Short-Chain Fatty Acids-A Healthy Bus between Gut Microbiota and Organs beyond the Gut

Ruyue Cao, Yunqing Zeng, Shuhua Li, Peiting Xue, Ming Li^*

Department of Gastroenterology and Endoscopy Center, Qilu Hospital of Shandong University, Jinan, China.

DOI: 10.4236/abb.2022.139024                

Abstract

The impact of the gut microbiota is not limited to the intestine, but its interaction with the host produces active metabolites, which can be transported by the blood circulation to play important roles in various parts of the body. Among them, short-chain fatty acids (SCFAs), as important active products of gut bacteria, have been shown to exert anti-inflammatory and immunomodulatory effects and can play active roles as signaling molecules in the development of various intestinal and extraintestinal diseases, such as inflammatory bowel disease, colon cancer, multiple sclerosis, hypertension, allergic airway disease, obesity, diabetes, kidney disease, rheumatoid arthritis, etc. In this way, modulation of the intestinal microbiota and metabolism-active substances has gradually become a popular therapeutic method for many diseases of organs beyond the gut. To find new therapeutic targets for major human health problems, this article reviews the research on SCFAs in extraintestinal diseases.

Keywords

Short-Chain Fatty Acids, Gut Microbiota, Extraintestinal Organs, Immune Regulation, Diet

1. Introduction

A diverse range of bacteria, fungi, and viruses live in the human gut, collectively known as the gut microbiota [1] [2]. Hosts benefit from multiple powerful functions provided by microorganisms, such as digesting dietary nutrients, maintaining intestinal barrier function, and regulating the immune inflammatory system [3] [4] [5]. Gut microbiota co-exist, co-evolve with their hosts and co-maintain the dynamic balance of each other [6]. Despite its significant impact on human health and the development of diseases, our gut microbiota has not been the focus of research until the past 20 years. In recent years, according to more and more studies, the intestinal microbiota has influenced the health of the human gut and organs beyond the gut through the production of bioactive metabolites, such as SCFAs [7] [8] [9] [10].

SCFAs are active metabolites produced by anaerobic microorganisms fermenting dietary fiber in the gut, mainly referring to fatty acids with carbon numbers between 2 and 6, such as acetate, propionate, butyrate, valerate, etc. [11] [12]. SCFAs are up taken by colonic cells via monocarboxylate transporters [13] [14], and most of them are used as energy substrates for supplying colonic cells [15]. The remaining small amount of them are transported through the bloodstream to various extraintestinal organs to act as signaling molecules through two major signaling pathways [13] [16] [17] : G protein-coupled receptors (GPCRs) and histone deacetylases (HDACs). Relying on its anti-inflammatory immunomodulatory effects, it plays a crucial role in neurological, cardiovascular, endocrine and other systems [18] [19].

SCFAs have been studied extensively in the context of intestinal and extraintestinal diseases, with the common mechanisms, anti-inflammatory and immunomodulatory effects. In this review, we summarize the beneficial effects of SCFAs on extraintestinal organs (Figure 1) and highlight the important value of dietary interventions to supplement probiotics and SCFAs in the treatment of

Figure 1. Association between short-chain fatty acids (SCFAs) and organs beyond the gut.

extraintestinal diseases. We aim to find new therapeutic strategies for diseases of organs beyond the gut.

2. Short-Chain Fatty Acids and Related Receptors and Epigenetic Regulation

SCFAs act as signaling molecules, which recognize and bind to G protein-coupled receptors on the cells surface or directly inhibit the activity of histone deacetylases after entering the cells. And then, they regulate gene expression and alter cell functions.

2.1. G Protein-Coupled Receptors

The G protein-coupled receptors (GPCRs) are a family of protein receptors with seven transmembrane structural domains that regulate almost all physiological functions [20]. When GPCRs recognize and bind to ligands, they can activate or inhibit downstream effectors via heterotrimeric G proteins, such as enzymes that produce second messengers or ion channels [21]. The identified G protein-coupled receptors for SCFAs include GPR40 (FFAR1), GPR41 (FFAR3), GPR43 (FFAR2), GPR120 (FFAR4), GPR84, GPR109a and Olfr78 [13] [22] [23]. These receptors are expressed in intestinal epithelial cells, immune cells, pancreatic islet cells, vascular endothelial cells, and adipose tissue. In turn, they play significant roles in maintaining the intestinal epithelial barrier, inflammatory immune regulation, stabilizing blood pressure, regulating blood glucose, and lipid metabolism. Among them, GPR41 and GPR43 are the two most prominent receptors.

2.2. Histone Deacetylases (HDACs)

Histone deacetylases (HDACs) is a protease that modifies chromosome structure and regulates gene expression at the cellular level [13]. In the nucleus, a dynamic balance between histone acetylation and deacetylation is maintained by both histone acetyltransferase (HAT) and histone deacetylases (HDACs). HAT transfers acetyl groups of acetyl coenzyme A to histone residues, thereby promoting gene expression. In contrast, HDACs deacetylates histones, coiling up chromatin and inhibiting gene transcription. SCFAs enter the cell directly through a transport channel in the cell membrane and act as a natural inhibitor of HDACs for its epigenetic regulation [24].

3. SCFAs and Nervous System

Neuropsychiatric disorders are serious threats to human health and affect the quality of life. However, at present, the treatment of these diseases mainly relies on medications to regulate neurotransmitters, and the treatment effect is not improved. In recent years, the development of the microbiota-gut-brain axis concept has attracted the interest of researchers worldwide. There is growing evidence that receptors of SCFAs exist in the central nervous system (CNS) and SCFAs enter the brain through the blood-brain barrier (BBB) [25]. They act as signaling molecules that bind to their receptors and exert its anti-inflammatory and immunomodulatory effects, affecting brain functions [25] [26] [27]. This will be a new treatment method for neuropsychiatric diseases.

3.1. Multiple Sclerosis

Multiple sclerosis (MS) is a common immunoinflammatory neurological disorder. The main pathogenesis is that the peripherally activated self-reactive lymphocytes cross the blood-brain barrier (BBB) and secrete pro-inflammatory cytokines in response to myelin antigens in the central nervous system. Duscha et al. found by comparative investigation that propionic acid (PA) significantly reduced in stool and serum, Th17 and Th1 cells significantly increased in blood, and Treg cell numbers significantly reduced in MS patients compared to health controls, and after 14 days of PA supplementation, Treg numbers significantly increased and Th17 and Th1 cells reduced [27]. This suggests that PA can serve as a potent immunomodulatory supplement to multiple sclerosis drugs. In addition, three animal studies based on Experimental Autoimmune Encephalomyelitis (EAE) models found that [28] [29] [30], SCFAs suppress inflammation by altering T cell differentiation, increasing anti-inflammatory Tregs cell and decreasing pro-inflammatory T cells (Th1 and Th17), which can improve the symptoms of EAE. In addition, through a study about a mouse model of thapsigarginone-induced demyelination, Chen et al. [31] have shown that butyrate treatment can inhibit demyelination, enhance remyelination, promote oligodendrocyte differentiation and attenuate EAE disease progression. Overall, all these studies suggest that SCFAs can be used as possible agents to improve multiple sclerosis, but there are few studies that specifically address the role of gut derived SCFAs in human multiple sclerosis patients.

3.2. Parkinson’s Disease

Parkinson’s disease (PD) is a neurodegenerative amyloid disease. PD patients often present with gastrointestinal symptoms [32] [33], with pathological features typical of PD in the enteric nervous system (ENS) — overexpression of αSyn [34] [35]. Patients with Parkinson’s disease exhibit unique changes in their gut microbiota. In several studies, the composition of the intestinal microbiota of Parkinson’s patients was compared with that of healthy controls, which have found significant variations in alpha diversity and/or beta diversity in patients with Parkinson’s disease [36] [37]. In addition, Unger et al. found a significant decrease in butyrate, acetate and propionate in the stools of PD patients, as well as a significant reduction in short-chain fatty acids (SCFAs)-producing bacteria [38]. It is thought that a decrease in SCFAs may induce changes in ENS and lead to gastrointestinal disorders in PD [38]. A PD mouse model test (induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)) demonstrated that Sodium butyrate (NaB) significantly improved neurobehavioral deficits in PD mice by enhancing intestinal endogenous glucagon-like peptide-1 (GLP-1) and activating brain GLP-1R, suggesting that NaB treatment can prevent MPTP-induced dopaminergic neuronal degeneration in mice and is a potential therapeutic target [39]. All the above studies suggest that regulating gut flora through dietary intervention can possibly be a safe treatment for PD patients.

3.3. Schizophrenia

Schizophrenia is a psychiatric disorder in which the underlying mechanisms of pathogenesis are not fully unclear. Recently, the gut-microbiota-brain axis has become a major topic of psychiatric interest. Li et al. found that patients with schizophrenia had significantly increased serum butyric acid levels and significantly decreased positive and negative symptom scale (PANSS) total and subscale scores after 24 weeks of risperidone treatment. There was a positive association between baseline serum levels of butyric acid and the rate of decrease in PANSS total and subscale scores, suggesting that elevated serum butyric acid levels may be associated with good treatment results in schizophrenia [40]. Therefore, modulating the gut microbiota can be used as a vital treatment for schizophrenia.

3.4. Depression

In mental disorders, depression is quite common, and it seriously impairs patients’ standard of living [41]. Current antidepressants produce complete remission in no more than half of major depression disorder (MDD) patients, and new targets are urgently needed and identified to improve treatment [42]. For many years, it was thought that human immune system played a vital role in depression disorder [43]. As important immunomodulators, SCFAs are emerging as new treatments for depression. Studies have found that transplanting feces from patients with major depressive disorder (MDD) into germ-free animals leads to behavioral and physical features of depression [44]. The results of an animal experiment showed that the three main SCFAs (acetic acid, propionic acid and valeric acid) were significantly reduced in depressed mice compared to control mice [45]. In addition, Bettina et al. analyzed fecal SCFAs from depressed patients and found a negative correlation between depressive symptoms and butyrate and propionate levels [46]. The above study further confirmed the strong association between short-chain fatty acids and depressive symptoms. Although the exact molecular mechanism is unknown, the gut microbiota plays an important role as a “mental probiotic” in alleviating depressive symptoms.

4. SCFAs and Cardiovascular System

Increasing morbidity and mortality from cardiovascular disease (CVD) pose a health threat and economic burden to our society. This forces us to actively search for more effective strategies to prevent and treat CVD. In recent years, there has been a strong passion on the interactions among the human gut microbiota, its metabolites SCFAs and cardiovascular disease. Treatment of cardiovascular disease with manipulation of the gut microbiota and active metabolites may prove to be an effective strategy.

