Despite great progress in their prevention and treatment, infectious diseases remain a major threat to global health, particularly in south Asia and sub-Saharan Africa. Major infectious diseases, such as hepatitis, acquired immune deficiency syndrome (AIDS), and tuberculosis, will continue to exist for a long time. For example, the number of patients with AIDS worldwide is approximately 37 million, and approximately 1 million died of AIDS in 2017.1 Although the tuberculosis vaccine has been used for more than 90 years and chemical anti-tuberculosis treatment has been used for more than 60 years, tuberculosis remains a leading cause of death among current infectious diseases. The World Health Organization estimates that 10 million new cases of tuberculosis resulted in approximately 1.3 million deaths in 2017.2 There are approximately 250 million people living with chronic hepatitis B infection and 80 million people with chronic hepatitis C infection. Approximately 1.5 million people die of hepatitis virus infection each year.3 Furthermore, dengue fever, global influenza pandemic, and ebola and other high-threat pathogens are now the main threats to human health as well. The number of infected people is so great that infectious diseases have become a globally important public health issue.4
There are trillions of microbial cells on the human body surface and in the body cavity. These microbes include bacteria, archaea, fungi, and viruses and colonize the gastrointestinal tract, the oral cavity, the skin, the genitourinary tract, and the respiratory tract.5 More than 80% of human microbiota live in the gut, where they play an important role in development, immunity, metabolism, and disease.6 In this review, we will summarize the alterations of gut microbiota in infectious diseases, their relationship with the development of infectious diseases, and the application of gut microbiota regulation in the prevention and treatment of infectious diseases.
Alterations in gut microbiota are frequently observed in patients with infectious diseases
The α-diversities of gut microbiota in patients with infectious diseases have usually been observed to be reduced compared with those in healthy controls. The α-diversity is the mean species diversity in sites or habitats at a local scale.7 Their decreases mean that there were reductions in the richness of the microbial types (such as species) and/or distribution of gut microbiota in these patients. The reduction in gut microbiota diversity occurs in the early stages of many infectious diseases. For example, in 31 healthy individuals and 46 newly diagnosed patients with active pulmonary tuberculosis before anti-tuberculosis treatment, Hu et al. found that the number of species and the Shannon index of fecal microbiota, which indicate α-diversity, were significantly lower in the tuberculosis-infected patients.8 Serrano-Villar et al. found a significant decrease in the α-diversity of fecal microbiota in female and male human immunodeficiency virus (HIV)-infected patients who had sex with females but did not observe changes in the α-diversity in male HIV-infected patients who had sex with males.9 In 31 healthy individuals and 46 hepatitis C virus (HCV)-infected patients, Takako et al. found that the HCV-infected individuals had significantly lower bacterial α-diversity, which was reflected in decreases in the Shannon index and the number of operational taxonomic units (OTU) compared with those in healthy individuals.10 Although no significant changes in α-diversity in fecal microbiota were observed in patients with chronic hepatitis B who had Child-Pugh scores between 5 and 6 and did not have cirrhosis or cancer, α-diversity in patients with an earlier onset of hepatitis B virus (HBV), such as HBV carriers, needs further exploration.11 We found that the number of OTUs in fecal microbiota in patients with Clostridium difficile infection (CDI), as indicated by the Chao 1 and Shannon indexes, was significantly lower than that in healthy controls.12 In addition, from the onset to the end stage of a disease, the α-diversity of gut microbiota in patients with some incurable infectious diseases may be affected by one or more processes that cause it to decrease and then gradually increase, but the observed α-diversity is usually significantly lower than that in healthy controls. For example, compared with that in controls, the α-diversity of fecal microbiota, as estimated by the Shannon index, the Simpson index and the Invsimpson index, was significantly decreased in patients with liver cirrhosis. In contrast, α-diversity was markedly increased in patients with early hepatocellular carcinoma versus that in patients with liver cirrhosis, but was still significantly lower than that in healthy controls.13 Animal experiments also showed that early infection will result in a general decline in gut microbiota diversity. For example, Winglee et al. used aerosols of two strains of Mycobacterium tuberculosis to infect BALB/C mice. In the first 6 days after infection, the Shannon diversity index of the intestinal microbiota in infected mice sharply decreased. The relative abundances of the OTUs significantly decreased, and subsequent restoration of microbiota diversity was observed until the mice died.14 It is worth noting that the microbes with increased abundances found after the recovery of intestinal microbiota diversity were not the same as those found before infection.
