Autoimmune
An example of an autoimmune disease influenced by gut microbiota is Type 1 diabetes (T
1DM), or juvenile diabetes. Studies comparing germ-free and gnotobiotic (populated with specific microbes) mice have revealed that T
1DM is among the diseases affected by reduced numbers of commensal bacteria [
7], especially low numbers of butyrate-producing bacteria such as those from the
Firmicutes phylum, leading to an altered ratio between
Bacteroidetes and
Firmicutes bacteria [
8]. The imbalance between these two dominant phyla could lead to more physiological problems for the patients. A study has also shown that diabetic patients younger than 2.9 years have less bacteria from
Clostridial clusters IV and XIVa, which also produce butyrate, hence corroborating data from the mice studies [
6].
Inflammatory bowel disease (IBD) is a gastrointestinal disorder also due to autoimmune dysregulation. IBD is a spectrum of chronic diseases marked by recurring inflammation of the intestinal mucosal lining. Two main phenotypes of IBD are Crohn’s disease (CD) and ulcerative colitis (UC), and both have been shown to be linked to gut microbiota dysbiosis. Various studies claim that IBD exhibits significant decrease in microbial diversity, increased bacterial count, and increase in detrimental bacteria [
9]. Studies indicate that UC is characterized by a decline in
Firmicutes and
Bacteroidetes, like in T
1DM, and an unusual increase in
Proteobacteria. Also like T
1DM, UC has also been associated with a loss of bacteria from butyrate-producing
Clostridial cluster XIVa [
10]. In CD, the disease was mainly observed in areas containing the highest concentrations of bacteria [
11]. Furthermore, a metabonomic study by Bjerrum et al. has shown that while UC is marked by a decrease in
Clostridial coccoides of
Clostridial cluster XIVa, CD showed a decrease in
Faecalibacterium prausnitzii. Interestingly, both
C. coccoides and
F. prausnitzii are important in the formation of short chain fatty acids, which includes butyrate. Although decreased butyrate stems from these specific bacterial deficiencies, decreased butyrate in itself can perpetuate the cycle of chronic inflammation and microbiotal dysbiosis in UC and CD. Therefore, these two phenotypes of IBD ultimately both end in dysbiosis even with decrease- in different species of bacteria.
There has also been interest shown in the link between genetics, microbiota, and IBD. In one study, the microbiota of siblings of CD patients were studied and compared to the patients’ microbiota. It was shown that siblings of CD patients have a higher risk of developing CD and, like the CD patients, show signs of fecal dysbiosis [
12]. Furthermore, since CD is caused by interactions between genetic and environmental factors, gut microbiota plays a role in the disease. The study confirmed microbiota alterations in CD patients, for example reduction in diversity, decrease in
Ruminococcaceae, and increase in
Enterbacteriaceae [
13].
Dysbiosis is also related to the development of CD and UC in children, which becomes readily apparent when looking at the methods used to treat pediatric IBD. One commonly used treatment for pediatric CD is exclusive enteral nutrition (EEN)—the total replacement of normal diet with liquid diet/ formula during the duration of treatment. Seeing as gut flora can be affected by environmental factors such as diet, the effectiveness of EEN suggests a relationship between microbiotal dysbiosis and the development of CD.
Other autoimmune conditions such as allergies have also been shown to be influenced by gut microbiota. Low microbial diversity has been observed to precede allergic diseases [
14]. A possible explanation for the low microbial diversity is linked to the hygiene hypothesis of allergy. In the context of microbiota, the hypothesis suggests that excessively hygienic practices impede the development of a diverse and balanced gut microflora in infants, resulting in irregular immune development and hence the emergence of allergic disease.
Two longitudinal studies by Azad et al. point towards a relationship between gut microbiota and the hygiene hypothesis. The first study looked at the influence of pets and siblings on microbiota composition and diversity and found that microbiota richness and diversity was increased in infants living with pets, but decreased in those living with older siblings, particular in relation to levels of Bifidobacteriaceae and Peptostreptococcaceae. The second study investigated food sensitization and gut microbiota, and found that low gut microbiota richness paired with an increased ratio between Enterobacteriaceae and Bacteroidaceae are linked to food sensitization. Thus, gut microflora composition in infants coupled with the hygiene hypothesis seems to be a reasonable connection.
Psychiatric
There is known to be bidirectional communication between the gut and the brain in the gut-brain axis. Established pathways of communication between the gut and the brain include the autonomic nervous system (ANS) and the enteric nervous system (ENS) [
15]. In addition, there has been increasing interest in the microbiota-gut-brain axis ever since the observation that oral antibiotics and laxatives improved cases of hepatic encephalopathy [
16]. The microbiota-gut-brain axis is also a point of interest for its role in both inducing and treating psychiatric stress-related conditions such as depression and anxiety.
