Sepsis is a life-threatening organ dysfunction caused by an unbalanced host response to infection and is a major medical burden worldwide (van der Poll et al., 2017). The pathogenesis of sepsis is closely related to intestinal flora, and clinical treatments for sepsis are still limited. Statistically, nearly 20% of deaths reported globally are due to sepsis (Rudd et al., 2020). A. muciniphila derived tripeptide RKH protects against lethal sepsis was reported recently and the mechanism was revealed (Xie et al., 2023) (Table 1; Figure 2). Compared with non-septic controls, gut A. muciniphila abundance in septic murine model significantly reduced. Interestingly, supplementation of both live A. muciniphila and its culture supernatant could significantly reduce the mortality of sepsis models. Live A. muciniphila and its supernatant could protect against sepsis associated organ damage and reduce pulmonary inflammation, whereas heat-killed A. muciniphila could not. Metabolomics analysis indicated elevated expression of a novel tripeptide Arg-Lys-His (RKH) in live A. muciniphila supernatant. Meanwhile, fecal RKH levels were significantly lower in patients with sepsis compared to healthy controls. RKH pretreatment could significantly extend the survival time of septic mice by alleviating acute tissue injuries and reducing inflammatory factor expression. RKH treatment suppressed the expression of proinflammatory cytokines in macrophages including bone marrow-derived macrophages (BMDMs) and human monocyte-derived macrophages (THP-1-dMs) after LPS stimulation. RKH inhibits systemic inflammation during sepsis through directly binding to the Toll-like receptor 4. Protection of RKH was also verified using a septic piglet model, and safety assessment indicated no obvious adverse effects in vivo. Hence, a novel tripeptide RKH produced by live A. muciniphila, may serve as a new promising treatment approach to combat lethal sepsis, which may need further evaluation before transformation into clinical practice.

Influenza is a global infectious disease caused by a single stranded negative sense RNA virus named influenza virus, which is Liu et al. (2023). According to the statistical data of World Health Organization, seasonal influenza epidemics cause an estimated 3 to 5 million cases of severe cases worldwide, resulting in approximately 500,000 deaths, and causing significant economic losses and social burdens (Eichberg et al., 2022). H7N9 influenza virus, an emerging zoonotic pathogen, has led to 1, 564 laboratory-confirmed cases of human infection from its initial outbreak until October 2017, and there are still sporadic infections now (Liu et al., 2023). Hu et al. reported that A. muciniphila improved host defense against influenza virus H7N9 infection (Hu et al., 2021). H7N9 infection could affect mouse gut microbiota including the increase of A. muciniphila abundance. Oral administration of pasteurized A. muciniphila (1 × 10⁸ CFU) and its cultures significantly reduced weight loss and mortality of H7N9 infected mice, by reducing pulmonary viral titers, decreasing IL-1β and IL-6 levels, enhancing IFN-β, IFN-γ, and IL-10 expression. Hence, A. muciniphila could enhance host anti-influenza role through improving the innate immune response to H7N9 infection by regulating anti-inflammatory and immunoregulatory properties (Table 1).

COVID-19, caused by severe acute respiratory syndrome-Coronavirus 2 (SARS-CoV-2), is a pandemic that has affected the globe, leading to nationwide lockdowns. Research suggests that the gut microbiome may be a key factor in regulating host response and disease severity in COVID-19 patients (Aggarwal et al., 2022). Yeoh et al. analyzed the gut microbiota composition and host immune response markers in patients with COVID-19, and found that A. muciniphila abundance elevated in the COVID-19 patients (Yeoh et al., 2021). Moreover, the abundance of A. muciniphila positively correlated with inflammatory cytokines IL-1β and IL-6 and proinflammatory cytokine C-X-C motif ligand 8 (CXCL8). The cytokine storm was reported to be related with COVID-19 severity (Han et al., 2020). Hence, A. muciniphila may participate in the pathogenesis of COVID-19 and more researches are required.