There are some potential common characteristics as indicated by the alterations of gut microbiota in several infectious diseases. First, some members of the order Clostridiales, which belongs to the phylum Firmicutes, were generally depleted in the gut of patients with several infectious diseases compared with healthy controls. For example, Clostridium spp clusters XI and XIVa were depleted in HBV carriers.11,15,16 Members of the order Clostridiales were depleted in HCV-infected patients.10Lachnospiraceae, Clostridium IV, and Ruminococcus were depleted in chronic hepatitis B patients.11Lachnospiraceae was depleted in patients with cirrhosis related to HBV infection.17,18 The levels of Clostridium members in newly diagnosed and patients with recurrent tuberculosis were shown to be significantly decreased.19 In patients with HIV, Ruminococcaceae, Ruminococcus, Lachnospira, Alistipes, and Coprococcus, all of which belong to Clostridiales, were depleted.20 In addition, Lachnospiraceae and Ruminococcaceae were depleted in patients with CDI.12,21 Second, some members of Bacteroides were generally depleted in these infectious diseases. For example, Bacteroides was depleted in HBV carriers.11,15,16 Bacteroides and Parabacteroides were depleted in patients with chronic hepatitis B,11 and members of the phylum Bacteroidetes were depleted in patients with liver cirrhosis related to HBV.16,17 Furthermore, Alistipes and Ruminococcus were depleted in patients with hepatocellular carcinoma,13,22 and Bacteroidaceae, Bacteroides, and Parabacteroides were depleted in HIV-infected patients.20 Third, members of the phylum Proteobacteria, especially Gammaproteobacteria, were enriched in gut microbiota in patients with these infectious diseases. For example, the enrichment of Enterobacteriaceae, especially Escherichia coli B, was observed in the guts of HBV carriers.15,23Klebsiella and Haemophilus were enriched in patients with hepatocellular carcinoma,13 and Proteobacteria were enriched in patients with liver cirrhosis related to HBV infection.17,18 Proteobacteria were also enriched in patients with recurrent tuberculosis,19 and Proteobacteria, Gammaproteobacteria, Enterobacteriales, and Fusobacterium were enriched in HIV-infected patients.20Gammaproteobacteria, Enterococcaceae, and Klebsiella were enriched in CDI patients.12 In addition, the enrichment of Streptococcaceae, which belong to Firmicutes, was observed in patients with HCV infection, cirrhosis and CDI.10,12,17 Since meta-analysis is usually conducted on randomized controlled trials, the above results are only based on literature review, but they still have important implications for understanding the alterations of gut microbiota in patients with infectious diseases.
Several issues that pertain to the study of the alterations of gut microbiota in patients with infectious diseases deserve attention. First, a prospective cohort study would be worth conducting. Based on the above summary, it can be observed that both similar and different alterations in gut microbiota occur in various diseases. However, most of the comparison results are from cross-sectional studies, and the comparison of different studies or different patients may affect the results. In addition, prospective cohort studies of gut microbiota alterations in populations susceptible to various infection stages play an important role in revealing causal relationships between microbiota and infectious diseases. Second, the absolute alterations in gut microbiota during the development of infectious diseases are rarely reported. Species with the same relative abundance may vary widely in terms of absolute abundance in different individuals. The impact of the overall numbers of different species of gut microbiota on infectious diseases is of concern. Third, it is critical to determine which intestinal microbes are active during the development of infectious diseases. Existing 16S rDNA and metagenomic methods do not distinguish between active, dead, and resting microbial cells. Serrano-Villar et al. found that Acidaminococcaceae, Prevotellaceae, Bacteroidaceae, Enterobacteriaceae, and Veillonellaceae were transcriptionally active in HIV-infected individuals.24 It is important to determine whether intestinal microbes are active during the infection period in the study of the cause and the prevention of infectious disease.
The relationship between alterations in gut microbiota and infectious diseases
The microbiota, especially those in the gut, play an important role in the development and maintenance of the immune system.25 Microbiota deficits lead to the incomplete development of the immune system. Compared with specific pathogen-free mice, germ-free mice showed broad decreases in T cells, including αβ T cells, in the small intestine, spleen, and blood and specific decreases in CD4+ T cells in the small intestine, mesenteric lymph nodes, and bone marrow and in Th1 cells in the small intestine, mesenteric lymph nodes, colon, and skin; these mice also showed decreases in Th17 cells in the colon, cecum, mesenteric lymph nodes, and skin, T regulatory cells in Peyer's patch and colon, CD8+ T cells in mesenteric lymph nodes, interferon gamma-positive CD8+ T cells in the small intestine, colon, and mesenteric lymph nodes, and interleukin 17 (IL-17)-positive γδ T cells in the small intestine, skin, and liver.26–28 At the same time, some non-T cell immune cells were also shown to be decreased in germ-free mice. For example, germ-free mice showed decreases in monocytes in bone marrow and spleen, macrophages in liver, dendritic cells in spleen, granulocytes in bone marrow, and neutrophils and B cells in blood.29,30 In addition, the antibody secretory capability and the immune response capability are significantly impaired in germ-free mice. For example, in germ-free mice, γδ T cells show reduced production of antimicrobials in the small intestine, reduced activation in the liver, and diminished enzyme-linked immunosorbent assay responses to mucosal injury in the colon; B cells show decreases in the production of IgA and IgG in the small intestine.28 In contrast, a small number of immune cell