Gut microbial metabolites SCFAs and chronic kidney disease.

The global incidence of Chronic Kidney Disease (CKD) is steadily escalating, with discernible linkage to the intricate terrain of intestinal microecology. The intestinal microbiota orchestrates a dynamic equilibrium in the organism, metabolizing dietary-derived compounds, a process which profoundly impacts human health. Among these compounds, short-chain fatty acids (SCFAs), which result from microbial metabolic processes, play a versatile role in influencing host energy homeostasis, immune function, and intermicrobial signaling, etc. SCFAs emerge as pivotal risk factors influencing CKD's development and prognosis. This paper review elucidates the impact of gut microbial metabolites, specifically SCFAs, on CKD, highlighting their role in modulating host inflammatory responses, oxidative stress, cellular autophagy, the immune milieu, and signaling cascades. An in-depth comprehension of the interplay between SCFAs and kidney disease pathogenesis may pave the way for their utilization as biomarkers for CKD progression and prognosis or as novel adjunctive therapeutic strategies.

Effects of short-chain fatty acids on blood glucose and lipid levels in mouse models of diabetes mellitus: A systematic review and network meta-analysis.

Short-chain fatty acids (SCFAs), the main metabolites of gut microbiota, have been associated with lower blood glucose and lipid levels in diabetic mice. However, a comprehensive summary and comparison of the effects of different SCFA interventions on blood glucose and lipid levels in diabetic mice is currently unavailable. This study aims to compare and rank the effects of different types of SCFAs on blood glucose and lipid levels by collecting relevant animal research. A systematic search through PubMed, Embase, Cochrane Library, and Web of Science database was conducted to identify relevant studies from inception to March 17, 2023. Both pairwise meta-analysis and Bayesian network meta-analysis were used for statistical analyses. In total, 18 relevant studies involving 5 interventions were included after screening 3793 citations and 53 full-text articles. Notably, butyrate therapy (mean difference [MD] = -4.52, 95% confidence interval [-6.29, -2.75]), acetate therapy (MD = -3.12, 95% confidence interval [-5.79, -0.46]), and propionate therapy (MD = -2.96, 95% confidence interval [-5.66, -0.26]) significantly reduced the fasting blood glucose levels compared to the control group; butyrate therapy was probably the most effective intervention, with a surface under the cumulative ranking curve (SUCRA) value of 85.5%. Additionally, acetate plus propionate therapy was probably the most effective intervention for reducing total cholesterol (SUCRA = 85.8%) or triglyceride levels (SUCRA = 88.1%). These findings underscore the potential therapeutic implications of SCFAs for addressing metabolic disorders, particularly in type 2 diabetes mellitus.

Revisiting the Role of Valeric Acid in Manipulating Ulcerative Colitis.

BACKGROUND: Ulcerative colitis (UC) is characterized by a complicated interaction between mucosal inflammation, epithelial dysfunction, abnormal activation of innate immune responses, and gut microbiota dysbiosis. Though valeric acid (VA), one type of short-chain fatty acids (SCFAs), has been identified in other inflammatory disorders and cancer development, the pathological role of VA and underlying mechanism of VA in UC remain under further investigation. METHODS: Studies of human clinical specimens and experimental colitis models were conducted to confirm the pathological manifestations of the level of SCFAs from human fecal samples and murine colonic homogenates. Valeric acid-intervened murine colitis and a macrophage adoptive transfer were applied to identify the underlying mechanisms. RESULTS: In line with gut microbiota dysfunction in UC, alteration of SCFAs from gut microbes were identified in human UC patients and dextran sodium sulfate -induced murine colitis models. Notably, VA was consistently negatively related to the disease severity of UC, the population of monocytes, and the level of interluekin-6. Moreover, VA treatment showed direct suppressive effects on lipopolysaccharides (LPS)-activated human peripheral blood mononuclear cells and murine macrophages in the dependent manner of upregulation of GPR41 and GPR43. Therapeutically, replenishment of VA or adoptive transfer with VA-modulated macrophages showed resistance to dextran sodium sulfate-driven murine colitis though modulating the production of inflammatory cytokine interleukin-6. CONCLUSIONS: In summary, the research uncovered the pathological role of VA in modulating the activation of macrophages in UC and suggested that VA might be a potential effective agent for UC patients.

