The increasing prevalence of common disorders like obesity and obesity related diseases is tightly associated with our westernized lifestyle and diet. The most prominent obesity-related ailments are insulin resistance, overt type 2 diabetes (T2D) and certain cancers. While the aetiology of these diseases is complex, many of them are characterized by a general state of low-grade inflammation, which may originate from a dysregulated intestinal microbiota and metabolome. Dysregulated intestinal health is indeed associated with an array of diverse diseases like obesity, rheumatoid arthritis. Recently, a connection between intestinal microbiota, and in particular the presence of certain lipopolysaccharides from Bacteroides, and the higher rate of occurrence of type 1 diabetes in Finland in comparison to neighbouring areas has been reported.

 

Obesity and its concomitant low-grade inflammation form a potent driver of dysregulated metabolic homeostasis. Turnbaugh et al. found that obesity-associated microbiota had an increased capacity for energy harvest, and 2 weeks after transplantation of microbiota from obese mice, germ-free mice showed significantly greater increase in fat mass than similar transplantation from lean mice. Turnbaugh et al. further and significantly discovered that changes in intestinal microbial composition were completely reversed after a shift back to the original diet in mice temporarily fed a high fat/sugar “Western” diet. These findings were confirmed in man by Vrieze et al., who demonstrated that transfer of intestinal microbiota from lean human donors increased insulin sensitivity in individuals with metabolic syndrome.

 

Manipulation of intestinal microbiota to increase weight and weight-gain rates has been employed for many years in agricultural live-stock through the use of low-dose antibiotics and probiotics such as Lactobacillus ingluviei. Intestinal microbiota manipulation for weight gain has been demonstrated in chickens, in ducksan d in mice. In humans, infants receiving antibiotics have also been found to be larger than their controls, and early exposure to oral antibiotics is associated with overweight in children. In pregnant women, the physiological increase in adiposity and potential development of gestational diabetes in the third trimester also appears to be associated with a profound change in intestinal microbiota.

 

The intestinal mucosa is by far the largest body surface (approximately 200 m2) exposed to the external environment. As such, the intestinal surface is in intimate contact with foreign material, metabolites (metabolome) derived from our diet, and the estimated more than 1.000 bacteria - the intestinal microbiota - that inhabit our intestine. Thus the intestinal barrier is under constant and intense immune surveillance, requiring a dynamic crosstalk among the immune system, dietary components, and the intestinal microbiota. Diet interventions have tremendous impact on immune regulation  and intestinal microbiota composition, both of which independently and synergistically influence metabolic homeostasis. In this regard, two very recent papers emphasize the (adverse) potential of food additives in microbiota-modulated changes to metabolic homeostasis. A recent paper illustrated how dietary emulsifiers impair glucose tolerance, thus increasing weight gain as well as colitis susceptibility by induction of a dysregulated intestinal microbiota. The observations could not be replicated in germ-free (GF) mice, suggesting a pivotal role for the intestinal microbiota. Similarly, Suez et al.  recently showed how non-caloric artificial sweeteners induced metabolic dysfunction through alterations of the intestinal microbiota. The authors validated their findings by faecal transfer to GF mice, after which the GF mice rapidly developed glucose intolerance. These observations mirror a pioneering study in GF mice, elucidating the role of intestinal microbes in the maintenance of metabolic health. This study showed that in the absence of commensal microbes, thereby causing an imbalanced mucosal immune homeostasis, the adipose tissues decreased in size and function in response to a high fat diet. Despite lack of weight gain, which normally would appear as a healthy phenotype, ectopic lipid accumulation (hepatic steatosis & increased levels of serum triglycerides) resulted in severe metabolic disorders. In man, it has been shown that gene richness of the microbiota is associated with a healthy phenotype, whereas gene poverty (low gene counts) correlates with increased risk of metabolic disorders.

 

Wertenbruch et al 2015 demonstrated that the levels of the anti-microbial peptide cathelicidin LL-37/CRAMP, human beta defensin 2 and complement factor C5a are elevated in blood serum from patients with liver diseases compared to healthy controls. Serum levels for all three markers are relatively narrow for healthy controls but there is a wide variation in the levels for liver patients. The authors speculate that the elevated levels of hBD2 might reflect an increased remodelling of biliary epithelia.

 

Harada et al 2004 have studied levels of hBD1 and hBD2 in intrahepatic biliary epithelial cells, in cell lines and in bile. hBD2 expression was found in bile ducts during active inflammation. The bile levels were found to correlate with the serum levels of CRP. The authors conclude that hBD2 is expressed in response to local infection or active inflammation and that hBD1 may be a pre-existing component of the biliary antimicrobial defence system.