populations increased, including B cells in bone marrow, natural killer T (NKT) cells in the colon, basophils in blood and bone marrow, Th17 cells in the cecal patch and colon, and group 2 innate lymphoid cells in the small intestine.26 These results indicate that the intestinal flora plays an important role in systemic immune development. In recent years, the important role of certain microbial strains in intestinal immune regulation has been revealed. For example, Bacteroides fragilis colonizes the colon and induces CD4+ T cell-dependent and -independent immune responses.31 Segmented filamentous bacteria colonize the small intestinal ileum, induce Th17 cells, and increase the expression of genes associated with inflammation and antimicrobial defenses.32Clostridium colonizes the colon and causes the accumulation of Foxp3+ regulatory T cells.33 However, the effect of most intestinal commensal bacteria on the development and balance of the immune system is unclear. Furthermore, the immunity of specific pathogen-free animals in which the flora was destroyed using broad-spectrum antibiotics was greatly impaired. For example, CD4+ T cells were decreased in Peyer's patch, cervical lymph nodes, the small intestine, colon, spleen, and blood; CD8+ T cells were decreased in the small intestine, colon, and blood; IL-17+ γδ T cells were decreased in liver; B cells were decreased in the small intestine, colon, and Peyer's patch; and natural killer cells were decreased in spleen.28 For another example, after the gut flora was disrupted in mice by broad-spectrum antibiotics, the colonization of M. tuberculosis was increased, and pathology was more severe after challenge with M. tuberculosis. Furthermore, treatment with antibiotics led to elevation in the number of Tregs and decline in the pool of interferon-gamma- and tumor necrosis factor-alpha-releasing CD4+ T cells in spleen. Antibiotic-treated mice transplanted with feces from mice that had not been treated with antibiotics had less severe infections than mice that did not receive transplantation when infected with M. tuberculosis. Interestingly, fecal transplantation in the gut microbiota disrupted animals exhibited improved Th1 immunity and lesser Tregs population.34 In the mouse model for Theiler's murine encephalomyelitis virus infection of the brain, mice pretreated with broad-spectrum antibiotics displayed significantly lower levels of CD4+ and CD8+ T cells in cervical and mesenteric lymph nodes during the acute phase at 14 days post-infection, and exhibited significantly higher mortality during the chronic phase at 28 days.35
Gut microbiota can directly prevent invasions by pathogens. In addition to regulating systemic immunity in hosts, gut microbes can fight against infections caused by foreign microorganisms through a variety of mechanisms. For example, intestinal microbes secrete antibacterial substances. More than 170 species of bacteria that secrete bacteriocins have been identified and sequenced.36 Eighty-eight percent of these bacteriocins are produced by Gram-positive bacteria. The remaining 12% are produced by Gram-negative bacteria and archaea. Among them, the more common bacteriocins, such as lantibiotics produced by Gram-positive bacteria, are active against many species, including Streptococcus pneumoniae, Staphylococcus aureus, C. difficile, and Enterococcus faecium; microcins produced by Gram-negative bacteria can combat infection caused by other species, including E. coli, Salmonella enterica, Enterobacter cloacae, Klebsiella pneumoniae, Citrobacter, and Shigella.36 A recent study found that indolepropionic acid, a metabolite produced by gut microbiota, may act as an antibiotic. In a mouse model of acute M. tuberculosis infection, 100 mg/kg indolepropionic acid was orally administered daily for 6 days per week for 4 weeks. At the end of the experiment, mice treated with indolepropionic acid had a seven-fold reduction in bacterial load in the spleen compared to untreated mice.37 Furthermore, in addition to small molecules and peptides, intestinal microbes produce antimicrobial proteins. For example, members of Bacteroidales, such as B. fragilis and Bacteroides uniformis, can secrete antimicrobial proteins.38 Colicins are antimicrobial proteins produced by Enterobacteriaceae that are active against related strains.39 In addition, gut microbiota can produce short-chain fatty acids. Many microbes, such as Streptococcus and Lactobacillus, are predominant in the small intestine. Some members of Firmicutes and Bacteroides are also predominant in the large intestine and can metabolize polysaccharides, simple sugars, and glycans to produce short-chain fatty acids, such as acetate, propionate, and butyrate. The concentrations of these fatty acids can reach 70–140 mM in the colon and thus inhibit the excessive growth of harmful bacteria such as E. coli and Salmonella.40 Moreover, gut microbiota can resist foreign microbial colonization through nutrient competition. The resistance to colonization and the proliferation of potential pathogens in the intestinal tract provided by the normal intestinal flora is called colonization resistance. There are great varieties and quantities of microbes in the gut. They form a large number of small communities to allocate and utilize nutrients. This produces a metabolic network that makes it difficult for foreign microbes to reproduce or colonize the intestines.41 In addition, gut microbiota can prevent foreign bacteria from entering and adhering to the intestinal wall. Some members of the local microbiota in hosts can adhere to intestinal epithelial receptors and colonize the outer layer of the intestinal mucus, thereby forming an “anatomical” barrier. For example, a large number of Bifidobacteria can colonize the surface of the mucous membrane in the human large intestine. Foreign pathogens must pass through this layer of microorganisms to reach the surface of the human intestine and must thereby compete for relevant intestinal surface receptors.42 The above defense mechanism is another example of the important role that intestinal microbes play in the prevention and treatment of infection.
