As originally proposed by J.B.S. Haldane, infectious diseases are a major driving force of natural selection (Haldane, 1949), occasionally precipitating ‘catastrophic-selection’ events: the replacement of an entire, susceptible, parental population by mutant offspring that are resistant to a given infectious disease (Lewis, 1962). Such an event is proposed to have occurred during primate evolution between 20–30 million‐years‐ago, possibly due to the selective pressure exerted by an airborne, enveloped virus carrying Galα1-3Galβ1-4GlcNAc (αGal)-like glycans (Galili, 2016; Galili, 2019). If proven correct, this would contribute to the evolutionary pressure that led to the selection and fixation of GGTA1 loss-of-function mutations in ancestral primates (Galili et al., 1988).

Loss of the α1,3-galactosyltransferase enzyme, encoded by GGTA1, eliminated the expression of protein-bound αGal, allowing for immune targeting of this non-self glycan (Galili et al., 1987). This increased resistance to infection by αGal-expressing pathogens (Repik et al., 1994; Takeuchi et al., 1996), including parasites of the Plasmodium spp. (Soares and Yilmaz, 2016; Yilmaz et al., 2014), which exerted a major impact on human evolution (Allison, 1954).

We recently uncovered a possible fitness advantage associated with loss of GGTA1 function, which acts independently of αGal-specific immunity (Singh et al., 2021). Namely, loss of αGal from immunoglobulin (Ig)G-associated glycan structures increased IgG effector function and resistance to bacterial sepsis in mice (Singh et al., 2021).

Sepsis is a life-threatening organ dysfunction caused by a deregulated response to infection (Singer et al., 2016) that accounts for 20% of global human mortality (Rudd et al., 2020). The pathogenesis of sepsis is modulated by stable host symbiotic associations with microbial communities composed of bacteria, fungi, and viruses, known as the microbiota (Rudd et al., 2020; Vincent et al., 2009). While host-microbiota interactions provide a broad range of fitness advantages to the host (Lane-Petter, 1962; Vonaesch et al., 2018), these also carry fitness costs, for example, when bacterial pathobionts (Chow et al., 2011) translocate across host epithelial barriers to elicit the development of sepsis (Rudd et al., 2020; Vincent et al., 2009). On the basis of this evolutionary trade-off (Stearns and Medzhitov, 2015), it has been argued that the immune system may have emerged, in part, to mitigate the pathogenic effects of the microbiota (Hooper et al., 2012; McFall-Ngai, 2007). Central to this host defence strategy is the transepithelial secretion of copious amounts of IgA natural antibodies (NAb), which target immunogenic bacteria in the microbiota (Macpherson et al., 2000).

IgA recognize a broad but defined subset of immunogenic bacteria in the gut microbiota (Bunker et al., 2017; Bunker et al., 2015; Macpherson et al., 2000), exerting negative or positive selection pressure on these bacteria, shaping the microbiota composition, ecology, and potentially its pathogenicity (Kubinak and Round, 2016). Negative selection can occur, for example, when IgA limits bacterial growth (Moor et al., 2017), while positive selection can occur, for example, when IgA promotes bacterial interactions with the host, favoring bacterial retention, fitness, and colonization (Donaldson et al., 2018; McLoughlin et al., 2016). Moreover, IgA can interfere with cognate interactions between bacteria and tissue resident immune cells at epithelial barriers, regulating microbiota-specific immune responses, including the production of circulating IgM and IgG NAb (Kamada et al., 2015; Zeng et al., 2016).

Here, we provide experimental evidence in mice to suggest that the fixation of GGTA1 loss-of-function mutations during primate evolution exerted a major impact on the composition of their gut microbiota. In support of this notion, mice in which Ggta1 is disrupted (Ggta1^-/-), mimicking human GGTA1 loss-of-function mutations, modulated their gut microbiota composition. This occurs predominantly via an Ig-dependent mechanism, associated with an enhancement of the production of IgA, targeting αGal-expressing bacteria in the gut microbiota. The pathogenicity of the Ig-shaped microbiota is reduced, failing to elicit lethal forms of sepsis upon systemic infection. We propose that GGTA1 loss-of-function mutations conferred a selective benefit during primate evolution, in part, by shaping commensal bacteria in the microbiota to mitigate the pathogenesis of sepsis.

While loss-of-function mutations in genes encoding glycosyltransferases can provide fitness advantages against infection, these can compromise the physiologic functions of the eliminated self-glycan, as illustrated by the occurrence of reproductive senescence upon Ggta1 deletion in mice (Singh et al., 2021). In an evolutionary context, such a trade-off could explain why loss-of-function mutations in these genes are rare, and in some cases unique, to the human lineage. The latter is illustrated by the loss of CMP-N-acetylneuraminic acid hydroxylase (CMAH) function, which eliminated expression of the sialic acid, N-glycolylneuraminic acid (Neu5Gc), in humans (Ghaderi et al., 2011).