4.1. Hypertension and Atherosclerosis

Hypertension is an independent and preventable risk factor for the development of cardiovascular disease, often coexisting with and accelerating the progression of atherosclerosis, posing a serious threat to human health. In recent years, there has been increasing interest in the role of gut microbes in hypertension and atherosclerosis and their potential mechanisms. According to several studies, gut microbiota imbalances may contribute to hypertension and cardiovascular injury [47] [48] [49], this may be related to intestinal epithelial barrier dysfunction and the resulting activation of inflammatory cells and production of proinflammatory cytokines [50] [51]. Evidence suggests that SCFAs keep the intestinal barrier and modulates intestinal immune cells to enhance intestinal immune function [52]. In turn, they prevented the development of hypertension and atherosclerosis and slowed their progression. In addition, SCFAs (propionate and butyrate) reduced the production of pro-inflammatory factors such as TNF-αand NO by LPS-stimulated neutrophils by inhibiting nuclear factor kappa B (NF-κB) activity and histone deacetylase (HDAC) [51] [53]. It exerts its anti-inflammatory effects and attenuates cardiovascular damage in hypertension. Another study demonstrated that SCFAs can be involved in the regulation of blood pressure through G olfactory receptor 78 (Olfr78) and G protein receptor 41 (Gpr41) expressed in vascular or renal tissues [54] [55]. The above studies provide further experimental evidence for the importance of microbiota derived SCFAs in promoting cardiovascular health in hosts, suggesting that SCFAs supplementation treatment can prevent hypertension and reduce atherosclerosis and cardiac damage, and is a new approach to prevent hypertension and cardiovascular damage.

4.2. Heart Failure

Heart failure is a result of imbalance in cardiac function due to various primary heart diseases [56]. Currently, more and more studies are confirming the “intestinal hypothesis of heart failure”, in which patients with heart failure have impaired intestinal barrier function, leading to bacterial translocation and increased levels of pro-inflammatory cytokines in the blood [57] [58] [59]. Recent data show that SCFAs can maintain the integrity of the intestinal epithelial barrier and reduce bacterial translocation [52]. This prevents the development of heart failure. An animal study showed that SCFAs can bypass carnitine palmitoyltransferase 1 (CPT1) to support energy production in the failing heart and improve cardiac energy failure in the presence of reduced CPT1 activity on the outer mitochondrial membrane [60].

4.3. Arrhythmias

Arrhythmias are intractable cardiovascular diseases that lead to heart failure or sudden cardiac death. Atrial fibrillation (AF) is the most prevalent common arrhythmia worldwide, and Zuo et al. found an imbalance in the composition of the gut microbiota in patients with AF [61] [62] [63]. Dysregulated gut microbiota viability may contribute to AF development. There is conclusive evidence for the coexistence of inflammation and the initiation of atrial fibrillation [64] [65]. Furthermore, as HDACs inhibitor, SCFAs can prevent the intestinal barrier from being disrupted by inhibiting the LPS-NLRP3 inflammasome axis [66]. Ca2+ and GPR43-dependent mechanisms reduce NLRP3 inflammasome activation by acetate, thereby preventing inflammation-related arrhythmias [67]. It has also been shown that propionate prevents the development of myocardial infarction-induced ventricular arrhythmias (VA) and cardiac electrophysiological instability through parasympathetic activation based on the gut-brain axis [68].

5. SCFAs and Respiratory System

The gut-lung axis is becoming a new hotspot for research because of the interaction between intestinal flora and the respiratory system [69]. A growing number of studies have shown that metabolites produced by the gut microbiota, SCFAs, play an important role as immunomodulators in the development of lung diseases.

5.1. Pulmonary Infections

Microbial infections are major public health problem. Today, antibiotic resistance is increasing, and infections caused by multi-drug resistant microorganisms are becoming more common. Therefore, we need to find alternative ways to enhance host defense and control inflammation. The pulmonary immune response can be modulated by metabolites produced by the intestinal flora, such as SCFAs [70] [71]. One study found that germ-free mice were more likely to contract lung disease than mice carrying commensal bacteria [72] [73]. Patients with intestinal disease have lower SCFAs levels and are also more likely to develop lung disease [74]. According to these findings, the gut microbiota influences lung immunity. The role of SCFAs as important active intestinal metabolites in the regulation of inflammation is not limited to the gut. In fact, SCFAs can enter the bloodstream and act at distal sites, such as the lungs [16], preventing the lung infections. SCFAs can directly inhibit the growth and virulence of pathogens [75] [76] [77]. Meanwhile, short-chain fatty acids can also bind to their free fatty acid receptor 2 (FFAR2) and FFAR3, and inhibit activity of histone deacetylases (HDACs), activating a signaling cascade that regulates the host defense response [78] [79]. These results suggest that SCFAs could potentially play a therapeutic role in infection control by exploiting their anti-inflammatory biological properties.

5.2. Asthma

Eosinophils are important effector cells in allergic asthma, and in animal model of allergic airway disease studies, mice fed SCFAs (butyrate, propionate, or acetate) exhibited lower severity than mice fed a normal diet [80]. According to another study, children with high levels of SCFAs in their stools had a lower risk of allergy to allergens and asthma later in life [81]. Many studies have further shown that butyrate and propionate limit eosinophil survival and migration through their inhibitory effects on HDACs [82]. SCFAs inhibit lymphocyte activation and presentation by Dendritic Cells (DCs), reduce IL-4-producing CD4+ T cells, and decrease immunoglobulin E (IgE) levels [80]. In addition, they can downregulate mast cell activation-related gene expression, inhibit antigen-induced mast cell degranulation and reduce the release of many inflammatory mediators (including tumor necrosis factor alpha (TNFα), interleukin 6 (IL-6)) [83]. This reduces lung inflammation in mice with allergic airway disease. In addition, B cells are essential for the development and maintenance of allergic disorders with their antigen-presenting role [84]. Butyrate reduces AID and Blimp-1 gene expression in vivo by inhibiting histone deacetylation of specific miRNA host genes in B cells, thereby suppressing local and systemic antibody responses [85]. Therefore, increasing SCFAs levels through dietary intake can help to reduce the inflammatory response in allergic airway disease and can be a potential new therapeutic strategy to prevent over this disease.

5.3. Other Pulmonary Diseases

Researchers have shown that the gut microbiota also affects the pathophysiology of other lung diseases. Hu et al. characterized the microbial composition of feces from Pulmonary Tuberculosis patients and healthy controls and found the intestinal flora of TB patients is characterized by a significant reduction of bacteria producing SCFAs as well as associated metabolic pathways, suggesting that gut bacterial characteristics could potentially be used to distinguish healthy from TB patients [86]. In addition, butyric acids blocked the expression of genes associated with transforming growth factor β1 (TGF-β1)-induced fibroblast activation, exhibiting potent antifibrotic activity [87]. This is expected to be the biologic agent in the treatment of Idiopathic pulmonary fibrosis (IPF).

6. SCFAs and Endocrine System

6.1. Diabetes

Diabetes mellitus (DM) and its complications remain a major global health problem. The data suggest that SCFAs play vital roles in the pathogenesis of diabetes. For one, disruption of the intestinal barrier may promote the development of DM [88]. It has been proven that SCFAs promote intestinal epithelial cell proliferation, strengthen the tight junctions between intestinal epithelial cells, and regulate the activity of immune cells to maintain and strengthen the physical, chemical, and immune barriers of the gut [52]. Thereby SCFAs can indirectly protect pancreatic β-cells from autoimmune damage. In addition, it was found that FFAR2 was expressed in pancreatic β-cells [89], suggesting that SCFAs may also directly regulate the proliferation and differentiation of pancreatic β-cells through FFAR2. Second, insulin resistance is also an important pathogenesis of DM [90]. The receptor of SCFAs, GPR43, was expressed in liver adipocytes [91]. SCFAs can enhance insulin sensitivity of liver and adipose tissue and promote glucose uptake and glycogen synthesis to regulate blood glucose. Third, appetite regulation is also an important therapeutic approach to control blood glucose. It has been shown that SCFAs (butyrate, acetate) can stimulate enteroendocrine cells (L cells), increase the secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), and reduce food intake [92] [93] [94] [95]. It also inhibits hypothalamic AMP-activated protein kinase (AMPK) activity to increase the expression of anorexigenic neuropeptides to control appetite [96].

6.2. Graves’ Disease

Graves’ Disease is a typical specific autoimmune disease [97]. Recently, many studies have shown that SCFAs produced by intestinal microorganisms can regulate regulatory T (Treg) cells and T helper cells (Th17) in extraintestinal tissues and play a crucial role in the development of extraintestinal autoimmune diseases [98]. Su et al. found that the abundance of SCFAs-producing bacteria of GD patients was reduced and the levels of SCFAs were significantly lower, especially propionic acid. These abnormalities led to a decrease in the number of Tregs and an increase in the number of Th17 cells, resulting in immune imbalance and inflammation in GD patients. It is proposed that dysregulated flora in stool has the potential to be used as an auxiliary marker for the diagnosis of GD. It can also be used as an adjuvant treatment method [99].

7. SCFAs and Fatty Liver

The increasing incidence of fatty liver disease has been one of the major challenges for human health. Recently, more and more attention has been paid to the role of gut microbes in liver diseases, and the gut-liver axis is gradually becoming a research hotspot [100]. Intestinal barrier dysfunction leads to the promotion of pathogen-associated molecular pattern (PAMP) through portal influx into the liver, triggering a pro-inflammatory cascade response, which is an important common mechanism in the development of alcoholic fatty liver disease (AFLD) and non-alcoholic fatty liver disease (NAFLD) [100] [101]. Compelling data from many animal models suggest that short-chain fatty acids reduce steatohepatitis by maintaining intestinal barrier function, reducing bacterial translocation, modulating immune inflammation, and preventing oxidative damage to the liver [102] [103] [104] [105] [106]. In addition, SCFAs can directly reduce hepatic cholesterol and fatty acid synthesis, while increasing hepatic lipid oxidation to reduce hepatic lipid deposition and prevent the development of fatty liver [107] [108] [109]. It is important to note that non-alcoholic fatty liver disease (NAFLD) is a manifestation of the metabolic syndrome in the liver and shares common mechanisms with obesity, diabetes and cardiovascular diseases [105]. SCFAs mediate the production of satiety in the brain by stimulating secretion of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) in a GPR-dependent manner [92] [93] [94] [95], that reduce excessive fat intake and decrease the incidence of fatty liver. Another study showed that inulin alleviated inflammation in alcoholic liver disease (ALD) by suppressing M1 and promoting M2 induced by SCFAs, providing a theoretical basis for regulating intestinal flora as an inexpensive intervention for the prevention and treatment of ALD [110]. Therefore, the increase in SCFAs produced by fermentation of dietary fiber is a valuable strategy for the prevention and mitigation of fatty liver.

8. SCFAs and Muscle

Skeletal muscle is the largest organ in humans and plays a key role in whole-body energy metabolism. Evidence is growing that the human gut microbiota regulates skeletal muscle metabolism and function. The “gut-muscle axis” [111] [112] has gradually become a research hotspot in recent years. Evidence shows that mice with depleted gut microbes exhibit reduced skeletal muscle mass, and reduced muscle strength [113] [114] [115]. In contrast, probiotics supplementation increases skeletal muscle mass in obese mice [116] [117]. This regulatory interaction between gut microbes and skeletal muscle is partially mediated by short-chain fatty acids. SCFAs has been proved to affect lipid, carbohydrate, and protein metabolism in skeletal muscle tissue. And activation of AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor (PPAR), and inhibition of HDACs may be key mechanisms for these changes in skeletal muscle [118] [119] [120] [121]. Therefore, modulating the gut microbiota with dietary interventions or probiotics supplementation would be an exciting therapeutic strategy for muscle-related diseases and syndromes. Among them, sarcopenia, characterized aging-related loss of skeletal muscle mass and function, is an age-related skeletal muscle disease that affects the quality of life of the elderly and increases the incidence of disability and mortality [122] [123]. To date, exercise and nutrients have been the primary treatment for the disease, but older patients have poor adherence and cannot achieve long-term sustainability [124]. One study found that patients with sarcopenia exhibit a different fecal microbiota composition: the species producing short-chain fatty acids (SCFAs) were significantly depleted (Faecalibacterium, prausnitzii et al.) [125] [126]. Further studies have shown that probiotics supplementation with SCFAs (acetate, propionate and butyrate) is beneficial in maintaining muscle mass and strength and enhancing exercise endurance in germ-free mice [116] [127] [128] [129] [130].