Severe fever with thrombocytopenia syndrome (SFTS) is an tick-born infectious disease caused by a negative-strand RNA virus belonging to phlebovirus, which is originally reported in mainland China in 2009 (Yu et al., 2011). About 13, 305 patients have been diagnosed with SFTS in China until December 2020 (Che et al., 2022). Symptoms of SFTS include fever, thrombocytopenia, and leukopenia, with a fatality rate ranged from10 to 30% (Zhuang et al., 2018). Xie et al. reported an A. muciniphila–BA–TGR5 axis that regulates host NF-κB-mediated immunopathogenic responses to SFTSV infections (Xie et al., 2023). Relative abundance of A. muciniphila increased during the course of SFTSV infection in the surviving patients compared with heathy controls, whereas A. muciniphila abundance reduced in samples from deceased SFTS patients (SF-D group) compared with surviving SFTS patients (SF-S group). SF-S patients had reduced serum levels of the proinflammatory cytokines IL-1β, IL-6 and TNF-α compared with SF-D patients. The proinflammatory cytokine levels was inversely related with the relative A. muciniphila abundance. Intragastric administration of live and pasteurized A. muciniphila showed significant protection for Abx mice (microbiota-depleted mice) against fatal SFTSV infection compared with controls of unrelated commensal bacteria. The β-carboline alkaloid harmaline (HAL) generated by A. muciniphila can regulate primary BA conjugation and protect host against SFTSV infection through the inhibition of NF-κB-mediated systemic inflammation.

Clostridioides difcile (C. difcile) is a Gram-positive anaerobic bacterium, which can cause C. difcile infection (CDI) in healthcare facilities, with a high CDI recurrence rate of 15–35% (Finn et al., 2021). Gut microbe diversity is associated with the recurrence and severity of CDI (Maziade et al., 2015). Probiotics are widely recommended for the prevention of CDI and its recurrence, and the protective roles and underlying mechanisms of A. muciniphila on CDI were reported (Wu et al., 2022; Nasiri et al., 2023). Wu et al. reported that oral supplementation of A. muciniphila could reduce C. difficile burden and its toxins, and improve clinical outcomes of CDI mice including reduced body weight loss, alleviated diarrhea, relieved colon shortening (Wu et al., 2022). The protection mechanisms of A. muciniphila on CDI include increasing intestinal barrier by increased tight junction protein expression, reduced local and systemic immune response (reduced expression of IL-6, IL-1β, TNF-α, CCL1, CCL2, CCL4, CCL5, CCL3, CXCL10, CCL17, CCL22, and CXCL13), changing autophagy and innate immunity, alleviating microbiome dysbiosis, and improving bile acid and short-chain fatty acids (SCFAs) metabolism. The expression of autophagy related proteins (light chain 3 (LC3)-II, beclin1, autophagy-related gene 5 (Atg5), Atg9a, Atg7, and Atg12) and immune markers (, cluster of differentiation 14 (CD14), TLR4 and myeloid differentiation 88, MyD88) downregulated in the A. muciniphila group. Nasiri et al. reported that A. muciniphila and its derivatives could suppress cytotoxicity and inflammatory response induced by C. difcile RT001 in vitro using Caco-2 cells (Nasiri et al., 2023). Compared with untreated controls, the survival rate of Caco-2 cells treated with live, UV-killed, cell-free supernatant (CFS, 10⁶ cfu/mL), and extracellular vesicles (EVs, 20 μg/mL) of A. muciniphila exceeded 90%. The treatment exerted function by reducing the expression of IL-1β, TNF-α, and IL-10 in Caco-2 cell model, and changing the expression of gut barrier–related genes and inflammatory response. Therefore, EVs and CFS of A. muciniphila may be a safe substitution to live bacteria that can prevent harmful effects of C. difficile toxins, which merits further in vivo verifications.

