SIBO and Liver Diseases

Small intestinal bacterial overgrowth (SIBO) is characterized by the presence of >10 5 colony forming units (CFU)/ml in the jejunal aspirate.  SIBO occurs as a result of disruption of the gut microbial community in response to various environmental and genetic factors, phenomenon called dysbiosis.

One of the outcomes of dysbiosis is the extension of colonic bacteria into the small intestine leading to SIBO. SIBO has been positively associated with conditions like irritable bowel syndrome, obesity, celiac disease and Crohn’s disease. Liver diseases such as liver cirrhosis and non- alcoholic fatty liver disease (NAFLD) including non-alcoholic steatohepatitis (NASH), NASH-related cirrhosis, and hepatocellular carcinoma are some of the complications found to be associated with SIBO.

Sibo and Liver Diseases

NAFLD is highly prevalent worldwide and is the most common liver disorder in Western countries. NASH is the third most common indication for liver transplantation in the United States. The major risk factors for NAFLD include obesity, type 2 diabetes mellitus, dyslipidemia, and metabolic syndrome.

Several studies report that SIBO is highly prevalent in patients with cirrhosis [1], [2], [3], [4] and is particularly frequent in patient with more severe liver disease [5], [3]. Moreover, there is a high prevalence of SIBO in NAFLD and NASH patients [6], [7], [8]. Occurrence of SIBO in NAFLD ranges from 50% to 77.8%. SIBO is also present in patients with cirrhosis with minimal hepatic encephalopathy (MHE). In addition, SIBO was found to be highly prevalent in morbid obesity and was associated with severe hepatic steatosis [9].

How does SIBO contribute to liver diseases: underlying mechanisms?

  1. Liver and gut are connected by the portal vein. The portal vein carries blood containing products of digestion and also microbial derived products derived from the gut microbiota to the liver. The liver is thus exposed to microbial components from the gut, such as endotoxin (Lipopolysaccharide or LPS), lipopeptides, unmethylated DNA, and double-stranded RNA. These products activate toll like receptors [10], especially TLR4 which are involved in the downstream inflammatory pathway [11], [12]. TLRs are pattern recognition receptors that recognize bacterial and viral ligands. Accumulating evidence demonstrates that gut microbiota and TLR signaling are closely associated with the development of NAFLD. Under the conditions of SIBO, there is an increased exposure to bacterial products such as endotoxin that causes increased expression of TLR4 . Once activated, TLRs induce the expression of proinflammatory cytokines such as TNFα and IL-1β, which further leads to the development of liver inflammation and fibrosis, and even hepatocellular carcinoma. LPS-induced proinflammatory cytokines play an important role in steatohepatitis [13], a condition characterized by fat accumulation in the liver and inflammation of the liver. Mice that were deficient in IL-1b signaling were protected from steatohepatitis induced by high fat diet [14]. Comparing NAFLD patients with (n = 12) and without (n = 20) SIBO, patients with SIBO had significantly higher endotoxin levels high NFκβ expression, a transcription factor  required for expression of inflammatory cytokines and higher TLR4 protein expression [15]. This study highlights the underlying mechanism of SIBO in pathogenesis of NAFLD. Increased expression of TLR4 and interleukin 8(IL-8), another proinflammatory cytokine was also observed in NASH patients and this was associated with SIBO [16]. Positive role on SIBO in liver cirrhosis is further confirmed by the observations with rifaximin, a non-absorbable antibiotic that is used for the treatment of SIBO. It was found that treatment with rifaximin for 4 weeks improved thrombocytopenia in patients with cirrhosis, and this was associated with a reduction in endotoxin levels [17].  Another study confirmed this finding and showed that treatment with rifaximin improved the clinical status of patients with NASH through the inhibition of LPS production [18] .
  1. Under normal conditions, intestinal barrier is maintained by tight junctions. However in the setting of SIBO, the integrity of tight junctions is compromised leading to intestinal permeability which causes translocation of bacteria and bacterial products into the liver [19], [7]. Consistent with these findings, the expression of tight junction proteins such as ZO-1 and occludin was found to be reduced in mouse models of NAFLD [20], [7]. A strong correlation was found between SIBO and the presence of bacterial DNA in the peripheral blood of patients with cirrhosis [21]. In addition, SIBO has also been associated with endogenous ethanol production which causes damage to the small intestine, increasing its permeability [22].


  1. Studies also show that patients with liver cirrhosis have slower intestinal motility [23], [24] . Decreased small intestinal motility may lead to development of SIBO [25], [26]. Small intestinal motility is reduced in cirrhotic patients with SIBO [27]. Improvement of intestinal motility with propranolol or cisapride was shown to reduce bacterial overgrowth and bacterial translocation [28], [29].
  1. Another mechanism by which SIBO may contribute to the severity of cirrhosis is by affecting bile secretion. Bile is antimicrobial and controls epithelial colonization by enteric bacteria [30] and also neutralizes toxins [31]. Bile inhibits SIBO in mice model of liver injury [32]. There is a decreased concentration of bile in cirrhosis. In experimental animals, it has been shown that absence of bile in small intestine leads to bacterial translocation [33]. Interestingly, oral administration of bile reduces these effects in cirrhotic rats [34]. In addition, compromised production of antimicrobial proteins may be induce SIBO leading to bacterial translocation [35]. A study demonstrated that  Paneth cell defensins can inhibit BT in a transgenic mouse model [36].

Protection by Probiotics

Probiotics have shown to confer protection against liver diseases in some studies. VSL#3 were found to suppress the LPS levels and TNF alpha expression in rodents [37], [38]. Bifidobacterium lactis 420, Escherichia coli Nissle 1917, and Lactobacillus plantarum were found to increase tight junction proteins and preserved barrier function in DSS-induced colitis [39], [40], [41].  An in vitro study showed that Lactobacillus rhamnosus GG suppresses the effects of interferon-g and tumor necrosis factor-α induced barrier dysfunction and proinflammatory signaling  and this was mediated by inhibition of NFkB pathway [42]. Kwak et al followed changes in the composition of fecal bacteria, SIBO and intestinal permeability after a 4 week intervention with probiotics containing Bifidobacterium bifidum, Bifidobacterium lactis, Bifidobacterium longum, Lactobacillus acidophilus, Lactobacillus rhamnosus, and Streptococcus thermophiles in patients with chronic liver disease. Probiotic administration was effective in diminishing SIBO and clinical symptoms, but  was ineffective in improving intestinal permeability and liver function [43].

Another study investigated the efficacy of probiotics for the primary prophylaxis of Hepatic encephalopathy (HE) in a randomized controlled trial and found that probiotics were effective in preventing HE in patients with cirrhosis [44].Thus probiotics represent a potential treatment options for various liver diseases. However existing data is inconclusive and more studies are needed to explore this possibility.

Pyrantel used for deworming is also known for causing inflammation of the liver and increased secretion of liver enzymes and this might be mediated by the harm caused to the gut bacteria. Common symptoms of inflamed liver are yellow eyes, darker urine, stool color is clay like, itching, swelling of the abdomen, reduced or complete loss of appetite.

Does Rifaximin for SIBO causes liver Disease?

It is very common to be confused between Refampicin and Rifaximin. Many think that Rifaximin may cause liver failure and should only be used to treat SIBO as a last resort. Rifaximin efficiently kills the bacteria in the small intestines, without being absorbed into the system. Hence it never reaches the liver, hence cannot damage it. On the other hand, Rifaximin has been shown to protect the liver instead.


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