9. SCFAs and Urinary System

In renal disease, uncontrollable inflammation, oxidative stress, and imbalance of immune response are associated with impairment of renal function [131]. Short-chain fatty acids (SCFAs) can improve renal function in acute kidney injury through their anti-inflammatory properties and inhibition of oxidative stress. An animal study, using an adenine-induced mouse model of chronic kidney disease (CKD), showed that propionic acids, via FFA2 and FFA3 receptors, inhibit the expression of pro-inflammatory factors, and significantly reduce serum creatinine (Cr) and urea nitrogen levels [132]. Another study showed that the key mechanism of SCFAs against acute kidney injury (AKI) is local and systemic reduction of inflammatory cytokine and chemokine production through inhibition of LPS-TLR4-induced NF-κB and MAPK inflammatory signaling pathways, which may be related to GPCRs activation and autophagy regulation [133] [134] [135]. In addition, renal anemia is a serious complication of chronic kidney disease (CKD) and current erythropoietic and iron supplementation treatments have limitations. Recently, several relevant studies have highlighted that inflammatory status affects the progression of renal anemia in various ways [136] [137]. Gut microbiota and SCFAs can produce anti-inflammatory and immunomodulatory effects by activating regulatory cells of the immune system to improve anemia [138]. Other studies using mouse kidney transplantation models have shown that allograft rejection can be reduced by supplementing the diet with short-chain fatty acids and high fiber [139].

10. SCFAs and Skin

Psoriasis is a common immune-related inflammatory disease of the skin that severely affects human physical and mental health. Its pathogenesis is multifactorial, with the accelerated TNF-α/IL-23/IL-17 axis being the main pathological mechanism of psoriasis [140]. It leads to excessive proliferation and abnormal differentiation of epidermal keratinocytes. In addition, Tregs defects are also important in the pathogenesis of psoriasis [141]. Restoring Tregs activity and reducing the release of pro-inflammatory factors is emerging as a promising therapeutic target for psoriasis [142]. SCFAs can promote the activity of regulatory T cells (Tregs), which play an active role in inflammatory skin diseases. Using a mouse model of psoriasis-like skin inflammation, Luu et al. demonstrated that SCFAs, particularly butyrate, reduced the skin inflammatory response by restoring suppressed regulatory T cell (Tregs) activity through GRP43 as well as HDACs to upregulate IL-10 and Foxp3 transcripts and downregulate IL-17 and IL-6 [143] [144] [145]. In addition, Smith et al. found that in vitro and in vivo treatment of germ-free mice using propionate both significantly increased the number of Tregs and the expression of Foxp3 and IL-10 [98].

11. SCFAs and Rheumatoid Arthritis (RA)

Rheumatoid arthritis is an immune-mediated chronic joint inflammation and injury featured by bone destruction and synovial hyperplasia [146]. In contrast, SCFAs, as modulators of the immune system [146], can alleviate arthritic symptoms and are emerging as a novel treatment strategy for RA. To explore the role and preliminary mechanisms of gut microbiota derived SCFAs in RA, a study conducted by Yao et al. analyzed feces samples from patients with RA and those with healthy controls.

Four SCFAs (acetate, propionate, butyrate and valerate) in stool were found to be positively correlated with regulatory B cells (Bregs) levels in peripheral blood in RA patients compared to healthy controls [147]. To investigate in depth the role of gut microbiota-derived SCFA in RA, Yao et al. using a collagen-induced arthritis (CIA) model, found significantly higher SCFAs levels in the stool of mice after treated with SCFAs and reduced inflammatory cell infiltration and synovial hyperplasia in the knee and ankle joint cavities of mice [147]. It was further elucidated that the therapeutic effect of SCFAs on arthritis was achieved through regulation of B-cell differentiation by the FFA2 receptor (GPR43), along with increased serum IL-10, IL-13 and TGF-β and decreased IL-6, IL-1β and TNF-α [147]. Therefore, increasing dietary fiber diet to enhance SCFAs levels may become an effective treat strategy for rheumatoid arthritis.

12. SCFAs and Tumor Immunology

There are indications that short-chain fatty acids (SCFAs) produced by gut microbes help to regulate immune cells and cytokines with anti-tumor properties. Therefore, manipulation of SCFAs in the gut by altering the microbiota structure could be a new approach for cancer prevention and treatment in a variety of extraintestinal organs [148]. Inflammatory factors and dysbiosis of the gut microbes may contribute to cancer risk in diets low in fiber, fat, and sugar [149]. A high fiber diet enhances the “healthy” microbiota and strengthens the tight junctions of the intestinal mucosa, thereby reducing the leakage of disease-causing bacteria and their carcinogenic effects, as well as limiting the proliferation of cancer cells by acting as HDACs inhibitors and stimulating cyclin-dependent kinase inhibitors [150]. Bindels et al. treated a mouse model with oral inulin-type fructose (ITF) and showed a reduction in cancer cell proliferation and a reduction in inflammation associated with cancer development [151]. Butyric acid also inhibits cell growth and activates programmed cell death, producing a direct inhibitory effect on cancer cells [152]. In addition, short-chain fatty acids (valerate and butyrate) enhanced the antitumor activity of cytotoxic T lymphocytes (CTL) and chimeric antigen receptor (CAR) T cells by modulating metabolism and epigenetics [153]. Butyrate and valerate were identified as having therapeutic potential in the immunotherapy of cellular carcinoma. Another study found that fecal SCFAs concentrations were associated with the efficacy of programmed cell death-1 inhibitors (PD-1i) in the treatment of solid tumors. Therefore, fecal short-chain fatty acids concentration could be used as a routine test to assess the effectiveness of PD-1i therapy [154]. These results confirm the role of gut microbiota and metabolites in controlling cancer progression. Therefore, supplementation of SCFAs in the gut by altering gut microbiota could be a new approach for cancer prevention and treatment.

13. Conclusion

Short-chain fatty acids play a central role in the diet-gut microbiota-host metabolic axis through their maintenance of the intestinal epithelial barrier, anti-inflammatory, immunomodulatory, and anti-tumor properties. As a result, short-chain fatty acids may provide an additional therapeutic target for extraintestinal diseases through altering the metabolic status of the host. How to regulate short-chain fatty acids is another hot topic of research. For example, SCFAs can be indirectly regulated through high dietary fiber diets (cereals, vegetables, and fruits), oral probiotics, fecal transplants, and targeted antimicrobial enzyme inhibitors to modulate the intestinal microbiota, as well as direct supplementation with SCFAs preparations [155]. In addition, it is recommended that short-chain fatty acids be routinely measured in feces and serum, such as glucose, glycated hemoglobin, and cholesterol levels, to more visually assess disease status, progression, and prognosis and implement more individualized therapeutic interventions. This will require the future development of convenient instrumentation to measure human gut microbes and their metabolite levels using multi-omics methods with higher taxonomic resolution. Further studies are also needed to clarify the role of various gut bacteria and SCFAs in the pathophysiology of human diseases and how they can be utilized and modulated to produce useful effects. Overall, the healthy value of deciphering, monitoring, and manipulating the SCFAs is tremendous, and that calls for the collective efforts from academic, industrial, and clinic entities.

SCFAs, as important active products of gut bacteria, can play a role as signaling molecules and exert anti-inflammatory and immunomodulatory effects on various organs beyond the gut, including brain, lung, heart, liver, pancreas, kidney, muscle, bone, etc. Modulation of the intestinal microbiota and metabolism-active substances has gradually become a popular therapeutic approach for extraintestinal diseases.

Acknowledgements

RC searched articles, determined the title and wrote the paper. YZ, SL, PX searched articles, determined the title. All authors approved the final manuscript. I hereby extend my grateful thanks to them for their kind help. Particularly, I thank Professor Li from the bottom of my heart. He guided me throughout my writing of this paper.

Conflicts of Interest

The authors declare no conflicts of interest regarding the publication of this paper.

