Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection (Singer et al., 2016). The central nervous system (CNS) is mainly the first to be affected in the course of sepsis, and it typically manifests as cognitive dysfunction, also known as sepsis-associated encephalopathy (SAE), which has a major role in the poor long-term prognosis of septic patients (Feng et al., 2019). Unfortunately, sepsis is still incurable, leading to high morbidity and mortality rates despite a broad range of therapeutic strategies, such as fluid resuscitation, enhanced screening, routine microbiological cultures for pathogenic factors, broad-spectrum antimicrobial therapy, etc (Rhodes et al., 2017). Consequently, it is necessary to improve the therapeutic strategies. Notably, sepsis leads to alterations in gut microbial diversity and abundance and a reduction in short-chain fatty acids (SCFAs), which may be associated with cognitive dysfunction in septic survivors (Wu et al., 2020; Giridharan et al., 2022; Yuan et al., 2022). Therefore, whether SCFAs are beneficial to treating neurological dysfunction in SAE has noticeably attracted researchers’ attention.

SCFAs are the primary end-products of the fermentation of non-digestible carbohydrates. The most abundant SCFAs in the colon and feces include acetate, propionate, and butyrate (Louis and Flint, 2017). In recent years, numerous studies have extensively investigated SCFAs in nerve injury. Butyrate administration facilitates the differentiation of oligodendrocytes, contributes to the suppression of demyelination, and enhances remyelination in the cuprizone-induced demyelination mice model (Chen et al., 2019). SCFAs ameliorate experimental autoimmune encephalomyelitis by promoting the polarization of naive T cells to regulatory T (Treg) cells and suppressing the p38 and JNK1 pathways. This manifests as reduced inflammatory cell infiltration, attenuated demyelination, and increased axonal preservation (Haghikia et al., 2015). Sadler et al. confirmed that the connection with the cerebral cortex induced by SCFAs leads to changes in the density of neurons in the spinal cord and synapses, significantly improving limb motor function recovery in stroke models (Sadler et al., 2020). In addition, SCFAs can effectively induce the transformation of microglia from M1 pro-inflammatory phenotype to M2 anti-inflammatory phenotype, thus reducing the inflammatory response after nerve injury, promoting the repair of the blood-brain barrier (BBB), and recovering the cerebral function in mice with depressive-like behaviors (Tang et al., 2022). Notably, SCFAs also influence neuroinflammation in the CNS by affecting glial cell morphology and function, thus providing a basis for subsequent research.

Herein, we reviewed the application background and mechanism of SCFAs as dietary nutrients in SAE to elucidate possible associations with the gut-microbiota-brain axis and provide more favorable evidence for the application of SCFAs in the field of SAE therapy.

SCFAs are the end products of the fermentation of dietary fibers by the anaerobic intestinal microbiota. Dietary fibers affect the human microbiome’s metabolism and change the host’s health status (Tanes et al., 2021). In sepsis, gut microbiota disturbance may reduce the concentrations of various components of SCFAs in feces and blood, which in turn induces cognitive impairment associated with the increased number of GFAP-positive cells in the prefrontal cortex and hippocampus (Giridharan et al., 2022). Also, in sepsis, the pathogenic colonization decreases the concentrations of SCFAs at 6 weeks after hospitalization (Yamada et al., 2015). Therefore, we summarized the background and underlying mechanisms to provide a theoretical basis for applying SCFAs in sepsis.

