysregulation, insulin resistance,

**Citation:** Magliocca, G.; Mone, P.; Di Iorio, B.R.; Heidland, A.; Marzocco, S. Short-Chain Fatty Acids in Chronic Kidney Disease: Focus on Inflammation and Oxidative Stress Regulation. *Int. J. Mol. Sci.* **2022**, *23*, 5354. https://doi.org/10.3390/ ijms23105354

Academic Editors: Márcia Carvalho and Luís Belo

Received: 15 April 2022 Accepted: 10 May 2022 Published: 11 May 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

cardiovascular disease, as well as local (gut) and systemic inflammation and oxidative stress conditions [12–15]. Thus, there has been a great interest in potentially healthy microbiota metabolites such as SCFAs, which levels result in impaired CKD.

SCFAs are produced in the distal small intestine and the colon by anaerobic bacteria and are the end products of fermentation from complex carbohydrates that are indigestible by the human host [16]. The three major SCFAs, consisting of one to six carbon atoms, produced by gut bacteria are acetic (two carbons), propionic (three carbons), and butyric acids (four carbons). SCFAs contribute to the health of the gut (microbiome and mucosa) and the overall health of the host, with properties including anti-diabetic, anti-cancer, antibacterial, anti-inflammatory, and anti-oxidative effects [17,18]. On the other hand, lower SCFA levels contribute to different diseases such as inflammatory bowel disease [19,20], rheumatoid arthritis, and multiple sclerosis [21,22]. Moreover, SCFAs supplementation exerts anti-inflammatory actions, both at the intestinal and cardiovascular levels [23,24], and influences immune reactions [25–27]. Considering the anti-inflammatory potential of SCFAs, their reduced levels in CKD, and that the CKD is associated with systemic, chronic microinflammation and oxidative stress conditions that contribute to both the disease progression and to its related complications, SCFAs and SCFAs producing microorganisms could be one of the missing pieces of the puzzle in CKD-associated inflammation and oxidative stress. This review will provide an overview of the current knowledge on the effect of SCFAs on CKD-associated inflammation and oxidative stress.