References

[1]	The Human Microbiome Project Consortium (2012) Structure, Function and Diversity of the Healthy Human Microbiome. Nature, 486, 207-214. https://doi.org/10.1038/nature11234
[2]	Guarner, F. and Malagelada, J.R. (2003) Gut Flora in Health and Disease. The Lancet, 361, 512-519. https://doi.org/10.1016/S0140-6736(03)12489-0
[3]	Morrison, D.J. and Preston, T. (2016) Formation of Short Chain Fatty Acids by the Gut Microbiota and Their Impact on Human Metabolism. Gut Microbes, 7, 189-200. https://doi.org/10.1080/19490976.2015.1134082
[4]	Ríos-Covián, D., Ruas-Madiedo, P., Margolles, A., Gueimonde, M., de Los Reyes-Gavilán, C.G. and Salazar, N. (2016) Intestinal Short Chain Fatty Acids and Their Link with Diet and Human Health. Frontiers in Microbiology, 7, Article 185. https://doi.org/10.3389/fmicb.2016.00185
[5]	Rooks, M.G. and Garrett, W.S. (2016) Gut Microbiota, Metabolites and Host Immunity. Nature Reviews Immunology, 16, 341-352. https://doi.org/10.1038/nri.2016.42
[6]	Bäckhed, F., Ley, R.E., Sonnenburg, J.L., Peterson, D.A. and Gordon, J.I. (2005) Host-Bacterial Mutualism in the Human Intestine. Science, 307, 1915-1920. https://doi.org/10.1126/science.1104816
[7]	Garrett, W.S. (2019) The Gut Microbiota and Colon Cancer. Science, 364, 1133-1135. https://doi.org/10.1126/science.aaw2367
[8]	Mentella, M.C., Scaldaferri, F., Pizzoferrato, M., Gasbarrini, A. and Miggiano, G.A.D. (2020) Nutrition, IBD and Gut Microbiota: A Review. Nutrients, 12, Article 944. https://doi.org/10.3390/nu12040944
[9]	Cox, A.J., West, N.P. and Cripps, A.W. (2015) Obesity, Inflammation, and the Gut Microbiota. The Lancet Diabetes & Endocrinology, 3, 207-215. https://doi.org/10.1016/S2213-8587(14)70134-2
[10]	Witkowski, M., Weeks, T.L. and Hazen, S.L. (2020) Gut Microbiota and Cardiovascular Disease. Circulation Research, 127, 553-570. https://doi.org/10.1161/CIRCRESAHA.120.316242
[11]	Miller, T.L. and Wolin, M.J. (1996) Pathways of Acetate, Propionate, and Butyrate Formation by the Human Fecal Microbial Flora. Applied and Environmental Microbiology, 62, 1589-1592. https://doi.org/10.1128/aem.62.5.1589-1592.1996
[12]	Macfarlane, S. and Macfarlane, G.T. (2003) Regulation of Short-Chain Fatty Acid Production. Proceedings of the Nutrition Society, 62, 67-72. https://doi.org/10.1079/PNS2002207
[13]	He, J., Zhang, P., Shen, L., Niu, L., Tan, Y., Chen, L., Zhao, Y., Bai, L., Hao, X., Li, X., Zhang, S. and Zhu, L. (2020) Short-Chain Fatty Acids and Their Association with Signalling Pathways in Inflammation, Glucose and Lipid Metabolism. International Journal of Molecular Sciences, 21, Article 6356. https://doi.org/10.3390/ijms21176356
[14]	Stumpff, F. (2018) A Look at the Smelly Side of Physiology: Transport of Short Chain Fatty Acids. Pflügers Archiv, 470, 571-598. https://doi.org/10.1007/s00424-017-2105-9
[15]	Schönfeld, P. and Wojtczak, L. (2016) Short- and Medium-Chain Fatty Acids in Energy Metabolism: The Cellular Perspective. Journal of Lipid Research, 57, 943-954. https://doi.org/10.1194/jlr.R067629
[16]	Cummings, J.H., Pomare, E.W., Branch, W.J., Naylor, C.P. and Macfarlane, G.T. (1987) Short Chain Fatty Acids in Human Large Intestine, Portal, Hepatic and Venous Blood. Gut, 28, 1221-1227. https://doi.org/10.1136/gut.28.10.1221
[17]	Koh, A., De Vadder, F., Kovatcheva-Datchary, P. and Bäckhed, F. (2016) From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites. Cell, 165, 1332-1345. https://doi.org/10.1016/j.cell.2016.05.041
[18]	Tan, J., McKenzie, C., Potamitis, M., Thorburn, A.N., Mackay, C.R. and Macia, L. (2014) The Role of Short-Chain Fatty Acids in Health and Disease. Advances in Immunology, 121, 91-119. https://doi.org/10.1016/B978-0-12-800100-4.00003-9
[19]	Michaudel, C. and Sokol, H. (2020) The Gut Microbiota at the Service of Immunometabolism. Cell Metabolism, 32, 514-523. https://doi.org/10.1016/j.cmet.2020.09.004
[20]	Venkatakrishnan, A.J., Deupi, X., Lebon, G., Tate, C.G., Schertler, G.F. and Babu, M.M. (2013) Molecular Signatures of G-Protein-Coupled Receptors. Nature, 494, 185-194. https://doi.org/10.1038/nature11896
[21]	Wu, F., Song, G., de Graaf, C. and Stevens, R.C. (2017) Structure and Function of Peptide-Binding G Protein-Coupled Receptors. Journal of Molecular Biology, 429, 2726-2745. https://doi.org/10.1016/j.jmb.2017.06.022
[22]	Tan, J.K., McKenzie, C., Mariño, E., Macia, L. and Mackay, C.R. (2017) Metabolite-Sensing G Protein-Coupled Receptors-Facilitators of Diet-Related Immune Regulation. Annual Review of Immunology, 35, 371-402. https://doi.org/10.1146/annurev-immunol-051116-052235
[23]	Li, L., Ma, L. and Fu, P. (2017) Gut Microbiota-Derived Short-Chain Fatty Acids and Kidney Diseases. Drug Design, Development and Therapy, 11, 3531-3542. https://doi.org/10.2147/DDDT.S150825
[24]	Fellows, R., Denizot, J., Stellato, C., Cuomo, A., Jain, P., Stoyanova, E., Balázsi, S., Hajnády, Z., Liebert, A., Kazakevych, J., Blackburn, H., Corrêa, R.O., Fachi, J.L., Sato, F.T., Ribeiro, W.R., Ferreira, C.M., Perée, H., Spagnuolo, M., Mattiuz, R., Matolcsi, C., Guedes, J., Clark, J., Veldhoen, M., Bonaldi, T., Vinolo, M.A.R. and Varga-Weisz, P. (2018) Microbiota Derived Short Chain Fatty Acids Promote Histone Crotonylation in the Colon through Histone Deacetylases. Nature Communications, 9, Article No. 105. https://doi.org/10.1038/s41467-017-02651-5
[25]	Oldendorf, W.H. (1973) Carrier-Mediated Blood-Brain Barrier Transport of Short-Chain Monocarboxylic Organic Acids. American Physiological Society, 224, 1450-1453. https://doi.org/10.1152/ajplegacy.1973.224.6.1450
[26]	Corrêa-Oliveira, R., Fachi, J.L., Vieira, A., Sato, F.T. and Vinolo, M.A. (2016) Regulation of Immune Cell Function by Short-Chain Fatty Acids. Clinical & Translational Immunology, 5, e73. https://doi.org/10.1038/cti.2016.17
[27]	Duscha, A., Gisevius, B., Hirschberg, S., Yissachar, N., Stangl, G.I., Eilers, E., Bader, V., Haase, S., Kaisler, J., David, C., Schneider, R., Troisi, R., Zent, D., Hegelmaier, T., Dokalis, N., Gerstein, S., Del Mare-Roumani, S., Amidror, S., Staszewski, O., Poschmann, G., Stühler, K., Hirche, F., Balogh, A., Kempa, S., Träger, P., Zaiss, M.M., Holm, J.B., Massa, M.G., Nielsen, H.B., Faissner, A., Lukas, C., Gatermann, S.G., Scholz, M., Przuntek, H., Prinz, M., Forslund, S.K., Winklhofer, K.F., Müller, D.N., Linker, R.A., Gold, R. and Haghikia, A. (2020) Propionic Acid Shapes the Multiple Sclerosis Disease Course by an Immunomodulatory Mechanism. Cell, 180, 1067-1080.e1016. https://doi.org/10.1016/j.cell.2020.02.035
[28]	Haghikia, A., Jörg, S., Duscha, A., Berg, J., Manzel, A., Waschbisch, A., Hammer, A., Lee, D.H., May, C., Wilck, N., Balogh, A., Ostermann, A.I., Schebb, N.H., Akkad, D.A., Grohme, D.A., Kleinewietfeld, M., Kempa, S., Thöne, J., Demir, S., Müller, D.N., Gold, R. and Linker, R.A. (2015) Dietary Fatty Acids Directly Impact Central Nervous System Autoimmunity via the Small Intestine. Immunity, 43, 817-829. https://doi.org/10.1016/j.immuni.2015.09.007
[29]	Mizuno, M., Noto, D., Kaga, N., Chiba, A. and Miyake, S. (2017) The Dual Role of Short Fatty Acid Chains in the Pathogenesis of Autoimmune Disease Models. PLOS ONE, 12, e0173032. https://doi.org/10.1371/journal.pone.0173032
[30]	Chitrala, K.N., Guan, H., Singh, N.P., Busbee, B., Gandy, A., Mehrpouya-Bahrami, P., Ganewatta, M.S., Tang, C., Chatterjee, S., Nagarkatti, P. and Nagarkatti, M. (2017) CD44 Deletion Leading to Attenuation of Experimental Autoimmune Encephalomyelitis Results from Alterations in Gut Microbiome in Mice. European Journal of Immunology, 47, 1188-1199. https://doi.org/10.1002/eji.201646792
[31]	Chen, T., Noto, D., Hoshino, Y., Mizuno, M. and Miyake, S. (2019) Butyrate Suppresses Demyelination and Enhances Remyelination. Journal of Neuroinflammation, 16, Article No. 165. https://doi.org/10.1186/s12974-019-1552-y
[32]	Hardoff, R., Sula, M., Tamir, A., Soil, A., Front, A., Badarna, S., Honigman, S. and Giladi, N. (2001) Gastric Emptying Time and Gastric Motility in Patients with Parkinson’s Disease. Movement Disorders, 16, 1041-1047. https://doi.org/10.1002/mds.1203
[33]	Cersosimo, M.G., Raina, G.B., Pecci, C., Pellene, A., Calandra, C.R., Gutiérrez, C., Micheli, F.E. and Benarroch, E.E. (2013) Gastrointestinal Manifestations in Parkinson’s Disease: Prevalence and Occurrence before Motor Symptoms. Journal of Neurology, 260, 1332-1338. https://doi.org/10.1007/s00415-012-6801-2
[34]	Braak, H., de Vos, R.A., Bohl, J. and Del Tredici, K. (2006) Gastric Alpha-Synuclein Immunoreactive Inclusions in Meissner’s and Auerbach’s Plexuses in Cases Staged for Parkinson’s Disease-Related Brain Pathology. Neuroscience Letters, 396, 67-72. https://doi.org/10.1016/j.neulet.2005.11.012
[35]	Wakabayashi, K., Takahashi, H., Takeda, S., Ohama, E. and Ikuta, F. (1988) Parkinson’s Disease: The Presence of Lewy Bodies in Auerbach’s and Meissner’s Plexuses. Acta Neuropathologica, 76, 217-221. https://doi.org/10.1007/BF00687767