Protective roles of A. muciniphila were reported for another intestinal pathogen Citrobacter rodentium, which can induce bacterial colitis (Mao et al., 2021). Increased A. muciniphila abundance was correlated with the alleviation of C. rodentium infection and intestinal inflammation in the hyaluronan treated mice. A. muciniphila is the key species responding to hyaluronan treatment, and fecal transplantation experiments demonstrated the transferable of hyaluronan induced microbiome. A. muciniphila colonization in mice can significantly reduce the symptoms and pathological changes of C. rodentium infection, with less body weight loss, pathogen tissue loads and reduced proinflammatory cytokine (IL-1β) expression. The protective function of A. muciniphila on C. rodentium induced-colitis is implemented throughenhanced mucus barrier (upregulated mucin gene expression including muc1, muc5, and muc13) and anti-microbial responses (upregulation of Reg3γ, CRAMP, and IL-22). Together, these results indicate that A. muciniphila acts as regulator of gut barrier and immune responses to enteric infectious diseases.

Periodontitis, which occurs in the periodontal support tissue, is a chronic inflammatory disease that could lead to tooth loss in adults, and severe periodontitis has become the sixth most prevalent disease worldwide (Slots, 2017; Tonetti et al., 2017). Porphyromonas gingivalis is a gram-negative anaerobe and a main pathogen of periodontitis (Shalihin et al., 2023). It was demonstrated that oral gavage with pasteurized A. muciniphila decreased P. gingivalis-associated periodontal destruction and ameliorated systemic inflammation in lean and obese mice (Huck et al., 2020; Mulhall et al., 2022). Oral administration of A. muciniphila and its pili-like protein Amuc_1100 could reduce alveolar bone loss and inflammatory destruction in murine periodontitis models (Huck et al., 2020). A. muciniphila and P. gingivalis co-culture resulted in decreased expression levels of P. gingivalis virulence factor gingipains and increased expression of A. muciniphila Amuc_1100. The protection of A. muciniphila may act through increasing anti-inflammatory effects (increased IL-10 and decreased IL-12) in Mouse bone marrow macrophages (BMMϕ), improving the expression level of tight junction molecules (ZO-1) and adhesion markers, and increasing anti-infective response by upregulating IL-8 expression in gingival epithelial cells. Interestingly, a similar protective effect was found for oral administration of pasteurized A. muciniphila, viable A. muciniphila and Amuc_1100 (Mulhall et al., 2022). The route of administration is key to preventing tissue destruction, as gavage does not significantly reduce periodontal destruction. The use of pasteurization A. muciniphila has more potential in an industrial point of view because it has minimal safety concerns and the same beneficial effects as live A. muciniphila.

Later, Song et al. reported an inhibition of A. muciniphila on the periodontitis caused by Fusobacterium nucleatum (Song et al., 2023). It has been verified that F. nucleatum can cause periodontitis and copolymerization with other periodontal pathogens, making it an important target for the prevention of periodontitis (Park et al., 2016). Bacterial co-culture experiments showed that A. muciniphila could restrain virulence gene expression of F. nucleatum by inhibiting TLR/MyD88/NF-κB pathway and inflammatory factor secretion. Finally, inhibition of A. muciniphila on the periodontitis caused by F. nucleatum was verified using BALB/c mice experiments. Therefore, A. muciniphila may act as a potential therapeutic strategy for periodontitis, which could inhibit the virulence factors of the pathogen causing periodontitis and reduce the immune response of the host.