Partial G protein-coupled receptors (GPRs) located on the surface of cells act as free fatty acid receptors (FFARs) that have an important role in disease regulation. In particular, FFAR2 (GPR43) and FFAR3 (GPR41) are activated by SCFAs (Kimura et al., 2020), while exogenous administration of SCFAs (acetate: propionate: butyrate at a ratio of 3: 1: 1) can effectively alleviate CLP -induced decrease levels of acetic acid and propionic acid in SAE mice. They can also significantly increase the relative abundance of SCFAs-producing bacteria such as Allobaculum. SCFAs are critical in alleviating neuroinflammation and improving cognitive dysfunction in SAE patients through FFAR2 (Liao et al., 2022). Moreover, the intestinal flora and its metabolite butyrate have an important role in host SAE susceptibility. Especially the antioxidant stress and neuroprotective effects of butyrate associated with SCFA receptor GPR109A contribute to ameliorating long-term cognitive impairment in SAE (Zhang et al., 2022). The studies above supported that binding SCFAs to receptors is essential in improving neuroinflammation and cognitive dysfunction. Meanwhile, studies that administered SCFAs before the onset of sepsis did not fully confirm the effectiveness of SCFAs treatment. However, the underlying mechanism is not only associated with these receptors, as intracellular targets associated with histone deacetylases (HDACs) also have a relevant role. HDACs are of essential importance in the modification of chromosome structure and gene expression regulation. SCFAs are natural inhibitors of HDACs. Sodium butyrate, as a histone deacetylase inhibitor (HDACi), may reverse aversive memory in septic animals by reducing HDAC activity after cecal ligation and puncture (CLP) surgery (Steckert et al., 2015). In addition to the administration of SCFAs at different times and different routes, the study of indole-3-propionic acid (IPA) as a microbiota metabolite of tryptophan (an essential amino acid derived from dietary supplementation), which contribute to modulating gut dysbiosis in septic mice also illustrates the role of the gut microbiome and its metabolites in the pathophysiology of sepsis through different pathways (Fang et al., 2022). In addition, butyrate may enhance synaptic plasticity and improve depressive-like behaviors and cognitive performance by inhibiting the histone deacetylase (Citraro et al., 2020; Yu et al., 2020). Collectively, the administration of SCFAs as HDACi contributes to a new treatment strategy for managing neurological dysfunction with cognitive impairment.

In addition, SCFAs can exert anti-inflammatory, antioxidant, and immunomodulatory effects. Exogenous administration of SCFAs enhances macrophage function, ameliorates K. pneumoniae-induced pulmonary inflammation, and improves pneumonia sepsis symptoms (Wu et al., 2020). Administration of sodium butyrate after the onset of sepsis can reduce proinflammatory cytokine production, attenuate intestinal injury and improve survival rate by inhibiting nuclear factor-κB (NF-κB) activation in CLP-induced septic rats, which suggests that clinical application of sodium butyrate may potentially contribute to inhibition of systemic inflammatory response and sequential organ dysfunction (Fu et al., 2019). Meanwhile, pretreatment with butyrate attenuated the elevation of pro-inflammatory mediators such as TNF-α, IL-6 and IL-1β levels in LPS–induced septic mice or in murine macrophage-like RAW 264.7 cells, which were stimulated by LPS. Moreover, significantly upregulating the expression of anti-inflammatory IL-10 is an important way butyrate alleviates the inflammatory response of sepsis (Wang et al., 2017). These studies suggested that SCFAs could improve the severity of sepsis and may even increase survival rate through anti-inflammatory pathways. Filippone et al. confirmed sodium propionate’s anti-inflammatory and antioxidant effects (Filippone et al., 2020). However, whether SCFAs have an active anti-inflammatory role depends on their concentrations, serum pH, and etiologies (Tedelind et al., 2007). Furthermore, in their clinical study, Weng et al. reported that propionate levels were well correlated with sepsis severity and prognostic information, which is of great significance for the next follow-up research (Weng et al., 2018) ( Table 1 ). Meanwhile, previous studies also confirmed significantly lower concentrations of stool SCFAs in clinical septic patients (Valdés-Duque et al., 2020). Moreover, ten days after sepsis induction, the animals still suffered cognitive impairment associated with decreased SCFAs levels, which were triggered by disruption of microbiota-gut-brain axis homeostasis (Giridharan et al., 2022). Accordingly, the treatment with SCFAs to maintain the concentration of SCFAs, especially after the onset of sepsis, may be more indicative of the reliability of SCFAs in critically ill patients with sepsis. However, future studies are needed to address this issue further. Additionally, when SCFAs are taken up into T lymphocytes, SCFAs-derived acetyl groups contribute to the increase of cellular acetyl-CoA, which may influence the histone acetylation and cytokine gene expression, including the promotion of IL-10 production (Sun et al., 2018; Luu and Visekruna, 2019). However, SCFAs have been found to drive the differentiation of naive CD4⁺ T cells into Treg cells and supply a viable target for treating autoimmune diseases (Bhutia and Ganapathy, 2015; Asarat et al., 2016). These findings confirmed the anti-inflammatory, antioxidant, and immunomodulatory effects of SCFAs. The role of SCFAs in energy metabolism is noteworthy. Previous studies have demonstrated that SCFAs can be used as substrates to participate in fat, cholesterol and glucose metabolism to regulate cellular energy metabolism (den Besten et al., 2013; Perry et al., 2016). The microglial mitochondrial functional deficiencies that are rectified by acetate, an SCFA, lead to improved microglial metabolism and the shaped innate immune mechanism during neurodegeneration (Erny et al., 2021). In summary, these findings better clarify the research background of SCFAs related to sepsis and lay the foundation for further research on the mechanism of application of SCFAs in SAE.