The study collectively indicated that valeric acid (VA) was consistently negatively related to the disease severity of UC, and hypofunction of macrophage driven by VA impeded the progression of UC.

Prophylactic Administration of Gut Microbiome Metabolites Abrogated Microglial Activation and Subsequent Neuroinflammation in an Experimental Model of Japanese Encephalitis.

Short-chain fatty acids (SCFAs) are gut microbial metabolic derivatives produced during the fermentation of ingested complex carbohydrates. SCFAs have been widely regarded to have a potent anti-inflammatory and neuro-protective role and have implications in several disease conditions, such as, inflammatory bowel disease, type-2 diabetes, and neurodegenerative disorders. Japanese encephalitis virus (JEV), a neurotropic flavivirus, is associated with life threatening neuro-inflammation and neurological sequelae in infected hosts. In this study, we hypothesize that SCFAs have potential in mitigating JEV pathogenesis. Postnatal day 10 BALB/c mice were intraperitoneally injected with either a SCFA mixture (acetate, propionate, and butyrate) or PBS for a period of 7 days, followed by JEV infection. All mice were observed for onset and progression of symptoms. The brain tissue was collected upon reaching terminal illness for further analysis. SCFA-supplemented JEV-infected mice (SCFA + JEV) showed a delayed onset of symptoms, lower hindlimb clasping score, and decreased weight loss and increased survival by 3 days (p < 0.0001) upon infection as opposed to the PBS-treated JEV-infected animals (JEV). Significant downregulation of inflammatory cytokines TNF-α, MCP-1, IL-6, and IFN-Υ in the SCFA + JEV group relative to the JEV-infected control group was observed. Inflammatory mediators, phospho-NF-kB (P-NF-kB) and iba1, showed 2.08 ± 0.1 and 3.132 ± 0.43-fold upregulation in JEV versus 1.19 ± 0.11 and 1.31 ± 0.11-fold in the SCFA + JEV group, respectively. Tissue section analysis exhibited reduced glial activation (JEV group─42 ± 2.15 microglia/ROI; SCFA + JEV group─27.07 ± 1.8 microglia/ROI) in animals that received SCFA supplementation prior to infection as seen from the astrocytic and microglial morphometric analysis. Caspase-3 immunoblotting showed 4.08 ± 1.3-fold upregulation in JEV as compared to 1.03 ± 0.14-fold in the SCFA + JEV group and TUNEL assay showed a reduced cellular death post-JEV infection (JEV-6.4 ± 1.5 cells/ROI and SCFA + JEV-3.7 ± 0.73 cells/ROI). Our study critically contributes to the increasing evidence in support of SCFAs as an anti-inflammatory and neuro-protective agent, we further expand its scope as a potential supplementary intervention in JEV-mediated neuroinflammation.

Glutamine alone or combined with short-chain fatty acids fails to enhance gut adaptation after massive enterectomy in rats