Nontyphoidal Salmonella enterica subsp. enterica serovars (S. typhimurium) is an intracellular bacterial pathogens causing hundreds of thousands of acute gastroenteritis cases each year (Vieira et al., 2022). There are two opposing reports about the effect of A. muciniphila on S. typhimurium infection in mouse model. Ganesh et al. reported that A. muciniphila exacerbated gut inflammation of S. typhimurium infection (Ganesh et al., 2013). A well-defined gnotobiotic C3H mouse model with a defined simplified human intestinal microbiota (SIHUMI) of eight bacterial species was used to analyze the influence of A. muciniphila on inflammatory and infectious symptoms caused by S. typhimurium. Additional A. muciniphila colonization in S. typhimurium-infected C3H mouse model significantly elevated histopathology scores and increased expression levels of IFN-γ, TNF-α, IL-12, IP-10, IL-17, and IL-6 in the cecal and colonic tissue of the mice, thereby exacerbating infectious and inflammatory symptoms. However, Liu et al. reported that A. muciniphila could decrease mice susceptibility to S. typhimurium infection (Liu et al., 2023). A streptomycin-treated C57B6J mouse infection model was constructed to evaluate the impact of live A. muciniphila (AKK) and pasteurized A. muciniphila (pAKK) on S. typhimurium infection. The results indicated that AKK and pAKK pretreatment significantly reduced pathogen burdens and decreased inflammation responses during S. typhimurium infection. There may have different protective mechanisms for AKK and pAKK treatments. Analysis of SCFAs levels indicated higher propionate levels in AKK-treated group compared to control or pAKK-treated mice. Live A. muciniphila promotes the expression of intestinal barrier genes and antimicrobial peptide secretion, and co-housing studies have shown that A. muciniphila-associated microbial communities play a role in alleviating infection symptom. The researchers verified that pAKK pretreatment could promote NLRP3 expression, and increase the antimicrobial activity of macrophage, possibly through increased production of nitric oxide (NO), reactive oxygen (ROS) and inflammatory cytokines. Differences between the composition of microbial community and infection conditions in mice could explain the opposite phenotypes observed between two studies, and further research is required to reveal the roles and mechanisms of A. muciniphila in S. typhimurium infection.

Listeria monocytogenes is a Gram-positive foodborne pathogen that causes mild to severe gastroenteritis in healthy individuals, whereas can cause bacterial sepsis, bacterial meningitis in children, elderly individuals, and immunocompromised individuals (Radoshevich and Cossart, 2018). L. monocytogenes is rod-shaped facultative anaerobes, which can tolerate low temperatures and has high resistance to environmental stresses, making it a major concern for the food industry (Gandhi and Chikindas, 2007). The effects of A. muciniphila on L. monocytogenes infection in the high-fat/westernized diet mice were investigated (Keane et al., 2023). A. muciniphila treatment could reduce systemic Listeria infection induced by diet by reducing the bacterial loads in the liver, spleen and mesenteric lymph nodes, demonstrating that oral gavage with A. muciniphila enhances mice L. monocytogenes resistance. The molecular mechanism may be that A. muciniphila ameliorated inflammatory gene expression (decreased expression of Tnfα and Foxp3, and elevated expression of Ccl2) in the distal ileum thus leading to a reduction in inflammatory cell infiltration. The results indicated potentials for the use of microbial interventions in the prevention of foodborne infectious diseases. The roles of A. muciniphila in infection related diseases were summarized in Figure 2.

Intestinal immune barrier refers to innate and adaptive immune cells and gut-associated lymphoid tissue colonized on the intestinal lamina propria (Di Tommaso et al., 2021). Environmental factors, intestinal flora and their metabolites could be recognized by specific receptors (toll-like receptors, TLRs) on immune cells, leading to intestinal immune homeostasis or imbalance (Shi et al., 2023). Multiple investigations have shown that A. muciniphila plays an important role in regulating the immune response and host inflammation. The regulatory roles could complete by a variety of forms such as live or inactivated bacteria, culture supernatant or derived components of A. muciniphila. Germ-free mice were utilized to analyze the influence of A. muciniphila on the host response (Derrien et al., 2011). A. muciniphila colonized most in the cecum, which produce the most mucin. Global transcriptional analysis indicated that A. muciniphila changed mucosal gene expression profiles by increasing the expression of genes involved in immune responses and cell fate. Exposure to SCFAs generated by A. muciniphila could alter the gene transcriptional levels in mouse ileal organoid model (Lukovac et al., 2014). The results indicated that A. muciniphila and its metabolites had an impact on the expression of transcription factors and genes involved in cellular lipid metabolism and growth. The β-carboline alkaloid harmaline (HAL) generated by A. muciniphila can regulate primary BA conjugation and suppressed NF-κB-mediated systemic inflammation (Xie et al., 2023). Oral administration of cultures and pasteurized A. muciniphila (1 × 10⁸ CFU) significantly reduced IL-6 and IL-1β levels, enhanced IFN-γ, IFN-β, and IL-10 expression in H7N9-infected mice (Hu et al., 2021). The inhibitory effects of A. muciniphila and its derivatives on cytotoxicity and inflammatory response were also reported for C. difcile RT001 induced Caco-2 cells (Nasiri et al., 2023). In summary, protective effect of A. muciniphila and its derivatives is inversely associated with inflammatory status and aids the immune response by regulating anti-inflammatory pathway (Figure 3).

