**Acknowledgements**

*Human Microbiome*

invasion, protection against intestinal permeability, and control of bacterial translocation from the gut to the portal vein circulation). The biological activity of probiotics depends on delivering anti-inflammatory mediators that downregulate proinflammatory cytokines [104]. Therefore, probiotic therapy offers an interesting

approach to control hepatic injury and a low-grade proinflammatory state.

use of probiotics and prebiotics for the prevention or treatment of NASH. Prophylactic use of antibiotics in patients with chronic liver diseases is an established method of preventing infections or innate immune dysfunction in acute liver failure (ALF) [13]. In addition, it has been demonstrated in animal and human models that the positive effect of polymyxin B and metronidazole in reducing the severity of NAFLD during total parenteral nutrition or after intestinal bypass could be interesting for their use to treat NAFLD [136, 137]. However, direct evidence is currently lacking, and thus, antibiotics cannot be routinely recommended to treat

Overall, to date, there have been only a few studies concerning the use of probiotics, prebiotics, and antibiotics in humans; therefore, large-scale randomized

Intestinal dysbiosis can trigger gut inflammation and increase the permeability of the intestinal epithelial barrier, exposing the gut-liver axis to GM-derived mediators of dysbiosis, such as bacterial components or metabolites, which may induce hepatotoxicity, inflammation, and consequently NAFLD progression. Gut-derived mediators of dysbiosis contribute to NAFLD progression by activating the immune system, inducing oxidative stress, enhancing inflammation, and finally promoting

Despite the evident association between GM dysbiosis, obesity, and NAFLD derived from several experimental studies, few studies have been conducted in patients with NAFLD to explore the role of GM-derived mediators of dysbiosis in the occurrence and progression of the disease. Additionally, few studies have focused on gut-derived mediators of dysbiosis as noninvasive markers of disease progression. The study of these mediators may provide an opportunity to develop a specific diagnostic and prognostic biomarker for NAFLD and NASH. In this sense, we propose the metabolomic study of these mediators and other metabolites involved to achieve a metabolomic profile that could be used as biomarkers for evaluating the status of NAFLD. On the other hand, some previous evidence has focused on GM modulation using probiotics, prebiotics, and antibiotics as therapeutic strategies to prevent or treat NAFLD and NASH, which is more uncertain and requires future research. In this sense, it remains important to promote study of GM targeting to find an effective treatment for NAFLD and

NASH, although further research is needed.

**6. Conclusions**

fibrogenesis.

controlled trials with histological endpoints are indicated.

Another alternative is the use of prebiotic fiber, which is defined as an amount of nondigestible food ingredients that beneficially affect the host, by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon [135]. The health effects of prebiotic fiber are related to improved glucoregulation and modified lipid metabolism as well as selective modulation of the GM. Some mechanisms have been proposed to explain the beneficial effects of prebiotics on the accumulation of triglycerides in the liver observed in animals, including reduced de novo fatty acid synthesis and SCFA production, body weight and fat loss, and improved glycemic control, GM modulation, and anti-inflammatory effects [13, 104]. These promising preliminary results strongly indicate the potential

**54**

overall for NASH.

This study was supported by the *Fondo de Investigación Sanitaria and Fondo Europeo de Desarrollo Regional* (FEDER, grant number PI16/00498, to Teresa Auguet), by funds from the *Agència de Gestió d'Ajuts Universitaris de Recerca* (AGAUR 2009 SGR 959 to Cristóbal Richart) and the *Grup de Recerca en Medicina Aplicada URV* (2016PFR-URV-B2-72 to Cristóbal Richart), and by the *Fundación Biociencia*.