[36]	Barichella, M., Severgnini, M., Cilia, R., Cassani, E., Bolliri, C., Caronni, S., Ferri, V., Cancello, R., Ceccarani, C., Faierman, S., Pinelli, G., De Bellis, G., Zecca, L., Cereda, E., Consolandi, C. and Pezzoli, G. (2019) Unraveling Gut Microbiota in Parkinson’s Disease and Atypical Parkinsonism. Movement Disorders, 34, 396-405. https://doi.org/10.1002/mds.27581
[37]	Aho, V.T.E., Pereira, P.A.B., Voutilainen, S., Paulin, L., Pekkonen, E., Auvinen, P. and Scheperjans, F. (2019) Gut Microbiota in Parkinson’s Disease: Temporal Stability and Relations to Disease Progression. eBioMedicine, 44, 691-707. https://doi.org/10.1016/j.ebiom.2019.05.064
[38]	Unger, M.M., Spiegel, J., Dillmann, K.U., Grundmann, D., Philippeit, H., Bürmann, J., Faßbender, K., Schwiertz, A. and Schäfer, K.H. (2016) Short Chain Fatty Acids and Gut Microbiota Differ between Patients with Parkinson’s Disease and Age-Matched Controls. Parkinsonism & Related Disorders, 32, 66-72. https://doi.org/10.1016/j.parkreldis.2016.08.019
[39]	Liu, J., Wang, F., Liu, S., Du, J., Hu, X., Xiong, J., Fang, R., Chen, W. and Sun, J. (2017) Sodium Butyrate Exerts Protective Effect against Parkinson’s Disease in Mice via Stimulation of Glucagon Like Peptide-1. Journal of the Neurological Sciences, 381, 176-181. https://doi.org/10.1016/j.jns.2017.08.3235
[40]	Li, X., Fan, X., Yuan, X., Pang, L., Hu, S., Wang, Y., Huang, X. and Song, X. (2021) The Role of Butyric Acid in Treatment Response in Drug-Naïve First Episode Schizophrenia. Frontiers in Psychiatry, 12, Article ID: 724664. https://doi.org/10.3389/fpsyt.2021.724664
[41]	Malhi, G.S. and Mann, J.J. (2018) Depression. The Lancet, 392, 2299-2312. https://doi.org/10.1016/S0140-6736(18)31948-2
[42]	Harmer, C.J., Duman, R.S. and Cowen, P.J. (2017) How Do Antidepressants Work? New Perspectives for Refining Future Treatment Approaches. The Lancet Psychiatry, 4, 409-418. https://doi.org/10.1016/S2215-0366(17)30015-9
[43]	Cruz-Pereira, J.S., Rea, K., Nolan, Y.M., O’Leary, O.F., Dinan, T.G. and Cryan, J.F. (2020) Depression’s Unholy Trinity: Dysregulated Stress, Immunity, and the Microbiome. Annual Review of Psychology, 71, 49-78. https://doi.org/10.1146/annurev-psych-122216-011613
[44]	Zheng, P., Zeng, B., Zhou, C., Liu, M., Fang, Z., Xu, X., Zeng, L., Chen, J., Fan, S., Du, X., Zhang, X., Yang, D., Yang, Y., Meng, H., Li, W., Melgiri, N.D., Licinio, J., Wei, H. and Xie, P. (2016) Gut Microbiome Remodeling Induces Depressive-Like Behaviors through a Pathway Mediated by the Host’s Metabolism. Molecular Psychiatry, 21, 786-796. https://doi.org/10.1038/mp.2016.44
[45]	Wu, M., Tian, T., Mao, Q., Zou, T., Zhou, C.J., Xie, J. and Chen, J.J. (2020) Associations between Disordered Gut Microbiota and Changes of Neurotransmitters and Short-Chain Fatty Acids in Depressed Mice. Translational Psychiatry, 10, Article No. 350. https://doi.org/10.1038/s41398-020-01038-3
[46]	Müller, B., Rasmusson, A.J., Just, D., Jayarathna, S., Moazzami, A., Novicic, Z.K. and Cunningham, J.L. (2021) Fecal Short-Chain Fatty Acid Ratios as Related to Gastrointestinal and Depressive Symptoms in Young Adults. Psychosomatic Medicine, 83, 693-699. https://doi.org/10.1097/PSY.0000000000000965
[47]	Yan, Q., Gu, Y., Li, X., Yang, W., Jia, L., Chen, C., Han, X., Huang, Y., Zhao, L., Li, P., Fang, Z., Zhou, J., Guan, X., Ding, Y., Wang, S., Khan, M., Xin, Y., Li, S. and Ma, Y. (2017) Alterations of the Gut Microbiome in Hypertension. Frontiers in Cellular and Infection Microbiology, 7, Article 381. https://doi.org/10.3389/fcimb.2017.00381
[48]	Sun, S., Lulla, A., Sioda, M., Winglee, K., Wu, M.C., Jacobs Jr., D.R., Shikany, J.M., Lloyd-Jones, D.M., Launer, L.J., Fodor, A.A. and Meyer, K.A. (2019) Gut Microbiota Composition and Blood Pressure. Hypertension, 73, 998-1006. https://doi.org/10.1161/HYPERTENSIONAHA.118.12109
[49]	Li, J., Zhao, F., Wang, Y., Chen, J., Tao, J., Tian, G., Wu, S., Liu, W., Cui, Q., Geng, B., Zhang, W., Weldon, R., Auguste, K., Yang, L., Liu, X., Chen, L., Yang, X., Zhu, B. and Cai, J. (2017) Gut Microbiota Dysbiosis Contributes to the Development of Hypertension. Microbiome, 5, Article No. 14. https://doi.org/10.1186/s40168-016-0222-x
[50]	Kim, S., Goel, R., Kumar, A., Qi, Y., Lobaton, G., Hosaka, K., Mohammed, M., Handberg, E.M., Richards, E.M., Pepine, C.J. and Raizada, M.K. (2018) Imbalance of Gut Microbiome and Intestinal Epithelial Barrier Dysfunction in Patients with High Blood Pressure. Clinical Science (Lond), 132, 701-718. https://doi.org/10.1042/CS20180087
[51]	Bartolomaeus, H., Balogh, A., Yakoub, M., Homann, S., Markó, L., Höges, S., Tsvetkov, D., Krannich, A., Wundersitz, S., Avery, E.G., Haase, N., Kräker, K., Hering, L., Maase, M., Kusche-Vihrog, K., Grandoch, M., Fielitz, J., Kempa, S., Gollasch, M., Zhumadilov, Z., Kozhakhmetov, S., Kushugulova, A., Eckardt, K.U., Dechend, R., Rump, L.C., Forslund, S.K., Müller, D.N., Stegbauer, J. and Wilck, N. (2019) Short-Chain Fatty Acid Propionate Protects From Hypertensive Cardiovascular Damage. Circulation, 139, 1407-1421. https://doi.org/10.1161/CIRCULATIONAHA.118.036652
[52]	Liu, W., Luo, X., Tang, J., Mo, Q., Zhong, H., Zhang, H. and Feng, F. (2021) A Bridge for Short-Chain Fatty Acids to Affect Inflammatory Bowel Disease, Type 1 Diabetes, and Non-Alcoholic Fatty Liver Disease Positively: By Changing Gut Barrier. European Journal of Nutrition, 60, 2317-2330. https://doi.org/10.1007/s00394-020-02431-w
[53]	Vinolo, M.A., Rodrigues, H.G., Hatanaka, E., Sato, F.T., Sampaio, S.C. and Curi, R. (2011) Suppressive Effect of Short-Chain Fatty Acids on Production of Proinflammatory Mediators by Neutrophils. The Journal of Nutritional Biochemistry, 22, 849-855. https://doi.org/10.1016/j.jnutbio.2010.07.009
[54]	Pluznick, J. (2014) A Novel SCFA Receptor, the Microbiota, and Blood Pressure Regulation. Gut Microbes, 5, 202-207. https://doi.org/10.4161/gmic.27492
[55]	Natarajan, N., Hori, D., Flavahan, S., Steppan, J., Flavahan, N.A., Berkowitz, D.E. and Pluznick, J.L. (2016) Microbial Short Chain Fatty Acid Metabolites Lower Blood Pressure via Endothelial G Protein-Coupled Receptor 41. Physiological Genomics, 48, 826-834. https://doi.org/10.1152/physiolgenomics.00089.2016
[56]	Yancy, C.W., Jessup, M., Bozkurt, B., Butler, J., Casey Jr., D.E., Colvin, M.M., Drazner, M.H., Filippatos, G.S., Fonarow, G.C., Givertz, M.M., Hollenberg, S.M., Lindenfeld, J., Masoudi, F.A., McBride, P.E., Peterson, P.N., Stevenson, L.W. and Westlake, C. (2017) 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation, 136, e137-e161. https://doi.org/10.1161/CIR.0000000000000509
[57]	Tang, W.H.W., Li, D.Y. and Hazen, S.L. (2019) Dietary Metabolism, the Gut Microbiome, and Heart Failure. Nature Reviews Cardiology, 16, 137-154. https://doi.org/10.1038/s41569-018-0108-7
[58]	Munger, M.A., Johnson, B., Amber, I.J., Callahan, K.S. and Gilbert, E.M. (1996) Circulating Concentrations of Proinflammatory Cytokines in Mild or Moderate Heart Failure Secondary to Ischemic or Idiopathic Dilated Cardiomyopathy. American Journal of Cardiology, 77, 723-727. https://doi.org/10.1016/S0002-9149(97)89206-5
[59]	Sandek, A., Bauditz, J., Swidsinski, A., Buhner, S., Weber-Eibel, J., von Haehling, S., Schroedl, W., Karhausen, T., Doehner, W., Rauchhaus, M., Poole-Wilson, P., Volk, H.D., Lochs, H. and Anker, S.D. (2007) Altered Intestinal Function in Patients with Chronic Heart Failure. Journal of the American College of Cardiology, 50, 1561-1569. https://doi.org/10.1016/j.jacc.2007.07.016
[60]	Carley, A.N., Maurya, S.K., Fasano, M., Wang, Y., Selzman, C.H., Drakos, S.G. and Lewandowski, E.D. (2021) Short-Chain Fatty Acids Outpace Ketone Oxidation in the Failing Heart. Circulation, 143, 1797-1808. https://doi.org/10.1161/CIRCULATIONAHA.120.052671
[61]	Zuo, K., Li, J., Li, K., Hu, C., Gao, Y., Chen, M., Hu, R., Liu, Y., Chi, H., Wang, H., Qin, Y., Liu, X., Li, S., Cai, J., Zhong, J. and Yang, X. (2019) Disordered Gut Microbiota and Alterations in Metabolic Patterns Are Associated with Atrial Fibrillation. Gigascience, 8, giz058. https://doi.org/10.1093/gigascience/giz058
[62]	Zuo, K., Li, J., Wang, P., Liu, Y., Liu, Z., Yin, X., Liu, X. and Yang, X. (2019) Duration of Persistent Atrial Fibrillation Is Associated with Alterations in Human Gut Microbiota and Metabolic Phenotypes. mSystems, 4, e00422-19. https://doi.org/10.1128/mSystems.00422-19
[63]	Zuo, K., Yin, X., Li, K., Zhang, J., Wang, P., Jiao, J., Liu, Z., Liu, X., Liu, J., Li, J. and Yang, X. (2020) Different Types of Atrial Fibrillation Share Patterns of Gut Microbiota Dysbiosis. mSphere, 5, e00071-20. https://doi.org/10.1128/mSphere.00071-20
[64]	Nattel, S., Heijman, J., Zhou, L. and Dobrev, D. (2020) Molecular Basis of Atrial Fibrillation Pathophysiology and Therapy: A Translational Perspective. Circulation Research, 127, 51-72. https://doi.org/10.1161/CIRCRESAHA.120.316363
[65]	Van Wagoner, D.R. and Chung, M.K. (2018) Inflammation, Inflammasome Activation, and Atrial Fibrillation. Circulation, 138, 2243-2246. https://doi.org/10.1161/CIRCULATIONAHA.118.036143
