Amoxicillin modulates gut microbiota to improve short-term high-fat diet induced pathophysiology in mice

Abstract

Background A high-fat diet (HFD) induced perturbation of gut microbiota is a major contributory factor to promote the pathophysiology of HFD-associated metabolic syndrome. The HFD could also increase the susceptibility to the microbial infections warranting the use of antibiotics which are independently capable of impacting both gut microbiota and metabolic syndrome. Further, the usage of antibiotics in individuals consuming HFD can impact mitochondrial function that can be associated with an elevated risk of chronic conditions like inflammatory bowel disease (IBD). Despite this high propensity to infections in individuals on HFD, the link between duration of HFD and antibiotic treatment, and its impact on diversity of the gut microbiome and features of metabolic syndrome is not well established. In this study, we have addressed these knowledge gaps by examining how the gut microbiota profile changes in HFD-fed mice receiving antibiotic intervention in the form of amoxicillin. We also determine whether antibiotic treatment in HFD-fed mice may adversely impact the ability of immune cells to clear microbial infections. Methods and Results We have subjected mice to HFD and chow diet (CD) for 3 weeks, and a subset of these mice on both diets received antibiotic intervention in the form of amoxicillin in the 3rd week. Body weight and food intake were recorded for 3 weeks. After 21 days, all animals were weighted and sacrificed. Subsequently, these animals were evaluated for basic haemato-biochemical and histopathological attributes. We used 16S rRNA sequencing followed by bioinformatics analysis to determine changes in gut microbiota in these mice. We observed that a HFD, even for a short-duration, could successfully induce the partial pathophysiology typical of a metabolic syndrome, and substantially modulated the gut microbiota in mice. The short course of amoxicillin treatment to HFD-fed mice resulted in beneficial effects by significantly reducing fasting blood glucose and skewing the number of thrombocytes towards a normal range. Remarkably, we observed a significant remodelling of gut microbiota in amoxicillin-treated HFD-fed mice. Importantly, some gut microbes associated with improved insulin sensitivity and recovery from metabolic syndrome only appeared in amoxicillin-treated HFD-fed mice reinforcing the beneficial effects of antibiotic treatment in the HFD-associated metabolic syndrome. Moreover, we also observed the presence of gut-microbiota unique to amoxicillin-treated HFD-fed mice that are also known to improve the pathophysiology associated with metabolic syndrome. However, both CD-fed as well as HFD-fed mice receiving antibiotics showed an increase in intestinal pathogens as is typically observed for antibiotic treatment. Importantly though, infection studies with S. aureus and A. baumannii, revealed that macrophages isolated from amoxicillin-treated HFD-fed mice are comparable to those isolated from mice receiving only HFD or CD in terms of susceptibility, and progression of microbial infection. This finding clearly indicated that amoxicillin treatment does not introduce any additional deficits in the ability of macrophages to combat microbial infections. Conclusions Our results showed that amoxicillin treatment in HFD-fed mice exert a beneficial influence on the pathophysiological attributes of metabolic syndrome which correlates with a significant remodelling of gut microbiota. A novel observation was the increase in microbes known to improve insulin sensitivity following amoxicillin treatment during short-term intake of HFD. Even though there is a minor increase in gut-resistant intestinal pathogens in amoxicillin-treated groups, there is no adverse impact on macrophages with respect to their susceptibility and ability to control infections. Taken together, this study provides a proof of principle for the exploration of amoxicillin treatment as a potential therapy in the people affected with metabolic syndrome.

Thermoneutral Housing Enables Studies of Vertical Transmission of Obesogenic Diet-Driven Metabolic Diseases

“…As some studies in mice and rats note increased weight and metabolic disease in middleaged or older offspring of HFD-fed mothers, even when they remain on CD [110,120,121], further studies are needed to determine whether middle-aged offspring in our model also develop metabolic dysfunction. In addition, the association between maternal obesity and dysregulated offspring immunity has been strongly supported in rodents, non-human primates, and humans [54], with both maternal obesity and obesogenic diet shown to decrease WBC count [122,123]. We noted only a trend toward decreased WBC count in offspring of HO dams compared to that of CL dams, but the differences were eliminated after 12 weeks of HFD feeding.…”

Assessing the short-term impact of a high-fat, high-salt diet on the gut bacteria and related pathophysiology in mice

“…In this study, HFD-fed mice showed a signi cantly higher increase in the relative abundance of Desulfovibrionaceae known to associate with obesity and Coriobacteriaceae considered commensal communities but some members associate with bile acid metabolism which leads to metabolic dysfunctions [33]. Further a higher reduction of Lachnospiraceae and S24-7 linked to disruption of gut epithelial barrier integrity and metabolic endotoxemia was observed in HFD-fed mice [33]. In this study HSD fed mice showed a higher abundance of Erysipelotrichaceae that coincided with in ammation-related gastrointestinal disorders [62].…”

“…At the genus level, we have consistently observed a high increase in the abundance of Granulicatella, Lactobacillus, Streptococcus, Turicibacte, Dorea, Desulfovibrio and Oscillospira in HFD-fed mice and at the species level [66-69]. There are also several reports suggesting that Lactobacillus abundance plays an active role in obesity and chronic in ammation associated with diabetes [33]. In addition, the majority of the above-mentioned gut microbes play a signi cant role in metabolic syndrome pathogenesis.…”

“…A positive correlation exists between Oscillospira and fasting serum insulin levels and a reduction in the levels of mRNA expression of Zonula occludens-1 (ZO-1) that prevents solute leakage from the gastrointestinal tract [33]. A striking observation was the reduction of Lactobacillus reuteri in HFD-fed mice, which prevents pathogen growth in the intestine [70].…”

“…The pathophysiology of metabolic syndrome induced by the consumption of a diet rich in fat and salt has become a major health concern due to the increasing risk of many chronic diseases such as diabetes and cardiovascular diseases [33,34]. In the long run, a diet rich in fat and salt increases cholesterol levels, blood sugar levels, triglyceride levels, chronic in ammation, and modulation of gut ecology [35][36][37].…”