PURPOSE: To investigate the effect of oral glutamine alone or combined with short chain fatty acids (SCFA) in the intestinal adaptation of rats submitted to an massive enterectomy. METHODS: After receiving 70 percent small bowel resection, 30 Wistar rats were randomized to received either standard rat chow (control group, n=10) or the same diet supplemented with 3,05 percent of glutamine alone (glutamine group, n=10) or combined with a solution containing SCFA (glutamine+SCFA group, n=10). Animals were killed on the 14th postoperative day. Mucosal weight, crypt depth, villus height, wall width, and the mucosal content of DNA, were assessed in basal conditions (resected gut specimen) and compared to the small bowel specimen collected on the postoperative day 14, at both jejunum and ileum sites. RESULTS: All groups presented similar pattern in weight evolution. In all groups, both the morphological findings and the DNA content were significantly higher at the end of the experiment than in basal conditions, at both the jejunum and ileum. Except for the jejunum wall width that was higher in control group (808±95 æ) than in the other two groups (glutamine = 649±88 æ and glutamine+SCFA = 656±92; p<0.01), there was no difference among them in all variables at both intestinal sites after 14 days. CONCLUSION: All groups presented adaptation of the intestinal mucosa in the remnant gut. Glutamine combined or not with short chain fatty acids fails to influence the adaptive response of the small bowel.

OBJETIVO: Investigar o efeito da glutamina oral isolada ou associada a ácidos graxos de cadeia curta (SCFA) na adaptação intestinal de ratos submetidos a resseção extensa. MÉTODOS: Após ressecção de 70 por cento do intestino delgado, 30 ratos Wistar foram randomizados para receber uma dieta padrão (grupo controle, n=10) ou a mesma dieta suplementada com 3,05 por cento de glutamina (grupo glutamina, n=10) ou combinada com SCFA (grupo glutamina+SCFA, n=10). Os animais foram sacrificados no 14° dia de PO. Foram estudados: peso da mucosa, profundidade da cripta, altura do vilo, espessura da parede e conteúdo de DNA no jejuno e no íleo, em condição basal e no dia do sacrifício. RESULTADOS: O peso evoluiu da mesma forma nos 3 grupos. No final do experimento todos os parâmetros morfológicos e o DNA aumentarem significantemente. Com exceção a espessura da parede do jejuno que foi mais alta no grupo controle (808±95 æ) que nos outros dois grupos (glutamina = 649±88 æ e glutamina+SCFA = 656±92; p<0.01), não houve diferença entre os grupos em todas as variáveis no 14° dia. CONCLUSÃO: A adaptação intestinal ocorreu em todos os grupos. Glutamina isolada ou associada a SCFA não influencia a resposta adaptativa do intestino delgado.

Intraluminal injection of short chain fatty acids diminishes intestinal mucosa injury in experimental ischemia-reperfusion

OBJETIVO: Investigou-se o efeito de ácidos graxos de cadeia curta (SCFA) na mucosa intestinal na presença de lesão por isquemia e reperfusão (IRI). MÉTODOS: Foram criados seis sacos fechados no intestino delgado (três no jejuno e três no íleo) em 10 ratos Wistar. Ao sacos laterais de ambas as regiões intestinais foram submetidos a IRI (15/15 minutos) enquanto que o saco medial não sofreu interrupção do suprimento sanguíneo. Nos sacos laterais ambas as regiões injetou-se SCFA ou solução fisiológica na luz intestinal. Nos sacos mediais não se injetou nenhuma solução. RESULTADOS: Tanto no jejuno quanto no íleo o escore de injuria da mucosa intestinal foi mais alto nos sacos tratados com solução salina do que nos controles. Os sacos que receberam SCFA apresentaram menor escore inflamatório no íleo (p=0.03) porém sem diferença no jejuno (p=0.083) quando comparados com os sacos injetados com solução salina. Observou-se um significante maior acumulo de neutrófilos nos sacos tratados com solução salina (p < 0.01) do que nos outros dois sacos em ambas as regiões. CONCLUSAO: Os SCFA protegem a mucosa intestinal distal e diminuem o acumulo de neutrófilos na lamina própria após IRI.