[66]	Feng, Y., Wang, Y., Wang, P., Huang, Y. and Wang, F. (2018) Short-Chain Fatty Acids Manifest Stimulative and Protective Effects on Intestinal Barrier Function Through the Inhibition of NLRP3 Inflammasome and Autophagy. Cellular Physiology and Biochemistry, 49, 190-205. https://doi.org/10.1159/000492853
[67]	Xu, M., Jiang, Z., Wang, C., Li, N., Bo, L., Zha, Y., Bian, J., Zhang, Y. and Deng, X. (2019) Acetate Attenuates Inflammasome Activation through GPR43-Mediated Ca2+-Dependent NLRP3 Ubiquitination. Experimental & Molecular Medicine, 51, 1-13. https://doi.org/10.1038/s12276-019-0276-5
[68]	Zhou, M., Li, D., Xie, K., Xu, L., Kong, B., Wang, X., Tang, Y., Liu, Y. and Huang, H. (2021) The Short-Chain Fatty Acid Propionate Improved Ventricular Electrical Remodeling in a Rat Model with Myocardial Infarction. Food & Function, 12, 12580-12593. https://doi.org/10.1039/D1FO02040D
[69]	Budden, K.F., Gellatly, S.L., Wood, D.L., Cooper, M.A., Morrison, M., Hugenholtz, P. and Hansbro, P.M. (2017) Emerging Pathogenic Links between Microbiota and the Gut-Lung Axis. Nature Reviews Microbiology, 15, 55-63. https://doi.org/10.1038/nrmicro.2016.142
[70]	Liu, Q., Tian, X., Maruyama, D., Arjomandi, M. and Prakash, A. (2021) Lung Immune Tone via Gut-Lung Axis: Gut-Derived LPS and Short-Chain Fatty Acids’ Immunometabolic Regulation of Lung IL-1β, FFAR2, and FFAR3 Expression. American Journal of Physiology-Lung Cellular and Molecular Physiology, 321, L65-L78. https://doi.org/10.1152/ajplung.00421.2020
[71]	Marsland, B.J., Trompette, A. and Gollwitzer, E.S. (2015) The Gut-Lung Axis in Respiratory Disease. Annals of the American Thoracic Society, 12, S150-S156. https://doi.org/10.1513/AnnalsATS.201503-133AW
[72]	Ichinohe, T., Pang, I.K., Kumamoto, Y., Peaper, D.R., Ho, J.H., Murray, T.S. and Iwasaki, A. (2011) Microbiota Regulates Immune Defense against Respiratory Tract Influenza A Virus Infection. Proceedings of the National Academy of Sciences of the United States of America, 108, 5354-5359. https://doi.org/10.1073/pnas.1019378108
[73]	Fagundes, C.T., Amaral, F.A., Vieira, A.T., Soares, A.C., Pinho, V., Nicoli, J.R., Vieira, L.Q., Teixeira, M.M. and Souza, D.G. (2012) Transient TLR Activation Restores Inflammatory Response and Ability to Control Pulmonary Bacterial Infection in Germfree Mice. The Journal of Immunology, 188, 1411-1420. https://doi.org/10.4049/jimmunol.1101682
[74]	Dang, A.T. and Marsland, B.J. (2019) Microbes, Metabolites, and the Gut-Lung Axis. Mucosal Immunology, 12, 843-850. https://doi.org/10.1038/s41385-019-0160-6
[75]	Roe, A.J., O’Byrne, C., McLaggan, D. and Booth, I.R. (2002) Inhibition of Escherichia coli Growth by Acetic Acid: A Problem with Methionine Biosynthesis and Homocysteine Toxicity. Microbiology (Reading), 148, 2215-2222. https://doi.org/10.1099/00221287-148-7-2215
[76]	Roe, A.J., McLaggan, D., Davidson, I., O’Byrne, C. and Booth, I.R. (1998) Perturbation of Anion Balance during Inhibition of Growth of Escherichia coli by Weak Acids. Journal of Bacteriology, 180, 767-772. https://doi.org/10.1128/JB.180.4.767-772.1998
[77]	Lawhon, S.D., Maurer, R., Suyemoto, M. and Altier, C. (2002) Intestinal Short-Chain Fatty Acids Alter Salmonella typhimurium Invasion Gene Expression and Virulence through BarA/SirA. Molecular Microbiology, 46, 1451-1464. https://doi.org/10.1046/j.1365-2958.2002.03268.x
[78]	Ang, Z., Xiong, D., Wu, M. and Ding, J.L. (2018) FFAR2-FFAR3 Receptor Heteromerization Modulates Short-Chain Fatty Acid Sensing. The FASEB Journal, 32, 289-303. https://doi.org/10.1096/fj.201700252RR
[79]	Sunkara, L.T., Jiang, W. and Zhang, G. (2012) Modulation of Antimicrobial Host Defense Peptide Gene Expression by Free Fatty Acids. PLOS ONE, 7, e49558. https://doi.org/10.1371/journal.pone.0049558
[80]	Cait, A., Hughes, M.R., Antignano, F., Cait, J., Dimitriu, P.A., Maas, K.R., Reynolds, L.A., Hacker, L., Mohr, J., Finlay, B.B., Zaph, C., McNagny, K.M. and Mohn, W.W. (2018) Microbiome-Driven Allergic Lung Inflammation Is Ameliorated by Short-Chain Fatty Acids. Mucosal Immunology, 11, 785-795. https://doi.org/10.1038/mi.2017.75
[81]	Roduit, C., Frei, R., Ferstl, R., Loeliger, S., Westermann, P., Rhyner, C., Schiavi, E., Barcik, W., Rodriguez-Perez, N., Wawrzyniak, M., Chassard, C., Lacroix, C., Schmausser-Hechfellner, E., Depner, M., von Mutius, E., Braun-Fahrländer, C., Karvonen, A.M., Kirjavainen, P.V., Pekkanen, J., Dalphin, J.C., Riedler, J., Akdis, C., Lauener, R. and O’Mahony, L. (2019) High Levels of Butyrate and Propionate in Early Life Are Associated with Protection Against Atopy. Allergy, 74, 799-809. https://doi.org/10.1111/all.13660
[82]	Theiler, A., Bärnthaler, T., Platzer, W., Richtig, G., Peinhaupt, M., Rittchen, S., Kargl, J., Ulven, T., Marsh, L.M., Marsche, G., Schuligoi, R., Sturm, E.M. and Heinemann, A. (2019) Butyrate Ameliorates Allergic Airway Inflammation by Limiting Eosinophil Trafficking and Survival. The Journal of Allergy and Clinical Immunology, 144, 764-776. https://doi.org/10.1016/j.jaci.2019.05.002
[83]	Folkerts, J., Redegeld, F., Folkerts, G., Blokhuis, B., van den Berg, M.P.M., de Bruijn, M.J.W., van, I.W.F.J., Junt, T., Tam, S.Y., Galli, S.J., Hendriks, R.W., Stadhouders, R. and Maurer, M. (2020) Butyrate Inhibits Human Mast Cell Activation via Epigenetic Regulation of FcεRI-Mediated Signaling. Allergy, 75, 1966-1978. https://doi.org/10.1111/all.14254
[84]	Wypych, T.P., Marzi, R., Wu, G.F., Lanzavecchia, A. and Sallusto, F. (2018) Role of B Cells in TH Cell Responses in a Mouse Model of Asthma. The Journal of Allergy and Clinical Immunology, 141, 1395-1410. https://doi.org/10.1016/j.jaci.2017.09.001
[85]	Sanchez, H.N., Moroney, J.B., Gan, H., Shen, T., Im, J.L., Li, T., Taylor, J.R., Zan, H. and Casali, P. (2020) B Cell-Intrinsic Epigenetic Modulation of Antibody Responses by Dietary Fiber-Derived Short-Chain Fatty Acids. Nature Communications, 11, Article No. 60. https://doi.org/10.1038/s41467-019-13603-6
[86]	Hu, Y., Feng, Y., Wu, J., Liu, F., Zhang, Z., Hao, Y., Liang, S., Li, B., Li, J., Lv, N., Xu, Y., Zhu, B. and Sun, Z. (2019) The Gut Microbiome Signatures Discriminate Healthy from Pulmonary Tuberculosis Patients. Frontiers in Cellular and Infection Microbiology, 9, Article 90. https://doi.org/10.3389/fcimb.2019.00090
[87]	Lee, H.Y., Nam, S., Kim, M.J., Kim, S.J., Back, S.H. and Yoo, H.J. (2021) Butyrate Prevents TGF-β1-Induced Alveolar Myofibroblast Differentiation and Modulates Energy Metabolism. Metabolites, 11, Article 258. https://doi.org/10.3390/metabo11050258
[88]	Gülden, E., Ihira, M., Ohashi, A., Reinbeck, A.L., Freudenberg, M.A., Kolb, H. and Burkart, V. (2013) Toll-Like Receptor 4 Deficiency Accelerates the Development of Insulin-Deficient Diabetes in Non-Obese Diabetic Mice. PLOS ONE, 8, e75385. https://doi.org/10.1371/journal.pone.0075385
[89]	Regard, J.B., Kataoka, H., Cano, D.A., Camerer, E., Yin, L., Zheng, Y.W., Scanlan, T.S., Hebrok, M. and Coughlin, S.R. (2007) Probing Cell Type-Specific Functions of Gi in Vivo Identifies GPCR Regulators of Insulin Secretion. Journal of Clinical Investigation, 117, 4034-4043. https://doi.org/10.1172/JCI32994
[90]	Stumvoll, M., Goldstein, B.J. and van Haeften, T.W. (2005) Type 2 Diabetes: Principles of Pathogenesis and Therapy. The Lancet, 365, 1333-1346. https://doi.org/10.1016/S0140-6736(05)61032-X
[91]	Hong, Y.H., Nishimura, Y., Hishikawa, D., Tsuzuki, H., Miyahara, H., Gotoh, C., Choi, K.C., Feng, D.D., Chen, C., Lee, H.G., Katoh, K., Roh, S.G. and Sasaki, S. (2005) Acetate and Propionate Short Chain Fatty Acids Stimulate Adipogenesis via GPCR43. Endocrinology, 146, 5092-5099. https://doi.org/10.1210/en.2005-0545
[92]	Tolhurst, G., Heffron, H., Lam, Y.S., Parker, H.E., Habib, A.M., Diakogiannaki, E., Cameron, J., Grosse, J., Reimann, F. and Gribble, F.M. (2012) Short-Chain Fatty Acids Stimulate Glucagon-Like Peptide-1 Secretion via the G-Protein-Coupled Receptor FFAR2. Diabetes, 61, 364-371. https://doi.org/10.2337/db11-1019
[93]	Reimer, R.A., Darimont, C., Gremlich, S., Nicolas-Métral, V., Rüegg, U.T. and Macé, K. (2001) A Human Cellular Model for Studying the Regulation of Glucagon-Like Peptide-1 Secretion. Endocrinology, 142, 4522-4528. https://doi.org/10.1210/endo.142.10.8415
[94]	Larraufie, P., Martin-Gallausiaux, C., Lapaque, N., Dore, J., Gribble, F.M., Reimann, F. and Blottiere, H.M. (2018) SCFAs Strongly Stimulate PYY Production in Human Enteroendocrine Cells. Scientific Reports, 8, Article No. 74. https://doi.org/10.1038/s41598-017-18259-0
[95]	Blaak, E.E., Canfora, E.E., Theis, S., Frost, G., Groen, A.K., Mithieux, G., Nauta, A., Scott, K., Stahl, B., van Harsselaar, J., van Tol, R., Vaughan, E.E. and Verbeke, K. (2020) Short Chain Fatty Acids in Human Gut and Metabolic Health. Beneficial Microbes, 11, 411-455. https://doi.org/10.3920/BM2020.0057
[96]	Frost, G., Sleeth, M.L., Sahuri-Arisoylu, M., Lizarbe, B., Cerdan, S., Brody, L., Anastasovska, J., Ghourab, S., Hankir, M., Zhang, S., Carling, D., Swann, J.R., Gibson, G., Viardot, A., Morrison, D., Louise Thomas, E. and Bell, J.D. (2014) The Short-Chain Fatty Acid Acetate Reduces Appetite via a Central Homeostatic Mechanism. Nature Communications, 5, Article No. 3611. https://doi.org/10.1038/ncomms4611