Some infectious diseases are one of the causes of alterations in gut microbiota. For example, 6 days after M. tuberculosis infection in mice, a decrease in Bacteroidales and Clostridiales occurred,14,43 indicating that M. tuberculosis infection can lead to alterations in gut microbiota. Infections by the monkey simian immunodeficiency virus (SIV) destroyed the previously stable gut flora in chimpanzees, resulting in broader changes in gut microbiota and the enrichment of potential pathogens.44 In a rat model of sublethal pulmonary infection with Aspergillus fumigatus, drop of intestinal bacterial microbiota diversity was observed early in infection with normalization starting from Day 7. From Day 3, appearance of new bacteria, some of which were pathogens, was seen.45 Intracranial inoculation of Theiler's murine encephalomyelitis virus to mice caused an enrichment of the Firmicutes, depletion of and Alloprevotela in feces during the acute phase at 14 days post-infection, but induced depletion of Akkermansia, Anaerotruncus, and enrichment of Clostridium XIVa during the chronic phase at 28 days.35 Changes in the gut microenvironment during the pathogenesis of infectious diseases may be responsible for these alterations in gut microbiota. Most infectious diseases occur at a specific site but may cause systemic immune changes, including within the gut. For example, both CD4+ T cells and Th17 cells were reduced in gut-associated lymphoid tissue following HIV infection, leading to intestinal barrier dysfunction.46 Influenza virus infection caused mucosal immune damage not only in the respiratory tract but also in the intestinal tract; a large number of pro-inflammatory Th17 cells aggregated in the intestinal mucosa, and the composition of mouse intestinal flora was also altered during influenza infection.47 Furthermore, certain infectious diseases can also cause changes in the physical and/or chemical properties of the intestines other than those involved in immunity. For example, patients with hepatitis virus infection have reduced bile secretion into the gut.11 Viruses such as West Nile virus and Zika virus that target the nervous system in the brain and spinal cord can also kill neurons in the intestines of mice, disrupting intestinal peristalsis and causing intestinal blockage.48
Gut microbiota imbalances may promote the development of infectious diseases. The health and balance of the gut microbiota is critical to the progression of infectious diseases. Pathogens often use signals from the host gut flora to spread and accelerate the process of infection. For example, a pathogenic bacterium, Citrobacter, which infects mice and humans, can use the signal molecules produced by the host gut flora to induce disease progression and cause long-lasting infections and several serious diseases.49 Animals with gut microbiota imbalances are more susceptible to infection. It was found that mice with dysbacteriosis showed innate immune- and adaptive antiviral immune-related damage, prolonged virus clearance after exposure to influenza virus, the decreased expression of antiviral immune-related genes in macrophages, reduced interferon expression, and the impaired ability to inhibit viral replication.50 Gut microbiota from men with a high risk of HIV infection who have sex with men can activate immunity in gnotobiotic mice and in vitro HIV infection. Men who have sex with men (MSM) differ from men who have sex with women (MSW) in terms of immune activation and gut microbiota composition, even if there is no HIV infection. Immunologically, HIV-negative MSM has significantly higher frequencies of CD38+HLADR+ and CD103+ T cells in peripheral blood, and gnotobiotic mice transplanted with feces from MSM has significantly higher frequencies of intestinal CD69+ and CD103+ T cells than gnotobiotic mice that received feces from HIV-negative MSW. HIV-infected cells are more frequently stimulated by microbiota from MSM than by that from MSW.51 A similar phenomenon may also be associated with intestinal microbiota in patients with tuberculosis who are more likely to suffer relapse after being cured. In relapsed patients with a history of tuberculosis, T cells lose reactivity against some M. tuberculosis strains that have a homologous epitope that reacts with certain bacteria in gut microbiota, indicating that the impact of previous tuberculosis treatment on gut microbiota may contribute to recurrent tuberculosis.52
The role of gut microbiota in the diagnosis and treatment of infectious diseases
The diagnosis of gut microbiota imbalance can be applied to the diagnosis of infectious diseases. Gut microbiota play an important role in health and diseases. However, there is no uniform standard for the assessment of the balance or imbalance of gut microbiota in terms of health and disease states. For easily diagnosed infectious diseases, the diagnostic value of alterations in gut microbiota may lie in the determination of disease progression and prognosis. For example, it is clinically difficult to distinguish between HBV-induced cirrhosis and liver cancer. Our study found that there is a significant difference in gut microbiota in patients with hepatitis B-induced cirrhosis and hepatocellular carcinoma. Gut microbiota-targeted biomarkers represent potential noninvasive tools for the early diagnosis of hepatocellular carcinoma.13 Furthermore, with the rapid development of high-throughput sequencing and bioinformatics, microbiota has become increasingly important in the diagnosis of unexplained infections. For example, the integration of host responses and unbiased microbiota detection for the diagnosis of significantly lower respiratory tract infections in critically ill adults suggests that a single streamlined protocol offering an integrated genomic portrait of the pathogen, the microbiome, and the host transcriptome may hold promise as a tool for the treatment of significantly lower respiratory tract infection.53
The effect of anti-infection treatments on gut microbiota is significant. Anti-infection treatments with antibiotics may damage gut microbiota. Here, we use anti-tuberculosis treatment as an example. One day after the combined administration of isoniazid, rifampicin, and pyrazinamide, the bacterial diversity in gut microbiota in both M. tuberculosis-infected mice and uninfected mice decreased, and the microbial community structure was disturbed, which was reflected in the reduction of Clostridia. The damage to gut microbiota worsened within 2 weeks and lasted for at least 3 months after treatment.54 In another study using mice, first-line tuberculosis treatment (isoniazid, rifampin, pyrazinamide, and ethambutol) resulted in a continuous alteration in gut microbiota that lasted for 14 months after cure in some individuals.55 In humans, one study showed that the overall microbiota diversity in patients with active tuberculosis treated using first-line drugs did not differ from that in uninfected or latent tuberculosis patients, as estimated by the Shannon diversity index, despite the fact that the patients were treated for an average of 3.4 months. However, the depletion of some members of