Adaptive immune cells play an important role in the protection of intestinal mucosal barrier and tissue homeostasis through immunoglobulin A (IgA) (Belkaid and Harrison, 2017). Mouse studies have shown that A. muciniphila can specifically induce immune responses to T cells during homeostasis (Ansaldo et al., 2019). A. muciniphila has been shown to induce IgG1 and T cell-related immune responses in mice, T-cell response induced by A. muciniphila could also occur independently through follicular T-cell. Amuc_1100 protein is a pili-like protein highly abundant in the outer membrane of A. muciniphila Muc^T, which could activate the NF-κB pathway through activation of receptors such as Toll-like receptor (TLR) 2 and TLR4 (Ottman et al., 2017). Recently, a phospholipidlipid was identified from the cell membrane A. muciniphila, with immunomodulatory activity in cell-based assays through toll-like receptor TLR2–TLR1 heterodimer (Bae et al., 2022). The phospholipidlipid could induce pro-inflammatory cytokines IL-6 and TNFα expression. Moreover, it can reset the activation threshold of dendritic cells and regulate the immune stimulation. Dendritic cells typically recognize and respond to bacterial metabolites through the pathogen-associated molecular pattern (PAMP) receptors such as TLR2 and TLR4 (Kang et al., 2009).

Besides T cells, A. muciniphila can also influence the intestinal immune through regulating the function of other immune cells (Figure 3). A. muciniphila derived tripeptide RKH could suppress the expression of proinflammatory cytokines in macrophages after LPS stimulation and directly bind to TLR4 and inhibit systemic inflammation of sepsis (Xie et al., 2023). Treatment of peripheral blood mononuclear cells (PBMCs) with A. muciniphila (live cells, heat-killed cells and supernatant) induce production of both anti-inflammatory and pro-inflammatory cytokines (IL-6, IL-1β, IL-8, IL-10, and TNF-α) (Ottman et al., 2017).

The intestinal barrier is a complex and well-organized physiological structure, which interacts with the external environment as a biochemical, physical, and immune barrier (Breugelmans et al., 2022). In healthy conditions, the intestinal barrier is semi-permeable, allowing the absorption of nutrients and water and protecting the internal environment from potential penetration by pathological molecules and microorganisms (Maynard et al., 2012). However, the damage of the intestinal barrier integrity results in multiple local and systemic diseases. Intestinal mucus consists of an inner layer without bacteria and a thicker outer layer with symbiotic bacteria (Hansson and Johansson, 2010). The integrity of the intestinal barrier requires normal epithelial boundary, maintenance of tight junctions, normal mucus secretion and a normal gut microbiome, as well as a finely regulated immune system (Shi et al., 2023).

Mucins, composed of amino acids and oligosaccharides, is a nutrient source for intestinal bacteria anda gatekeeper of the gastrointestinal mucosal barrier (Breugelmans et al., 2022). A. muciniphila bacteria can grow using mucins as sole carbon and nitrogen source in the intestinal mucus layer, and settle in the intestinal tract through competitive rejection and protect the intestinal tract from pathogens (Figure 3). The presence of mucin could increase the expression levels of mucin-degrading enzymes, whereas most genes involved in glycolysis and energy metabolic pathways upregulated under low mucin conditions (Shin et al., 2019). A. muciniphila abundance was positively related with mucin content in the cecum (van den Abbeele et al., 2011). Antibiotic treatment increased the mucus barrier by reducing the abundance of mucin-degrading A. muciniphila and decreasing Muc2 gene (encoding the major mucin of the colonic mucus in colonic tissues) expression (Ijssennagger et al., 2015). Mucin levels in the small intestine increased indicated by increased expression of MUC5 and MUC2 after metformin treatment in female mice, and thickened intestinal mucosa was confirmed by immunohistochemical assays and A. muciniphila abundance increased (Lee and Ko, 2014). A. muciniphila abundance was positively associated with the number of mucin-producing goblet cells in mice after metformin treatment (Shin et al., 2014). A. muciniphila also simulates mucin production in addition to its ability to degrade mucin. Therefore, although A. muciniphila make use of mucin as an energy source, it can positively regulate the thickness and stability of intestinal mucus layer and the intestinal barrier integrity.

