Treatment of MAFLD with probiotics
Current interventions for MAFLD management are focused on drug administration in order to control lipid levels, diabetes and TNF-α production, while others try to encourage dietary and lifestyle modifications, despite poor patient compliance.74 However, in the past few years, as the knowledge about gut-liver relationship has grown, several efforts have been directed towards the development of new strategies using this information. Two approaches to modulate gut dysbiosis have been established: 1) the untargeted methods, that use diet, probiotics, and antibiotics; and 2) microbiota-targeted therapy, which specifically aims at certain bacteria and host metabolites. Throughout this section we will discuss the findings related to beneficial effects of probiotic administration on the onset/treatment of MAFLD.
Probiotics are defined by the World Health Organization as a “live microorganism that—when administered in adequate amounts—confers a health benefit on the host,” not to be confused with prebiotics, which are compounds in food that induce the growth or activity of microorganisms. Probiotics must be able to survive and transit the gut, as well as be able to grow and multiply in order to benefit the host.75 Several probiotics, like Streptococcus, Bifidobacterium and Lactobacillus have been commercialized as fermented dairy products due to beneficial effects on the survivability of the gut epithelium and the promotion of anti-inflammatory cytokines, as well as interaction with the immune system.74 The expected effects of these probiotics are reversion of adverse gut microbiota growth and its consequences related to the constant inflammation through the recognition of LPS, production of ethanol, alteration of the BA metabolism, SCFAs metabolism, cellular stress, and so forth; ultimately, the desired outcome is returning the microbiota to a healthy state.
Multiple animal-based studies have shown significant therapeutic effects in fatty liver mice models. Administration of probiotics could prevent the onset of liver steatosis and improve steatohepatitis and fibrosis. The mechanisms behind these protective effects are the reduction of hepatic lipid accumulation, less endotoxemia, oxidative stress and activation of anti-inflammatory pathways through the modulation of NF-κB and TNF production, as well as the regulation of collagen production.72,75,76 For example, a study conducted by Xin et al.75 showed prevention of the onset of hepatic steatosis and cellular apoptosis in mice fed with a high-fat diet through the administration of the probiotic Lactobacillus johnsonii BS15; the end result was an improvement in hepatic inflammation and oxidative stress. A more recent study by Liang et al.77 gave a compound of probiotics to a group of mice fed with a high-fat diet and also showed an improvement in gut dysbiosis and a reduction of the hepatic lipid deposition. VSL#3 is a multi-strain probiotic that contains eight different species (Lactobacillus plantarum, Lactobacillus delbrueckii, Lactobacillus casei, Lactobacillus acidophilus, Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis and Streptococcus thermophilus), and is the most studied therapy in animals and humans. In mouse-based studies, its effects have included the modulation of NF-κB and TNF, and antifibrotic effects through TGF-β modification.75,77
Despite these promising results, it is important to bear in mind that animal models have their limitations. The mice used have been germ-free and even though their intestinal microbiota resembles that of the human, they are not the same. Nonetheless, the findings point to the potential benefits of pharmacologic intervention with probiotics.76
In terms of clinical studies, few have been conducted to explore the role of probiotics as a treatment therapy for any of the MAFLD stages, mostly due to the novelty of these discoveries.78 Among the currently available studies, the results have been measured by biochemical parameters or through hepatic histology.
Human studies have shown, through double-blind trials, that the administration of some Lactobacillus species, like rhamnosus and acidophilus, in 20 obese children and 30 adults with diagnosed MAFLD, respectively, influence the reduction of hypertransaminasemia.78–83 Other studies, using administration of other species of Lactobacillus (bulgaricus, plantarum), also found improvement in aspartate aminotransferase, as well as the reduction of total cholesterol and low density lipoprotein cholesterol.84,85
Other randomized trials have identified better effects on the disease through the administration of combined probiotics. Administration to adolescents of a capsule containing Lactobacillus acidophilus, Bifidobacterium lactis, Bifidobacterium bifidum and Lactobacillus rhamnosus showed a reduction in alanine aminotransferase, lipid profile and hepatic fat content compared to a placebo group after 12 weeks.79 A meta-analysis conducted by Ma et al.85 highlighted the beneficial impacts of probiotic therapy with Lactobacillus, Bifidobacterium, and Streptococcus, by reducing hepatic fat content, cholesterol, and alanine aminotransferase levels. The widely studied multi-strain probiotic VSL#3 has also been demonstrated to protect the intestine in humans by enhancing the barrier integrity, dampening endotoxemia and reducing oxidative stress, thereby leading to an improvement in chronic liver diseases.66,86 A 24-week trial conducted by Bakhshimoghaddam et al.13,87 studied 102 MAFLD patients divided into the following three groups: one control, and two intervention groups with intake of either 300 g of symbiotic yogurt or conventional yogurt. The authors concluded, after ultrasonography, that the MAFLD scores in those that consumed the symbiotic had decreased aspartate aminotransferase, alanine aminotransferase, and steatosis compared to the other groups. Some other studies have found a decrease in fibrosis levels after treatment with probiotics, apart from the results already mentioned.88,89
Unfortunately, and despite their effectiveness in other stages of MAFLD, studies on the effect of probiotics on cirrhosis have been controversial. Few studies have analyzed the use of probiotics as therapy for HCC; nonetheless, the ones available have presented encouraging data through positive effects. It has been observed that they favor liver function recovery and reduce complications in patients who undergo hepatic resection.90 Drugs like norfloxacin and rifaximin, the latter being capable of inducing overgrowth of beneficial bacteria such as Bifidobacterium, Faecalibacterium, and Lactobacillus, have favored an increase in the survival of patients with cirrhosis and HCC, as well as prevented associated complications, like hepatic encephalopathy, portal hypertension, and spontaneous bacterial peritonitis.63
A meta-analysis conducted by Pan et al.60 compared the mechanisms of action of a wide variety of probiotics used in MAFLD treatment and found that the most predominant was the reduction of inflammatory factors (C-reactive protein and TNF-α). Other less determinant findings were the regulation of NF-κB and a reduction of serum liver enzymes (alanine aminotransferase, gamma-glutamyltranspeptidase, and aspartate aminotransferase) and fibrotic factors (TGF-β).