Clostridiales and the enrichment of some members of Bacteroides were observed during treatment.56 Another study found that the diversity of microbiota was slightly decreased and that gut microbiota was similarly altered in tuberculosis patients undergoing first-line anti-tuberculosis treatment when compared with that in healthy controls.57 Further research found that disorder in gut microbiota is mainly due to the use of the broad-spectrum antibiotic rifampicin, rather than the use of isoniazid alone or the narrow-spectrum antibiotic pyrazinamide.14,58 Second, anti-infection treatments, especially antiviral treatment for nonintestinal infections, may help to restore intestinal flora. It was reported that combined treatment with nucleoside reverse transcriptase inhibitors and integrase strand transfer inhibitors reduced the decrease in fecal bacterial diversity caused by HIV infection.59 After 1 year of treatment with direct-acting antiviral drugs in HCV-infected cirrhosis patients, the α-diversity of the gut microbiota was significantly increased, and the composition of the gut microbiota was also significantly altered, as reflected in the depletion of members of certain taxa in Enterobacteriaceae, Enterococci, and Staphylococcus, which consist of many opportunistic pathogens.60
Gut microbiota and their products have a major impact on the treatment of infectious diseases. The maturation of gut microbiota in adult mice stimulates liver immunity, leading to rapid clearance of HBV. Adult (12-week-old) C3H/HeN mice cleared HBV within 6 weeks, but their offspring (6 weeks old), whose gut microbiota were stable only after 9 weeks, remained HBV positive for 26 weeks after infection. The use of antibiotics to sterilize the gut microbiota in 6- to 12-week-old mice impairs their ability to rapidly clear HBV as they age.61 Young rats with a Toll-like receptor 4 mutation showed rapid HBV clearance, suggesting that there is a Toll-like receptor 4-dependent pathway involved in HBV immune tolerance in young rats before gut microbiota formation.61 The microbial stimulation of intestinal immunity improves the outcomes of tuberculosis prevention and treatment. One study found that a 2-week administration of heat-inactivated Mycobacterium manresensis via the drinking water of C3HeB/FeJ mice reduced the load of M. tuberculosis, granuloma infiltration, and the levels of pro-inflammatory cytokines (interferon-γ, IL-6, and IL-17) in the lungs. The oral administration of M. manresensis during standard treatment significantly reduced the recurrence rate of active tuberculosis after treatment in mice.62 In addition, gut microbiota and their products also contribute to antiviral treatment. For example, in the human gut microbiota, Clostridium orbiscindens can produce deaminotyrosine and protect against influenza infection by increasing type I interferon signaling and reducing immune injury of the lung, thus protecting mice from influenza infection after antibiotic treatment.63 The responses of CD4+ T and B cells induced by the HIV-1 Env vaccine may be derived from a pool of immune cells that are cross-reactive with gut microbiota. Moreover, antibodies induced by HIV-1 Env that are cross-reactive with gut microbiota are ineffective in protecting against HIV-1 infection.64 A study based on murine models of coinfection by helminths and respiratory syncytial virus showed that intestinal helminth infections can produce a long-term protective effect against respiratory syncytial virus infection in the lungs by inducing a microbial-dependent type I interferon response.65
Some probiotics have exhibited beneficial roles in the prevention and treatment of several infectious diseases or their complications. Probiotics are live microbes that confer health benefits when consumed in adequate amounts.66 For example, no clinical signs of mastitis were observed in women with staphylococcal mastitis after the oral administration of Lactobacillus salivarius CECT5713 and L. gasseri CECT5714 for 30 days, but mastitis persisted throughout the study period in the control group. Further research found that the use of L. fermentum CECT5716 or L. salivarius CECT5713 appears to be an efficient alternative to the use of commonly prescribed antibiotics for the treatment of infectious mastitis during lactation.67 A significant reduction in the number of cases of CDI was found after the routine use of LP299v. compared with the number of cases in the previous 12-month period of observation.68 Compared with the placebo group, in the Saccharomyces boulardii treatment group, HIV-infected patients had decreased Catenibacterium and increased Megamonas, and some gut microbes were associated with markers of bacterial translocation and systemic inflammation.69 The oral administration of L. rhamnosus GG to patients with HIV reduced gut inflammation and Enterobacteriaceae in the gut.70 After a median follow up of 14 months (range 9–30 months) the chance to solve human papillomavirus-related cytological anomalies was twice higher in L. rhamnosus BMX 54 long-term users versus short probiotics implementation group; moreover, a total human papillomavirus-clearance was shown in 11.6% of short schedule probiotics implementation patients compared to a percentage of 31.2% in vaginal Lactobacilli long term users.71 However, although many strains of probiotics are beneficial in the prevention and treatment of several infectious diseases, more clinical trials are needed to identify useful strains and validate their applications.
Fecal microbiota transplantation (FMT) plays a significant role in the prevention and treatment of infectious diseases, especially for refractory infections. FMT involves the transfer of a minimally manipulated microbial community from the stool of a healthy donor into the gut of a patients.72 FMT has shown good clinical effects in the treatment of refractory intestinal infections, especially CDI. In a meta-analysis of 610 patients with CDI who underwent a single FMT treatment in 13 trials, 439 patients obtained a clinical cure. The cure rates in the randomized trial were significantly lower than those in the open-label study (67.7% vs 82.7%).73 Analysis of the FMT delivery modality showed that the cure rates of FMT through enema were significantly lower than those through colonoscopy, but there was no difference between those of colonoscopy and oral transplantation.73 FMT in patients with blood disorders inhibits gut colonization with antibiotic-resistant bacteria.74 Not only that, FMT also showed good clinical results in nonintestinal infections. A small clinical trial found FMT induces hepatitis B virus e-antigen clearance in patients with positive hepatitis B virus e-antigen after long-term antiviral therapy, suggesting the benefits of modulating gut microbiota for chronic hepatitis B treatment.75 Although FMT shows good results in refractory infections, the relationship between FMT and adverse events such as inflammatory bowel attacks, other infectious diseases, and autoimmune diseases is an issue of concern.76 In the future, well-defined multistrain treatments may be more acceptable and more efficient than FMT.