In addition to affecting the mucin layer, other mechanisms may affect the integrity of the intestinal barrier (Figure 3). The interaction between A. muciniphila and the host might influence immune tolerance and homeostasis in the gut (Everard et al., 2013). Viable A. muciniphila administration elevated the levels of intestinal endocannabinoids and improved the metabolic profile and the mucus layer thickness (Everard et al., 2013). Endocannabinoids play roles in the gut inflammation, gut peptide secretion and the gut barrier. A. muciniphila and Amuc_1100 increased trans-epithelial resistance (TEER) in Caco2-cells, indicating their roles in strengthening the epithelial barrier function (Ottman et al., 2017).

Tight junctions are the connections between intestinal epithelial cells, which consist of zonula occluden (ZO), claudins (Cldns) and occludin (Ocln) proteins, are critical for normal function of epithelial cells and maintenance of intestinal barrier functions (Allam-Ndoul et al., 2020). A muciniphila could increase the expression of intestinal tight junction proteins including ZO-1 and occluding proteins, thereby decreasing Western diet-induced gut permeability and contributing to the gut barrier function (Li et al., 2016). Luo et al. reported that active or autoclaved A. muciniphila could induce the expression of tight junction proteins (ZO-1 and occluding proteins) in intestinal epithelial cells (Luo et al., 2021). The apoptosis rate can reflect the degree of cellular damage, and A. muciniphila treatment significantly suppressed the apoptotic rate of the inflammatory IPEC-J2 cells, thus reducing the degree of cellular damage. Therefore, A. muciniphila may protect intestinal barrier integrity by regulation of epithelial cells, mucus secretion, tight junctions, normal gut microbiota and cellular damage level.

A. muciniphila genome encodes a large number of mucin-degrading enzymes, which can degrade mucin and generate short-chain fatty acids, such as butyrate, propionate, acetate, etc., playing important roles in the regulation of host metabolism and disease development (Cani and de Vos, 2017). Live, pasteurized bacterium and Amuc_1100 protein could improve metabolism in obese and diabetic mice (Plovier et al., 2017). Interestingly, pasteurized A. muciniphila showed stronger impacts on glucose intolerance, body weight and fat mass gain and in HFD-fed mice, which was associated with modulation of host urinary metabolomics and energy absorption of the intestinal tract. Everard et al. reported the roles of A. muciniphila in metabolic regulation including adipose tissue metabolism, fat storage and glucose metabolism in diet-induced obesity mouse model (Everard et al., 2013). A. muciniphila therapy completely reversed diet-induced fasting hyperglycemia via decreasing hepatic glucose-6-phosphatase expression, and affected adipose tissue metabolism by increasing the mRNA expression of adipocyte differentiation and lipid oxidation markers. Meanwhile, the colonization of A. muciniphila in IFNγKO and wild-type mice can improve host glucose metabolism was reported and verified in humans (Greer et al., 2016). IFNγ may control gut A. muciniphila levels by regulating Irgm1 gene expression in the mouse ileum. The relation between IFNγ, A. muciniphila and glucose tolerance exists in humans, suggesting a conserved mechanism in the regulation of metabolic health in mice and humans. Hence, A. muciniphila played roles in host metabolism regulation including glucose and lipid metabolism (Figure 3).