[97]	Davies, T.F., Andersen, S., Latif, R., Nagayama, Y., Barbesino, G., Brito, M., Eckstein, A.K., Stagnaro-Green, A. and Kahaly, G.J. (2020) Graves’ Disease. Nature Reviews Disease Primers, 6, Article No. 52. https://doi.org/10.1038/s41572-020-0184-y
[98]	Smith, P.M., Howitt, M.R., Panikov, N., Michaud, M., Gallini, C.A., Bohlooly, Y.M., Glickman, J.N. and Garrett, W.S. (2013) The Microbial Metabolites, Short-Chain Fatty Acids, Regulate Colonic Treg Cell Homeostasis. Science, 341, 569-573. https://doi.org/10.1126/science.1241165
[99]	Su, X., Yin, X., Liu, Y., Yan, X., Zhang, S., Wang, X., Lin, Z., Zhou, X., Gao, J., Wang, Z. and Zhang, Q. (2020) Gut Dysbiosis Contributes to the Imbalance of Treg and Th17 Cells in Graves’ Disease Patients by Propionic Acid. The Journal of Clinical Endocrinology & Metabolism, 105, 3526-3547. https://doi.org/10.1210/clinem/dgaa511
[100]	Albillos, A., de Gottardi, A. and Rescigno, M. (2020) The Gut-Liver Axis in Liver Disease: Pathophysiological Basis for Therapy. Journal of Hepatology, 72, 558-577. https://doi.org/10.1016/j.jhep.2019.10.003
[101]	Son, G., Kremer, M. and Hines, I.N. (2010) Contribution of Gut Bacteria to Liver Pathobiology. Gastroenterology Research and Practice, 2010, Article ID: 453563. https://doi.org/10.1155/2010/453563
[102]	Zhou, D., Pan, Q., Xin, F.Z., Zhang, R.N., He, C.X., Chen, G.Y., Liu, C., Chen, Y.W. and Fan, J.G. (2017) Sodium Butyrate Attenuates High-Fat Diet-Induced Steatohepatitis in Mice by Improving Gut Microbiota and Gastrointestinal Barrier. World Journal of Gastroenterology, 23, 60-75. https://doi.org/10.3748/wjg.v23.i1.60
[103]	Ye, J., Lv, L., Wu, W., Li, Y., Shi, D., Fang, D., Guo, F., Jiang, H., Yan, R., Ye, W. and Li, L. (2018) Butyrate Protects Mice against Methionine-Choline-Deficient Diet-Induced Non-Alcoholic Steatohepatitis by Improving Gut Barrier Function, Attenuating Inflammation and Reducing Endotoxin Levels. Frontiers in Microbiology, 9, Article 1967. https://doi.org/10.3389/fmicb.2018.01967
[104]	Jin, C.J., Sellmann, C., Engstler, A.J., Ziegenhardt, D. and Bergheim, I. (2015) Supplementation of Sodium Butyrate Protects Mice from the Development of Non-Alcoholic Steatohepatitis (NASH). British Journal of Nutrition, 114, 1745-1755. https://doi.org/10.1017/S0007114515003621
[105]	Rau, M., Rehman, A., Dittrich, M., Groen, A.K., Hermanns, H.M., Seyfried, F., Beyersdorf, N., Dandekar, T., Rosenstiel, P. and Geier, A. (2018) Fecal SCFAs and SCFA-Producing Bacteria in Gut Microbiome of Human NAFLD as a Putative Link to Systemic T-Cell Activation and Advanced Disease. United European Gastroenterology Journal, 6, 1496-1507. https://doi.org/10.1177/2050640618804444
[106]	Kelly, C.J., Zheng, L., Campbell, E.L., Saeedi, B., Scholz, C.C., Bayless, A.J., Wilson, K.E., Glover, L.E., Kominsky, D.J., Magnuson, A., Weir, T.L., Ehrentraut, S.F., Pickel, C., Kuhn, K.A., Lanis, J.M., Nguyen, V., Taylor, C.T. and Colgan, S.P. (2015) Crosstalk between Microbiota-Derived Short-Chain Fatty Acids and Intestinal Epithelial HIF Augments Tissue Barrier Function. Cell Host & Microbe, 17, 662-671. https://doi.org/10.1016/j.chom.2015.03.005
[107]	Demigné, C., Morand, C., Levrat, M.A., Besson, C., Moundras, C. and Rémésy, C. (1995) Effect of Propionate on Fatty Acid and Cholesterol Synthesis and on Acetate Metabolism in Isolated Rat Hepatocytes. British Journal of Nutrition, 74, 209-219. https://doi.org/10.1079/BJN19950124
[108]	Deng, M., Qu, F., Chen, L., Liu, C., Zhang, M., Ren, F., Guo, H., Zhang, H., Ge, S., Wu, C. and Zhao, L. (2020) SCFAs Alleviated Steatosis and Inflammation in Mice with NASH Induced by MCD. Journal of Endocrinology, 245, 425-437. https://doi.org/10.1530/JOE-20-0018
[109]	Canfora, E.E., van der Beek, C.M., Jocken, J.W.E., Goossens, G.H., Holst, J.J., Olde Damink, S.W.M., Lenaerts, K., Dejong, C.H.C. and Blaak, E.E. (2017) Colonic Infusions of Short-Chain Fatty Acid Mixtures Promote Energy Metabolism in Overweight/Obese Men: A Randomized Crossover Trial. Scientific Reports, 7, Article No. 2360. https://doi.org/10.1038/s41598-017-02546-x
[110]	Wang, Z., Zhang, X., Zhu, L., Yang, X., He, F., Wang, T., Bao, T., Lu, H., Wang, H. and Yang, S. (2020) Inulin Alleviates Inflammation of Alcoholic Liver Disease via SCFAs-Inducing Suppression of M1 and Facilitation of M2 Macrophages in Mice. International Immunopharmacology, 78, Article ID: 106062. https://doi.org/10.1016/j.intimp.2019.106062
[111]	Grosicki, G.J., Fielding, R.A. and Lustgarten, M.S. (2018) Gut Microbiota Contribute to Age-Related Changes in Skeletal Muscle Size, Composition, and Function: Biological Basis for a Gut-Muscle Axis. Calcified Tissue International, 102, 433-442. https://doi.org/10.1007/s00223-017-0345-5
[112]	Ticinesi, A., Lauretani, F., Milani, C., Nouvenne, A., Tana, C., Del Rio, D., Maggio, M., Ventura, M. and Meschi, T. (2017) Aging Gut Microbiota at the Cross-Road between Nutrition, Physical Frailty, and Sarcopenia: Is There a Gut-Muscle Axis? Nutrients, 9, Article 1303. https://doi.org/10.3390/nu9121303
[113]	Lahiri, S., Kim, H., Garcia-Perez, I., Reza, M.M., Martin, K.A., Kundu, P., Cox, L.M., Selkrig, J., Posma, J.M., Zhang, H., Padmanabhan, P., Moret, C., Gulyás, B., Blaser, M.J., Auwerx, J., Holmes, E., Nicholson, J., Wahli, W. and Pettersson, S. (2019) The Gut Microbiota Influences Skeletal Muscle Mass and Function in Mice. Science Translational Medicine, 11. https://doi.org/10.1126/scitranslmed.aan5662
[114]	Nay, K., Jollet, M., Goustard, B., Baati, N., Vernus, B., Pontones, M., Lefeuvre-Orfila, L., Bendavid, C., Rué, O., Mariadassou, M., Bonnieu, A., Ollendorff, V., Lepage, P., Derbré, F. and Koechlin-Ramonatxo, C. (2019) Gut Bacteria Are Critical for Optimal Muscle Function: A Potential Link with Glucose Homeostasis. American Journal of Physiology-Endocrinology and Metabolism, 317, E158-e171. https://doi.org/10.1152/ajpendo.00521.2018
[115]	Hsu, Y.J., Chiu, C.C., Li, Y.P., Huang, W.C., Huang, Y.T., Huang, C.C. and Chuang, H.L. (2015) Effect of Intestinal Microbiota on Exercise Performance in Mice. The Journal of Strength & Conditioning Research, 29, 552-558. https://doi.org/10.1519/JSC.0000000000000644
[116]	Chen, Y.M., Wei, L., Chiu, Y.S., Hsu, Y.J., Tsai, T.Y., Wang, M.F. and Huang, C.C. (2016) Lactobacillus plantarum TWK10 Supplementation Improves Exercise Performance and Increases Muscle Mass in Mice. Nutrients, 8, Article 205. https://doi.org/10.3390/nu8040205
[117]	Buigues, C., Fernández-Garrido, J., Pruimboom, L., Hoogland, A.J., Navarro-Martínez, R., Martínez-Martínez, M., Verdejo, Y., Mascarós, M.C., Peris, C. and Cauli, O. (2016) Effect of a Prebiotic Formulation on Frailty Syndrome: A Randomized, Double-Blind Clinical Trial. International Journal of Molecular Sciences, 17, Article 932. https://doi.org/10.3390/ijms17060932
[118]	Liu, L., Fu, C. and Li, F. (2019) Acetate Affects the Process of Lipid Metabolism in Rabbit Liver, Skeletal Muscle and Adipose Tissue. Animals (Basel), 9, Article 799. https://doi.org/10.3390/ani9100799
[119]	Maruta, H., Yoshimura, Y., Araki, A., Kimoto, M., Takahashi, Y. and Yamashita, H. (2016) Activation of AMP-Activated Protein Kinase and Stimulation of Energy Metabolism by Acetic Acid in L6 Myotube Cells. PLOS ONE, 11, e0158055. https://doi.org/10.1371/journal.pone.0158055
[120]	Han, J.H., Kim, I.S., Jung, S.H., Lee, S.G., Son, H.Y. and Myung, C.S. (2014) The Effects of Propionate and Valerate on Insulin Responsiveness for Glucose Uptake in 3T3-L1 Adipocytes and C2C12 Myotubes via G Protein-Coupled Receptor 41. PLOS ONE, 9, e95268. https://doi.org/10.1371/journal.pone.0095268
[121]	Fushimi, T., Tayama, K., Fukaya, M., Kitakoshi, K., Nakai, N., Tsukamoto, Y. and Sato, Y. (2001) Acetic Acid Feeding Enhances Glycogen Repletion in Liver and Skeletal Muscle of Rats. The Journal of Nutrition, 131, 1973-1977. https://doi.org/10.1093/jn/131.7.1973
[122]	Kelley, G.A. and Kelley, K.S. (2017) Is Sarcopenia Associated with an Increased Risk of All-Cause Mortality and Functional Disability? Experimental Gerontology, 96, 100-103. https://doi.org/10.1016/j.exger.2017.06.008
[123]	Beaudart, C., Rizzoli, R., Bruyère, O., Reginster, J.Y. and Biver, E. (2014) Sarcopenia: Burden and Challenges for Public Health. Archives of Public Health, 72, Article No. 45. https://doi.org/10.1186/2049-3258-72-45
[124]	Beaudart, C., Dawson, A., Shaw, S.C., Harvey, N.C., Kanis, J.A., Binkley, N., Reginster, J.Y., Chapurlat, R., Chan, D.C., Bruyère, O., Rizzoli, R., Cooper, C. and Dennison, E.M. (2017) Nutrition and Physical Activity in the Prevention and Treatment of Sarcopenia: Systematic Review. Osteoporosis International, 28, 1817-1833. https://doi.org/10.1007/s00198-017-3980-9
[125]	Ticinesi, A., Mancabelli, L., Tagliaferri, S., Nouvenne, A., Milani, C., Del Rio, D., Lauretani, F., Maggio, M.G., Ventura, M. and Meschi, T. (2020) The Gut-Muscle Axis in Older Subjects with Low Muscle Mass and Performance: A Proof of Concept Study Exploring Fecal Microbiota Composition and Function with Shotgun Metagenomics Sequencing. International Journal of Molecular Sciences, 21, Article 8946. https://doi.org/10.3390/ijms21238946