Stress is chiefly monitored by the hypothalamic-pituitary-adrenal (HPA) axis. Depression and anxiety have both been linked to unregulated HPA axes and over-secretion of corticotropin-releasing factor (CRF), and in turn, adrenocorticotropic hormone (ACTH) in the presence of stress [
17]. This relates to gut microbiota because stress is known to increase intestinal permeability, allowing bacteria to travel across the intestinal mucosa and interact with the nervous system. In fact, a 2004 report established a direct link between microbiota and the HPA axis [
15], connecting microbiota with depression and anxiety. This link was further supported more recently in April 2014 in a study involving germ-free (GF) and specific pathogen free (SPF) rats [
18]. It was found that in social experiments, GF rats spent less time sniffing unknown partners, indicating higher levels of stress in unfamiliar social situations. Furthermore, GF rats had higher CRF mRNA expression in the hypothalamus and lower dopaminergic turnover rates in the frontal cortex, hippocampus, and striatum. However, the GF rats did not have any sensorimotor differences from the SPF rats [
18], which isolate the impact of gut microbiota chiefly to the HPA axis. This evidence supports that an absence, and possibly imbalance, of gut microbiota impacts behavioral responses to acute stress, contributing to depression and anxiety.
Besides the connection between gut microbiota and the brain via the HPA axis, there has been evidence attributing microbiota-gut-brain communication to the vagus cranial nerve [
19,
20]. A study involving mice proved that chronic treatment with
lactobacillus rhamnosus altered GABA mRNA in the brain and reduced stress-induced corticosteroid, but that these changes were not observed in vagotomized mice [
21]. However, further investigation should be carried out with regards to this specific pathway to obtain more definitive knowledge.
In terms of pediatrics, one of the more frequently studied psychiatric conditions in relation to gut microbiota has been autism. It has been noted that autism—a developmental disorder marked by impaired social interactions and restricted/repetitive behavior—tends to present with digestive issues. Finegold et al. found that autistic children have higher counts of Clostridial bacteria than control children, including nine species of Clostridium not found in the controls. In addition, it was found that autistic children have increased Bacteroidetes, and decreased Firmicutes and Bifidobacterium species. Although correlation does not necessitate maen causative association, such findings provide new insight towards the studying of autism.
Cancers
Cancer has a variety of causes, such as genetics, UV exposure, radiation exposure, carcinogens, and diet and physical activity. It has also been found that gut microbiota may be related to the development of some cancers, such as colorectal cancer (CRC). CRC is cancer of the colon, rectum, and anus in the form of malignant tumors. Although the development of CRC is influenced by genetic factors such as damaged DNA and genetic instability, environmental factors that impact the gut microbiota may also promote CRC development [
22]. This has been supported by mouse models, where fecal microbiota from CRC patients and healthy individuals were transplanted into GF mice and induced different levels of tumorigenesis in the mice. With regards to specific bacterial types involved in the tumorigenesis, gram-negative bacteria had the highest correlation while gram-positive bacteria such as
Clostridial cluster XIVa were strongly negatively correlated with tumors [
23]. Even though the mice were transplanted with distinct microbial populations from different human patients, they all underwent structural changes and the extent of these changes was related to tumor incidence. The study concluded that the initial structure of gut microbiota affects susceptibility to colonic tumorigenesis [
23]. Obesity, another prominent risk factor for cancer, has been associated with microbiotal dysbiosis, and could result in physiological changes towards cancer. Microbial metabolism has also been speculated to be related to cancer development [
24].
Hepatocellular carcinoma (HCC) is another instance of cancer impacted by gut microbiota. Liver cirrhosis and HCC are not unusual in end-stage chronic liver disease, but the molecular mechanisms relating HCC and liver disease are still not completely clear [
25]. However, it was recently discovered that increased translocation of gut microbiota is characteristic of chronic liver disease [
26], and that gut microbiota may be the main source of portal vein lipopolysaccharide (LPS), thus promoting tumorigenesis [
25]—a theory also supported by the earlier example of a high correlation of gram-negative bacteria in CRC development. It has been speculated that LPS from the gram-negative bacteria promotes hepatocarcinogenesis but does not actually change the gut microbiota composition [
26].
However, there exists some controversy over the effect of gut microbiota in the early stages of hepatocarcinogenesis. Yu et al. found a link between gut microbiota and TLR4 to tumor initiation. On the other hand, Dapito et al. concluded that gut microbiota and TLR4 do not have a role in initiating HCC but rather promote it [
26]. Dapito et al. also found that even though gut sterilization prevented the development of HCC, it did not lead to regression of already existing tumors. Therefore, although some information is known about gut microbiota relating to cancer, much remains to be clarified, particularly in terms of HCC, before it can be considered conclusive.