The effect of consecutive fecal microbiota transplantation on Non-Alcoholic Fatty Liver Disease (NAFLD) - a randomized-controlled trial -

Nonalcoholic fatty liver disease (NAFLD) is a disease of alarmingly increasing
prevalence, linked to metabolic, cardiovascular and malignant morbidity and
without any officially approved treatment. It is considered to be more than a
single entity, since it compasses a range of phenotypes, starting from
nonalcoholic simple steatosis, in which the predominant histological
characteristic is lipid accumulation in the hepatocytes, to nonalcoholic
steatohepatitis (NASH), characterized by the addition of hepatic inflammation
and/or fibrosis, and NASH-related cirrhosis and hepatocellular carcinoma.
Abdominal, particularly visceral, obesity leading to insulin resistance is
strongly associated NAFLD, both via increased delivery of free fatty acids to
the liver and through increases of hepatic lipogenesis associated with
hyperglycemia and hyperinsulinemia.
It is increasingly recognized that the gut microbiome is implicated in the
pathogenesis and progression of numerous chronic diseases, including NAFLD.
Through the so-called gut-liver axis, the liver is exposed to
gut-bacterial-derived products, including toxins (lipopolysaccharides), enzymes
(methylamines), alcohol, and short-chain fatty acids (mainly acetate,
propionate, and butyrate), that may lead to accumulation of triglycerides,
inflammatory responses, oxidative stress and accompanying damage to the
hepatocytes.
Previously, an obese microbiome has been demonstrated in mice models, which has
an increased capacity to harvest energy from the diet. Moreover, this obesity
trait is transmissible, as colonization of germ-free mice with the *obese
microbiome* results in a significantly greater increase in total body fat than
colonization with a *lean microbiome*. Interestingly, this concept has been
tested in humans recently, showing similar findings. Although weight loss could
not be proven, fecal microbiota transplantation (FMT) of lean males to obese
males resulted in improved hepatic insulin sensitivity.

The primary objective is to study the effect on consecutive FMT on liver fat
accumulation measured by Magnetic Resonance Images (MRI) LiverMultiscan at 12
weeks. Secondary objectives are weight, waist, blood pressure, metabolic
parameters (including glucose, cholesterol, pancreatic beta-cell function,
HOMA-IR), gut-microbiota and bile composition, objective and subjective stress,
and liver enzymes. Stool samples will be collected for microbiota analysis at
time point 0, 3, 6 and 12 weeks.

Single center double-blind randomized placebo-controlled pilot study.

Patients will be randomized for infusion of allogenic (lean donor) or
autologous (own) feces through a nasoduodenal tube at time points 0, 3 and 6
weeks.

Nonalcoholic fatty liver disease (NAFLD) has been recognized as a global public
health problem, affecting 6-45% of the general population, rising up to 70% in
patients with type 2 diabetes mellitus (T2DM) and 90% in morbidity obese
patients. It is considered to be more than a single entity, since it compasses
a range of phenotypes, starting from non-alcoholic simple steatosis, in which
the predominant histological characteristic is lipid accumulation in the
hepatocytes, to nonalcoholic steatohepatitis (NASH), characterized by the
addition of hepatic inflammation and/or fibrosis, and NASH-related cirrhosis
and hepatocellular carcinoma (HCC). At present, NAFLD is among the leading
causes of liver cirrhosis, HCC and liver transplantation. Multiple factors
(*hits*) contribute to the pathogenesis of NAFLD, considered to be a
multiple-hit disorder. Abdominal, particularly visceral, obesity leading to
insulin resistance is strongly associated NAFLD, both via increased delivery of
free fatty acids to the liver and through increases of hepatic lipogenesis
associated with hyperglycemia and hyperinsulinemia. Other pathogenetic factors
are divided into those with an established association with NAFLD, including
genetic [e.g. polymorphism of patatine-like phospholipase domain-containing
protein 3 (PNPLA3) gene, dietary factors (e.g., fructose), and adipokines, as
well as those with a potential association needing validation, including
endocrine disruptors and dysbiosis of the gut microbiota. Although it is a
disease of alarmingly increasing prevalence, linked to metabolic,
cardiovascular and malignant morbidity, NAFLD is at present without any
officially approved treatment.