Probiotics may also have antagonistic actions against specific microorganisms, reducing the number and effects, while others ensure the intestine has an adequate pH by releasing products like butyric acid, lactic acid, and propionic acid. They can also enhance immunity by activating macrophages, antibody effectiveness and even competitively against other pathogens for nutrients and growth factors (Fig. 2).91
As a side note, we consider it important to mention that probiotics have a wide variety of beneficial effects apart from direct gut microbiota regulation and reduction of carcinogenesis; for example, benefits have been found on mental health, mainly related with the regulation of depression through the increase of serotonin production (Table 2).91
Table 2Main results and discoveries of MAFLD treatment with probiotics
| Results and discoveries |
|---|
| Animal trials (mice) | Reduction of hepatic lipid accumulation, less endotoxemia, oxidative stress and activation of anti-inflammatory pathways
Modulation of NF-κB, TNF and fibrotic factors |
| Hepatic steatosis (single strain probiotics) | Reduction of hypertransaminasemia
Reduction of aspartate aminotransferase, low density lipoprotein, and total cholesterol levels |
| Hepatic steatosis (multi-strain probiotics) | Reduction of alanine aminotransferase and aspartate aminotransferase levels
Less hepatic fat content
Reduction of cholesterol levels
Enhancement of the gut barrier |
| Hepatocellular carcinoma | Increased liver function recovery and reduced complications after hepatic resection |
Treatment of MAFLD diet and exercise therapies
As discussed earlier, the onset and severity of MAFLD, obesity, insulin resistance and other chronic metabolic diseases are closely correlated with the lifestyle of the afflicted individual. The following paragraphs provide a summary of the related evidence and proposed therapies for the two pivotal elements of a lifestyle-focused treatment: diet and exercise.
Both clinical and basic research have produced robust evidence that physical exercise has a beneficial effect on MAFLD, by reducing hepatic fat content through the activation of various metabolic pathways that improve the systemic sensibility to insulin and degradation of fatty acids and glucose. Ultimately, these processes prevent excessive fatty acid influx to the liver and mitochondrial and hepatocellular damage from cellular stress. In terms of treatment regimen, many have shown effects on liver fat content, but there is no evidence as to prioritizing one over the others; rather, the selection of a training method should be based on the preferences, capability, and likelihood of continuation of each individual patient. Two regimens worth mentioning are aerobic exercise which, even if done at low intensity and volume, has a beneficial effect on the reduction of hepatic fat content, and resistance training, which could be an alternative that provides the same improvements and results for patients who are unable to follow the aerobic regimen. It is worth mentioning that reduction of the hepatic fat content can be achieved even without an overall weight loss.93
On the other hand are the dietary interventions. Even though they are very controversial in terms of the determination of the most optimal regimen, they remain as a key factor in the evolution and improvement of MAFLD. In general, the recent literature reports that diets based on antioxidant intake and reduction of fatty processed foods have a better impact on metabolic health. A famous model that follows these recommendations is the Mediterranean diet, characterized by the consumption of plant-based foods and fish, and reduced meat and dairy products.94 Future dietary approaches might include a fasting regimen (every other day fasting regimen) as experiments in mouse models have demonstrated that it selectively stimulates beige fat development within white adipose tissue, through modification of the gut microbiota composition, which drastically ameliorates obesity, insulin resistance and hepatic steatosis. Although the underlying mechanisms are poorly understood, the participation of microbial fermentation products, such as lactate and acetate, and the upregulation of the monocarboxylate transporter 1 expression in beige cells are some of the main proposed protagonists.95
Vitamin supplementation approaches have also been suggested as treatment for MAFLD, specifically the administration of vitamin D. This is not only because vitamin D, in particular, is a molecule with notorious anti-fibrotic, anti-inflammatory, and insulin-sensitizing properties, but also because epidemiological research has found a relationship between hypovitaminosis D and the progress of liver fibrosis. Even though several pathophysiological pathways link MAFLD with vitamin D, the results from trials are still controversial and require further work; so far, available evidence supports that certain populations of MAFLD patients may benefit from vitamin D supplementation, such as those with shorter disease duration and mild to moderate liver damage.96