The α-diversities of gut microbiota decrease during the development of most infectious diseases, which reflects the general observation that members of Clostridiales or Bacteroides were depleted while members of Proteobacteria were enriched. The gut microbiota plays an important role in the development and maintenance of host immunity. It can protect against gut invasion by foreign microbes through nutritional competition and colonization resistance. On the one hand, infectious diseases can cause alterations in gut microbiota by affecting gut function and immunity. On the other hand, inflammation caused by alterations of gut microbiota may aggravate infectious diseases. The gut microbiota plays an important role in influencing the courses of infectious diseases and in diagnosing infectious diseases with unknown etiology. Antibiotics, especially broad-spectrum antibiotics, can destroy gut microbiota during anti-infection treatment. However, some anti-viral drugs appear to be helpful for the restoration of gut microbiota. Thus far, probiotics have been shown to be the most important means for microbiota regulation to prevent and control infectious diseases. Recently, the use of FMT in the treatment of refractory infections, especially CDIs, has shown good results.
. Joint United Nations Programme on HIV/AIDS (UNAIDS). AIDSinfo. Geneva, Switzerland: UNAIDS; 2017. http://aidsinfo.unaids.org/
. Global tuberculosis report 2018. World Health Organization, Geneva; 2018. http://www.who.int/tb/publications/global_report/en/
. Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet 2015;386(10003):1546–1555.
. Mehand MS, Al-Shorbaji F, Millett P, Murgue B. The WHO R&D blueprint: 2018 review of emerging infectious diseases
requiring urgent research and development efforts. Antiviral Res 2018;159:63–67.
. Xu X, Wang Z, Zhang X. The human microbiota associated with overall health. Crit Rev Biotechnol 2015;35(1):129–140.
. Gentile CL, Weir TL. The gut microbiota
at the intersection of diet and human health. Science 2018;362(6416):776–780.
. Whittaker RH. Vegetation of the Siskiyou mountains, Oregon and California. Ecol Monogr 1960;30(3):280–338.
. Hu Y, Feng Y, Wu J, et al. The Gut microbiome signatures discriminate healthy from pulmonary tuberculosis patients. Front Cell Infect Microbiol 2019;9:90.
. Tuddenham SA, Koay WLA, Zhao N, et al. The impact of HIV infection on gut microbiota
alpha-diversity: an individual level meta-analysis. Clin Infect Dis 2019. doi.org/10.1093/cid/ciz258.
. Inoue T, Nakayama J, Moriya K, et al. Gut dysbiosis associated with hepatitis C virus infection. Clin Infect Dis 2018;67(6):869–877.
. Wang J, Wang Y, Zhang X, et al. Gut microbial dysbiosis is associated with altered hepatic functions and serum metabolites in chronic hepatitis B patients. Front Microbiol 2017;8:2222.
. Lopez P, de Paz B, Rodriguez-Carrio J, et al. Th17 responses and natural IgM antibodies are related to gut microbiota
composition in systemic lupus erythematosus patients. Sci Rep 2016;6:24072.
. Ren Z, Li A, Jiang J, et al. Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for early hepatocellular carcinoma. Gut 2019;68(6):1014–1023.
. Winglee K, Eloe-Fadrosh E, Gupta S, Guo H, Fraser C, Bishai W. Aerosol Mycobacterium tuberculosis
infection causes rapid loss of diversity in gut microbiota
. PLoS One 2014;9(5):e97048.
. Lu H, Wu Z, Xu W, Yang J, Chen Y, Li L. Intestinal microbiota was assessed in cirrhotic patients with hepatitis B virus infection. Microb Ecol 2011;61(3):693–703.
. Wu ZW, Lu HF, Wu J, et al. Assessment of the fecal lactobacilli population in patients with hepatitis B virus-related decompensated cirrhosis and hepatitis B cirrhosis treated with liver transplant. Microb Ecol 2012;63(4):929–937.
. Chen Y, Yang F, Lu H, et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 2011;54(2):562–572.
. Qin N, Yang F, Li A, et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 2014;513(7516):59–64.
. Luo M, Liu Y, Wu PF, et al. Alternation of gut microbiota
in patients with pulmonary tuberculosis. Front Physiol 2017;8:822.
. Kang Y, Cai Y. Altered gut microbiota
in HIV infection: future perspective of fecal microbiota transplantation therapy. AIDS Res Hum retrov 2019;35(3):229–235.
. Gu S, Chen Y, Zhang X, et al. Identification of key taxa that favor intestinal colonization of Clostridium difficile
in an adult Chinese population. Microbes Infect 2016;18(1):30–38.
. Liu Q, Li F, Zhuang Y, et al. Alteration in gut microbiota
associated with hepatitis B and non-hepatitis virus related hepatocellular carcinoma. Gut pathogens 2019;11:1.
. Wei X, Yan XB, Zou DY, et al. Abnormal fecal microbiota community and functions in patients with hepatitis B liver cirrhosis as revealed by a metagenomic approach. BMC Gastroenterol 2013;13(1):175.
. Serrano-Villar S, Rojo D, Martinez-Martinez M, et al. Gut bacteria metabolism
impacts immune recovery in HIV-infected individuals. EBioMedicine 2016;8:203–216.
. Honda K, Littman DR. The microbiota in adaptive immune homeostasis and disease. Nature 2016;535(7610):75–84.