The gut microbiota influences the neuroendocrine system by regulating endocrine signals that enteroendocrine cells (EECs) produce. Then, the cerebral function may be further regulated through the correlation between the enteric nervous system (ENS) and CNS (Rao and Gershon, 2018). The gut microbiota and some metabolites can be translocated from the gut to distant organs through the portal vein or into the thoracic duct through mesenteric lymph nodes, and may ultimately transfer to the blood, influencing the brain (Doig et al., 1998; Deitch, 2012) ( Figure 1 ). However, the increase of pathogenic microbiota in the gut and the decrease of gut microbiota products, such as SCFAs, can aggravate brain disorders such as anxiety, pain, depression, autism, Alzheimer’s disease, Parkinson’s disease, etc (Nagpal et al., 2019; Sharon et al., 2019; Zhu et al., 2020). In sepsis, this may be followed by SAE. The pathophysiology of SAE comprises neuroinflammation and microglial activation, BBB dysfunction, mitochondrial dysfunction, neurotransmitter dysfunction, etc (Mazeraud et al., 2020). Previous research indicated that the mechanisms related to SCFAs and SAEs might involve the following aspects.

The effects of alterations in microbiome and SCFAs on brain function were previously confirmed, providing a potential target for dietary intervention of SAE (Wu et al., 2021). However, it is essential to balance the predictable risk factors, such as transmitting infectious agents to new recipients caused by fecal microbiota transplantation (FMT) (Blaser, 2019). The remaining challenges can be summarized as follows: (1) it remains unclear what dietary nutrients can be used as a source of SCFAs for SAE remission, and what are the qualitative and quantitative criteria for the species and abundance of the gut microbiota associated with the metabolism of SCFAs in SAE; (2) although there is a close correlation between SCFAs and changes in pro-inflammatory and anti-inflammatory cytokines at mRNA levels during the inflammatory response to sepsis (Wang et al., 2017; Fu et al., 2019; Wu et al., 2020), the effects of SCFAs on gene expression in brain cells require further research; (3) further studies are needed to establish the exact relationship between different components of SCFAs and brain energy metabolism and energy acquisition in patients with SAE; and whether overdose and toxicity are involved. Solving the problems mentioned above and elucidating the exact mechanism may be remarkably beneficial for the prognosis of SAE patients.

SCFAs may be involved in developing SAE by regulating neuroinflammation, immunity, BBB function, energy metabolism, etc., through multiple pathways. More importantly, SCFAs act on the CNS through the gut-microbiota-brain axis and exert some neuropsychological interventional effects. Therefore, alteration of the components of SCFAs via direct administration or dietary interventions may be a promising approach. In the future, the effects of different constituents of SCFAs on SAE should be studied in the context of gut microbiota to reveal the exact mechanism and improve the prognosis of SAE.

QZ: contributed to the conceptualization, project administration, and preparation of the primary draft of the manuscript. CL and WF: contributed to the investigation and curation of resources and data. JZ and YY: contributed to supervision, funding acquisition, and review of the manuscript. All authors read and approved the final manuscript.