[126]	Lv, W.Q., Lin, X., Shen, H., Liu, H.M., Qiu, X., Li, B.Y., Shen, W.D., Ge, C.L., Lv, F.Y., Shen, J., Xiao, H.M. and Deng, H.W. (2021) Human Gut Microbiome Impacts Skeletal Muscle Mass via Gut Microbial Synthesis of the Short-Chain Fatty Acid Butyrate among Healthy Menopausal Women. Journal of Cachexia, Sarcopenia and Muscle, 12, 1860-1870. https://doi.org/10.1002/jcsm.12788
[127]	Soares, A.D.N., Wanner, S.P., Morais, E.S.S., Hudson, A.S.R., Martins, F.S. and Cardoso, V.N. (2019) Supplementation with Saccharomyces boulardii Increases the Maximal Oxygen Consumption and Maximal Aerobic Speed Attained by Rats Subjected to an Incremental-Speed Exercise. Nutrients, 11, Article 2352. https://doi.org/10.3390/nu11102352
[128]	Chen, L.H., Huang, S.Y., Huang, K.C., Hsu, C.C., Yang, K.C., Li, L.A., Chan, C.H. and Huang, H.Y. (2019) Lactobacillus paracasei PS23 Decelerated Age-Related Muscle Loss by Ensuring Mitochondrial Function in SAMP8 Mice. Aging (Albany NY), 11, 756-770. https://doi.org/10.18632/aging.101782
[129]	Walsh, M.E., Bhattacharya, A., Sataranatarajan, K., Qaisar, R., Sloane, L., Rahman, M.M., Kinter, M. and Van Remmen, H. (2015) The Histone Deacetylase Inhibitor Butyrate Improves Metabolism and Reduces Muscle Atrophy during Aging. Aging Cell, 14, 957-970. https://doi.org/10.1111/acel.12387
[130]	Okamoto, T., Morino, K., Ugi, S., Nakagawa, F., Lemecha, M., Ida, S., Ohashi, N., Sato, D., Fujita, Y. and Maegawa, H. (2019) Microbiome Potentiates Endurance Exercise through Intestinal Acetate Production. American Journal of Physiology-Endocrinology and Metabolism, 316, E956-e966. https://doi.org/10.1152/ajpendo.00510.2018
[131]	Thadhani, R., Pascual, M. and Bonventre, J.V. (1996) Acute Renal Failure. The New England Journal of Medicine, 334, 1448-1460. https://doi.org/10.1056/NEJM199605303342207
[132]	Mikami, D., Kobayashi, M., Uwada, J., Yazawa, T., Kamiyama, K., Nishimori, K., Nishikawa, Y., Nishikawa, S., Yokoi, S., Kimura, H., Kimura, I., Taniguchi, T. and Iwano, M. (2020) Short-Chain Fatty Acid Mitigates Adenine-Induced Chronic Kidney Disease via FFA2 and FFA3 Pathways. Biochimica et Biophysica Acta-Molecular and Cell Biology of Lipids, 1865, Article ID: 158666. https://doi.org/10.1016/j.bbalip.2020.158666
[133]	Huang, W., Zhou, L., Guo, H., Xu, Y. and Xu, Y. (2017) The Role of Short-Chain Fatty Acids in Kidney Injury Induced by Gut-Derived Inflammatory Response. Metabolism, 68, 20-30. https://doi.org/10.1016/j.metabol.2016.11.006
[134]	Machado, R.A., Constantino Lde, S., Tomasi, C.D., Rojas, H.A., Vuolo, F.S., Vitto, M.F., Cesconetto, P.A., de Souza, C.T., Ritter, C. and Dal-Pizzol, F. (2012) Sodium Butyrate Decreases the Activation of NF-κB Reducing Inflammation and Oxidative Damage in the Kidney of Rats Subjected to Contrast-Induced Nephropathy. Nephrology Dialysis Transplantation, 27, 3136-3140. https://doi.org/10.1093/ndt/gfr807
[135]	Magliocca, G., Mone, P., Di Iorio, B.R., Heidland, A. and Marzocco, S. (2022) Short-Chain Fatty Acids in Chronic Kidney Disease: Focus on Inflammation and Oxidative Stress Regulation. International Journal of Molecular Sciences, 23, Article 5354. https://doi.org/10.3390/ijms23105354
[136]	Gluba-Brzózka, A., Franczyk, B., Olszewski, R. and Rysz, J. (2020) The Influence of Inflammation on Anemia in CKD Patients. International Journal of Molecular Sciences, 21, Article 725. https://doi.org/10.3390/ijms21030725
[137]	Yilmaz, M.I., Solak, Y., Covic, A., Goldsmith, D. and Kanbay, M. (2011) Renal Anemia of Inflammation: The Name Is Self-Explanatory. Blood Purification, 32, 220-225. https://doi.org/10.1159/000328037
[138]	Al Bander, Z., Nitert, M.D., Mousa, A. and Naderpoor, N. (2020) The Gut Microbiota and Inflammation: An Overview. International Journal of Environmental Research and Public Health, 17, Article 7618. https://doi.org/10.3390/ijerph17207618
[139]	Wu, H., Singer, J., Kwan, T.K., Loh, Y.W., Wang, C., Tan, J., Li, Y.J., Lai, S.W.C., Macia, L., Alexander, S.I. and Chadban, S.J. (2020) Gut Microbial Metabolites Induce Donor-Specific Tolerance of Kidney Allografts through Induction of T Regulatory Cells by Short-Chain Fatty Acids. Journal of the American Society of Nephrology, 31, 1445-1461. https://doi.org/10.1681/ASN.2019080852
[140]	Furue, K., Ito, T. and Furue, M. (2018) Differential Efficacy of Biologic Treatments Targeting the TNF-α/IL-23/IL-17 Axis in Psoriasis and Psoriatic Arthritis. Cytokine, 111, 182-188. https://doi.org/10.1016/j.cyto.2018.08.025
[141]	Nussbaum, L., Chen, Y.L. and Ogg, G.S. (2021) Role of Regulatory T Cells in Psoriasis Pathogenesis and Treatment. British Journal of Dermatology, 184, 14-24. https://doi.org/10.1111/bjd.19380
[142]	Kanda, N., Hoashi, T. and Saeki, H. (2021) The Defect in Regulatory T Cells in Psoriasis and Therapeutic Approaches. Journal of Clinical Medicine, 10, Article 3880. https://doi.org/10.3390/jcm10173880
[143]	Luu, M. and Visekruna, A. (2019) Short-Chain Fatty Acids: Bacterial Messengers Modulating the Immunometabolism of T Cells. The European Journal of Immunology, 49, 842-848. https://doi.org/10.1002/eji.201848009
[144]	Arpaia, N., Campbell, C., Fan, X., Dikiy, S., van der Veeken, J., deRoos, P., Liu, H., Cross, J.R., Pfeffer, K., Coffer, P.J. and Rudensky, A.Y. (2013) Metabolites Produced by Commensal Bacteria Promote Peripheral Regulatory T-Cell Generation. Nature, 504, 451-455. https://doi.org/10.1038/nature12726
[145]	Schwarz, A., Philippsen, R. and Schwarz, T. (2021) Induction of Regulatory T Cells and Correction of Cytokine Disbalance by Short-Chain Fatty Acids: Implications for Psoriasis Therapy. Journal of Investigative Dermatology, 141, 95-104.e102. https://doi.org/10.1016/j.jid.2020.04.031
[146]	Yao, Y., Cai, X., Fei, W., Ren, F., Wang, F., Luan, X., Chen, F. and Zheng, C. (2020) Regulating Gut Microbiome: Therapeutic Strategy for Rheumatoid Arthritis during Pregnancy and Lactation. Frontiers in Pharmacology, 11, Article 594042. https://doi.org/10.3389/fphar.2020.594042
[147]	Yao, Y., Cai, X., Zheng, Y., Zhang, M., Fei, W., Sun, D., Zhao, M., Ye, Y. and Zheng, C. (2022) Short-Chain Fatty Acids Regulate B Cells Differentiation via the FFA2 Receptor to Alleviate Rheumatoid Arthritis. British Journal of Pharmacology, 179, 4315-4329. https://doi.org/10.1111/bph.15852
[148]	Mirzaei, R., Afaghi, A., Babakhani, S., Sohrabi, M.R., Hosseini-Fard, S.R., Babolhavaeji, K., Khani Ali Akbari, S., Yousefimashouf, R. and Karampoor, S. (2021) Role of Microbiota-Derived Short-Chain Fatty Acids in Cancer Development and Prevention. Biomedicine & Pharmacotherapy, 139, Article ID: 111619. https://doi.org/10.1016/j.biopha.2021.111619
[149]	Bodai, B.I. and Nakata, T.E. (2020) Breast Cancer: Lifestyle, the Human Gut Microbiota/Microbiome, and Survivorship. The Permanente Journal, 24, Article 129. https://doi.org/10.7812/TPP/19.129
[150]	Walker, G.E., Wilson, E.M., Powell, D. and Oh, Y. (2001) Butyrate, a Histone Deacetylase Inhibitor, Activates the Human IGF Binding Protein-3 Promoter in Breast Cancer Cells: Molecular Mechanism Involves an Sp1/Sp3 Multiprotein Complex. Endocrinology, 142, 3817-3827. https://doi.org/10.1210/endo.142.9.8380
[151]	Bindels, L.B., Porporato, P., Dewulf, E.M., Verrax, J., Neyrinck, A.M., Martin, J.C., Scott, K.P., Buc Calderon, P., Feron, O., Muccioli, G.G., Sonveaux, P., Cani, P.D. and Delzenne, N.M. (2012) Gut Microbiota-Derived Propionate Reduces Cancer Cell Proliferation in the Liver. British Journal of Cancer, 107, 1337-1344. https://doi.org/10.1038/bjc.2012.409
[152]	Maruyama, T., Yamamoto, S., Qiu, J., Ueda, Y., Suzuki, T., Nojima, M. and Shima, H. (2012) Apoptosis of Bladder Cancer by Sodium Butyrate and Cisplatin. Journal of Infection and Chemotherapy, 18, 288-295. https://doi.org/10.1007/s10156-011-0322-2
[153]	Luu, M., Riester, Z., Baldrich, A., Reichardt, N., Yuille, S., Busetti, A., Klein, M., Wempe, A., Leister, H., Raifer, H., Picard, F., Muhammad, K., Ohl, K., Romero, R., Fischer, F., Bauer, C.A., Huber, M., Gress, T.M., Lauth, M., Danhof, S., Bopp, T., Nerreter, T., Mulder, I.E., Steinhoff, U., Hudecek, M. and Visekruna, A. (2021) Microbial Short-Chain Fatty Acids Modulate CD8+ T Cell Responses and Improve Adoptive Immunotherapy for Cancer. Nature Communications, 12, Article No. 4077. https://doi.org/10.1038/s41467-021-24331-1
[154]	Nomura, M., Nagatomo, R., Doi, K., Shimizu, J., Baba, K., Saito, T., Matsumoto, S., Inoue, K. and Muto, M. (2020) Association of Short-Chain Fatty Acids in the Gut Microbiome with Clinical Response to Treatment with Nivolumab or Pembrolizumab in Patients with Solid Cancer Tumors. JAMA Network Open, 3, e202895. https://doi.org/10.1001/jamanetworkopen.2020.2895
[155]	Yang, F., Chen, H., Gao, Y., An, N., Li, X., Pan, X., Yang, X., Tian, L., Sun, J., Xiong, X. and Xing, Y. (2020) Gut Microbiota-Derived Short-Chain Fatty Acids and Hypertension: Mechanism and Treatment. Biomedicine & Pharmacotherapy, 130, Article ID: 110503. https://doi.org/10.1016/j.biopha.2020.110503