. Kernbauer E, Ding Y, Cadwell K. An enteric virus can replace the beneficial function of commensal bacteria. Nature 2014;516(7529):94–98.
. Naik S, Bouladoux N, Wilhelm C, et al. Compartmentalized control of skin immunity
by resident commensals. Science 2012;337(6098):1115–1119.
. Kennedy EA, King KY, Baldridge MT. Mouse microbiota models: comparing germ-free mice and antibiotics treatment as tools for modifying gut bacteria. Front Physiol 2018;9:1534.
. Ganal SC, Sanos SL, Kallfass C, et al. Priming of natural killer cells by nonmucosal mononuclear phagocytes requires instructive signals from commensal microbiota. Immunity
. Zhang D, Chen G, Manwani D, et al. Neutrophil ageing is regulated by the microbiome. Nature 2015;525(7570):528–532.
. Erturk-Hasdemir D, Kasper DL. Finding a needle in a haystack: Bacteroides fragilis
polysaccharide A as the archetypical symbiosis factor. Ann N Y Acad Sci 2018;1417(1):116–129.
. Ivanov II, Atarashi K, Manel N, et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 2009;139(3):485–498.
. Atarashi K, Tanoue T, Shima T, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 2011;331(6015):337–341.
. Khan N, Vidyarthi A, Nadeem S, Negi S, Nair G, Agrewala JN. Alteration in the gut microbiota
provokes susceptibility to tuberculosis. Front Immunol 2016;7:529.
. Carrillo-Salinas FJ, Mestre L, Mecha M, et al. Gut dysbiosis and neuroimmune responses to brain infection with Theiler's murine encephalomyelitis virus. Sci Rep 2017;7:44377.
. Aresti Sanz J, El Aidy S. Microbiota and gut neuropeptides: a dual action of antimicrobial activity and neuroimmune response. Psychopharmacology (Berl) 2019;236(5):1597–1609.
. Negatu DA, Liu JJ, Zimmerman M, et al. Whole-cell screen of fragment library identifies gut microbiota
metabolite indole propionic acid as antitubercular. Antimicrob Agents Chemother 2018;62(3):e01571–e01517.
. Roelofs KG, Coyne MJ, Gentyala RR, Chatzidaki-Livanis M, Comstock LE. Bacteroidales secreted antimicrobial proteins target surface molecules necessary for gut colonization and mediate competition in vivo. MBio 2016;7(4):e01055-16.
. Kirkup BC, Riley MA. Antibiotic-mediated antagonism leads to a bacterial game of rock-paper-scissors in vivo. Nature 2004;428(6981):412–414.
. Sorbara MT, Pamer EG. Interbacterial mechanisms of colonization resistance and the strategies pathogens use to overcome them. Mucosal Immunol 2019;12(1):1–9.
. Pereira FC, Berry D. Microbial nutrient niches in the gut. Environ Microbiol 2017;19(4):1366–1378.
. Dyrmann Leser, Thomas & Gottlieb, Caroline & Johansen, Eric. Bifidobacteria: Regulators of Intestinal Homeostasis. 2015. doi: 10.21775/9781910190098.04.
. Ericsson AC, Gagliardi J, Bouhan D, Spollen WG, Givan SA, Franklin CL. The influence of caging, bedding, and diet on the composition of the microbiota in different regions of the mouse gut. Sci Rep 2018;8:4065.
. Moeller AH, Shilts M, Li Y, et al. SIV-induced instability of the chimpanzee gut microbiome. Cell Host Microbe 2013;14(3):340–345.
. Kulas J, Mirkov I, Tucovic D, et al. Pulmonary Aspergillus fumigatus
infection in rats affects gastrointestinal homeostasis. Immunobiology 2019;224(1):116–123.
. Assimakopoulos SF, Dimitropoulou D, Marangos M, Gogos CA. Intestinal barrier dysfunction in HIV infection: pathophysiology, clinical implications and potential therapies. Infection 2014;42(6):951–959.
. Wang J, Li F, Wei H, Lian ZX, Sun R, Tian Z. Respiratory influenza virus infection induces intestinal immune injury via microbiota-mediated Th17 cell-dependent inflammation. J Exp Med 2014;211(12):2397–2410.
. White JP, Xiong S, Malvin NP, et al. Intestinal dysmotility syndromes following systemic infection by Flaviviruses. Cell 2018;175(5):1198–1212.
. Connolly JPR, Slater SL, O’Boyle N, et al. Host-associated niche metabolism
controls enteric infection through fine-tuning the regulation of type 3 secretion. Nat Commun 2018;9(1):4187.
. Oh JZ, Ravindran R, Chassaing B, et al. TLR5-mediated sensing of gut microbiota
is necessary for antibody responses to seasonal influenza vaccination. Immunity
. Li SX, Sen S, Schneider JM, et al. Gut microbiota
from high-risk men who have sex with men drive immune activation in gnotobiotic mice and in vitro HIV infection. PLoS Pathog 2019;15(4):e1007611.
. Scriba TJ, Carpenter C, Pro SC, et al. Differential recognition of Mycobacterium tuberculosis-
specific epitopes as a function of tuberculosis disease history. Am J Resp Crit Care 2017;196(6):772–781.
. Langelier C, Kalantar KL, Moazed F, et al. Integrating host response and unbiased microbe detection for lower respiratory tract infection diagnosis in critically ill adults. Proc Natl Acad Sci U S A 2018;115(52):E12353–E12362.