Enhanced mucosal re-epithelialization induced by short chain fatty acids in experimental colitis

The short chain fatty acids (SCFA) are the best nutrients for the colonocytes. Glucose is poorly used as a fuel but may be transformed into SCFA by colonic bacteria. The aim of this study was to investigate the effect of SCFA or glucose on experimental colitis. Colitis was induced in 30 Wistar rats by colonic instillation of 4 percent acetic acid. Five days later they were randomized to receive twice a day colonic lavage containing saline (controls, N = 10), 10 percent hypertonic glucose (N = 10) or SCFA (N = 10) until day 8 when they were killed. At autopsy, the colon was removed and weighed and the mucosa was evaluated macro- and microscopically and stripped out for DNA assay. Data are reported as mean + or -SD or median [range] as appropriate. All animals lost weight but there was no difference between groups. Colon weight was significantly lower in the SCFA group (3.8 + or - 0.5 g) than in the control (5.3 + or - 2.1 g) and glucose (5.2 + or - 1.3 g) groups (PP<0.05). Macroscopically, the severity of inflammation was less in SCFA (grade 2 [1-5]) than in control (grade 9 [4-10]) and glucose-treated (grade 9 [2-10]) animals (P<0.01). Microscopically, ulceration of the mucosa was more severe in the glucose and control groups than in the SCFA group. The DNA content of the mucosa of SCFA-treated animals (8.2 [5.0-20.2] mg/g of tissue) was higher than in glucose-treated (5.1 [4.2-8.5] mg/g of tissue; P<0.01) and control (6.2 [4.5-8.9] mg/g of tissue; P<0.05) animals. We conclude that SCFA may enhance mucosal re-epithelialization in experimental colitis, whereas hypertonic glucose is of no benefit

Acidos graxos de cadeia curta e doenças colorretais / Short-chain fatty acids and colorectal diseases

O cólon humano contribui de maneira importante para a fermentaçäo de polissacárides näo absorvidos, produzindo ácidos graxos de cadeia curta (AGCC). Este artigo analisa a importância fisiológica dos AGCC para os colonócitos e as perspectivas de sua utilizaçäo clínica no tratamento das doenças colorretais. Diversos efeitos benéficos säo atribuídos ao processo de fermentaçäo e à subsequente produçäo de AGCC, como a contribuiçäo às necessidades energéticas, à manutençäo da integridade e funçäo da mucosa colônica e implicaçöes no metabolismo nitrogenado, de lipídes e glicídios. Além disso, diversas afecçöes colorretais tem sido relacionadas a deficiência de AGCC, como a colite por desuso, colite ulcerativa, bolsite pós-proctocolectomia com anastomose íleo-anal e câncer colorretal. Por este motivo, o fornecimento de AGCC diretamente à mucosa intestinal ou por via intravenosa tem sido preconizado em diversas condiçöes clínicas

Acidos grasos de cadena corta: futuras aplicaciones en clínica / Short chain fatty acids: future clinical applications

Los ácidos grasos de cadena larga, son isotónicos, aportan un alto contenido calorico (9 kcal por gramo), previenen la defeciencia de ácidos grasos esenciales, se pueden administrar conjuntamente con aminoácidos y glucosa por via periférica. Entre los efectos metabolicos desfavorables, se puede anotar que requieren camitina para su oxidacion y son metabolizados lentamente en situaciones de estres. Por otra parte, se ha informado bloqueo del sistema reticuloendotelial en modelos in vitro y con dosis mayores de 3 gr, esteatosis hepática y disminucion de la capacidad de difusion pulmonar en hombres sanos. Los acidos grasos de cadena media no requieren camitina para su oxidación, y entran rapidamente a la mitocondria, pero no previenen la deficiencia de acidos grasos esenciales. Los acidos grasos de cadena corta (AGCC), son metabolizados en el ciego, con produccion de acido acetico, ácido propionico y acido butirico. Este ultimo es el principal sustrato del colonocito. Por otra parte, lo AGCC estimulan la absorcion de sodio y agua en el colon, son troficos intestinales y facilitan la cicatrizacion. Son solubles en agua y podrian administrarse como acidos libres o como sales. Podrian constituir adicionalmente un aporte calorico complementario. Su uso potencial debe ser comprobado en estudios clinicos subsiguientes.