. Namasivayam S, Maiga M, Yuan W, et al. Longitudinal profiling reveals a persistent intestinal dysbiosis triggered by conventional anti-tuberculosis therapy. Microbiome 2017;5(1):71.
. Naidoo CC, Nyawo GR, Wu BG, et al. The microbiome and tuberculosis: state of the art, potential applications, and defining the clinical research agenda. Lancet Respir Med 2019. doi: 10.1016/S2213-2600(18)30501-0.
. Wipperman MF, Fitzgerald DW, Juste MAJ, et al. Antibiotic treatment for Tuberculosis induces a profound dysbiosis of the microbiome that persists long after therapy is completed. Sci Rep 2017;7(1):10767.
. Hu Y, Yang Q, Liu B, et al. Gut microbiota
associated with pulmonary tuberculosis and dysbiosis caused by anti-tuberculosis drugs. J Infect 2019;78(4):317–322.
. Namasivayam S, Sher A, Glickman MS, Wipperman MF. The microbiome and tuberculosis: early evidence for cross talk. MBio 2018;9(5):e01420-18.
. Villanueva-Millan MJ, Perez-Matute P, Recio-Fernandez E, Lezana Rosales JM, Oteo JA. Differential effects of antiretrovirals on microbial translocation and gut microbiota
composition of HIV-infected patients. J Int AIDS Soc 2017;20(1):21526.
. Ponziani FR, Putignani L, Paroni Sterbini F, et al. Influence of hepatitis C virus eradication with direct-acting antivirals on the gut microbiota
in patients with cirrhosis. Aliment Pharmacol Ther 2018;48((11–12)):1301–1311.
. Chou HH, Chien WH, Wu LL, et al. Age-related immune clearance of hepatitis B virus infection requires the establishment of gut microbiota
. Proc Natl Acad Sci U S A 2015;112(7):2175–2180.
. Cardona P, Marzo-Escartin E, Tapia G, et al. Oral administration of heat-killed Mycobacterium manresensis
delays progression toward active tuberculosis in C3HeB/FeJ mice. Front Microbiol 2015;6:1482.
. Steed AL, Christophi GP, Kaiko GE, et al. The microbial metabolite desaminotyrosine protects from influenza through type I interferon. Science 2017;357(6350):498–502.
. Williams WB, Han Q, Haynes BF. Cross-reactivity of HIV vaccine responses and the microbiome. Curr Opin HIV AIDS 2018;13(1):9–14.
. McFarlane AJ, McSorley HJ, Davidson DJ, et al. Enteric helminth-induced type I interferon signaling protects against pulmonary virus infection through interaction with the microbiota. J Allergy Clin Immunol 2017;140(4):1068–1078.
. Suez J, Zmora N, Segal E, Elinav E. The pros, cons, and many unknowns of probiotics. Nat Med 2019;25(5):716–729.
. Arroyo R, Martin V, Maldonado A, Jimenez E, Fernandez L, Rodriguez JM. Treatment of infectious mastitis during lactation: antibiotics versus oral administration of Lactobacilli isolated from breast milk. Clin Infect Dis 2010;50(12):1551–1558.
. Kujawa-Szewieczek A, Adamczak M, Kwiecien K, Dudzicz S, Gazda M, Wiecek A. The effect of Lactobacillus plantarum
299 v on the incidence of Clostridium difficile
infection in high risk patients treated with antibiotics. Nutrients 2015;7(12):10179–10188.
. Villar-Garcia J, Guerri-Fernandez R, Moya A, et al. Impact of probiotic Saccharomyces boulardii
on the gut microbiome composition in HIV-treated patients: a double-blind, randomised, placebo-controlled trial. PLoS One 2017;12(4):e0173802.
. Arnbjerg CJ, Vestad B, Hov JR, et al. Effect of Lactobacillus rhamnosus
GG supplementation on intestinal inflammation assessed by PET/MRI scans and gut microbiota
composition in HIV-infected individuals. J Acquir Immune Defic Syndr 2018;78(4):450–457.
. Palma E, Recine N, Domenici L, Giorgini M, Pierangeli A, Panici PB. Long-term Lactobacillus rhamnosus
BMX 54 application to restore a balanced vaginal ecosystem: a promising solution against HPV-infection. BMC Infect Dis 2018;18(1):13.
. Samarkos M, Mastrogianni E, Kampouropoulou O. The role of gut microbiota
in Clostridium difficile infection. Eur J Intern Med 2018;50:28–32.
. Tariq R, Pardi DS, Bartlett MG, Khanna S. Low cure rates in controlled trials of fecal microbiota transplantation for recurrent Clostridium difficile
infection: a systematic review and meta-analysis. Clin Infect Dis 2019;68(8):1351–1358.
. Bilinski J, Grzesiowski P, Sorensen N, et al. Fecal microbiota transplantation in patients with blood disorders inhibits gut colonization with antibiotic-resistant bacteria: results of a prospective, single-center study. Clin Infect Dis 2017;65(3):364–370.
. Ren YD, Ye ZS, Yang LZ, et al. Fecal microbiota transplantation induces hepatitis B virus e-antigen (HBeAg) clearance in patients with positive HBeAg after long-term antiviral therapy. Hepatology 2017;65(5):1765–1768.
. Li YT, Cai HF, Wang ZH, Xu J, Fang JY. Systematic review with meta-analysis: long-term outcomes of faecal microbiota transplantation for Clostridium difficile infection. Aliment Pharmacol Ther 2016;43(4):445–457.