Co-evolution of ancestral hominids with commensal bacteria in their microbiota (Dethlefsen et al., 2007; Huttenhower et al., 2012; Moeller et al., 2016), is thought to have provided a series of fitness advantages including, among others, optimization of nutrient intake from diet, regulation of different aspects of organismal metabolism or colonization resistance against pathogenic bacteria (Buffie and Pamer, 2013). Here we propose that the loss of αGal expression, as it occurred during primate evolution, might have exerted a major impact on the nature of these symbiotic associations. In support of this notion, we found that Ggta1 deletion in mice was associated with major changes in the composition of the gut microbiota (Figure 1). This occurred over several generations under experimental conditions of exposure to environmental-derived pathobionts, and minimum relative impact exerted by other environmental factors on microbiota composition (Ubeda et al., 2012), arguing that the Ggta1 genotype modulates the microbiota composition. On the basis of this observation alone (Figure 1), one cannot exclude the observed divergence in the microbiota bacterial population frequencies harbored by wild type vs. Ggta1-deleted mice (Figure 1) from being a stochastic event. However, the observation that these changes occur via an Ig-dependent mechanism that differs in wild type vs. Ggta1-deleted mice (Figure 3) does suggest that loss of αGal contributes critically to shape the microbiota composition of Ggta1-deleted mice.

While our studies do not provide direct evidence that the loss of αGal played a major role in shaping the microbiota composition of Old- vs. New World primates, this notion is supported, indirectly, by the recent finding that mutations altering the expression of human ABO blood group glycans are associated with shaping of the bacterial composition of the gut microbiota (Rühlemann et al., 2021). In light of the structural similarity between the human B blood group (i.e. Galα1-3(Fucα1-2)Galβ1-4GlcNAcβ1-R), and αGal (i.e. Galα1-3Galβ1-4GlcNAcβ1-R) glycans, our findings probably reflect a general mechanism whereby host ‘αGal-like’ glycans shape the microbiota composition of mice and primates, including that of humans. Whether or not this is the case, considering that microbiota composition is shaped mostly by environmental factors, remains to be formally established.

The mechanism via which Ggta1 deletion shapes the gut microbiota is associated with targeting of αGal-expressing bacteria by IgA (Figure 2). Consistent with this notion, a relatively large proportion of probiotic bacteria as well as bacteria present in the mouse microbiota express αGal-like glycans at the cell surface (Figure 2). About 30% of these carry IgA at the cell surface in the mouse microbiota and, as such, are considered as immunogenic (Palm et al., 2014). The proportion of IgA⁺αGal⁺ bacteria was reduced in the microbiota of Ggta1-deleted mice and was presumably eliminated (Figure 2). This suggests that Ggta1 deletion probably broadens bacterial recognition by IgA to include immunogenic αGal⁺ bacteria, which as a result are probably purged from the microbiota. Whether this occurs via a mechanism involving the recognition of αGal-like glycans, and/or other related epitopes expressed at the surface of these bacteria, by IgA, has not been established. Of note, these are not mutually exclusive possibilities since: (i) IgA can target αGal-like glycans and modulate bacterial pathogenicity (Hamadeh et al., 1995), (ii) IgA are poly-reactive and can target common antigens expressed by bacteria (Bunker et al., 2017; Bunker et al., 2015) and (iii) αGal-reactive antibodies present a degree of poly-reactivity against non-αGal related bacterial epitopes (Bernth Jensen et al., 2021).

The identity of the αGal⁺ bacteria targeted by IgA remains elusive but likely includes Gram-negative pathobionts from the Enterobacteriaceae family, as demonstrated for Escherichia (E.) coli O86:B7 (Yilmaz et al., 2014), which expresses the αGal-like glycan Galα1-3Gal(Fucα1–2)β1-3GlcNAcβ1-4Glc as part of the lipopolysaccharide (LPS) O-antigen (Guo et al., 2005). Of note, this pathobiont can induce a systemic αGal-specific NAb response in humans (Springer and Horton, 1969) as well as in Ggta1-deleted mice, which is protective against infection by pathogens expressing αGal-like glycans (Yilmaz et al., 2014). The finding that several commensal bacteria in the human gut microbiota express αGal-like glycans (Figure 2—figure supplement 2) suggests that other bacteria might contribute to this protective response.

Our findings also suggest that Ggta1 deletion shapes the bacterial community structure among highly abundant bacterial taxa in the microbiota via an Ig-dependent mechanism, and among low abundant bacterial taxa independently of Ig (Figure 3). Presumably, shaping of highly abundant taxa by Ig occurs via a mechanism that involves not only IgA produced by the offspring, but also maternal IgG transferred through the placenta as well as IgM, IgG, and IgA transferred through maternal milk (Koch et al., 2016). These regulate neonatal innate (Gomez de Agüero et al., 2016) and adaptive (Koch et al., 2016) immunity, shaping the offspring microbiota composition (Gensollen et al., 2016; Koch et al., 2016). Whether this occurs via targeting of αGal-like glycans, as discussed above, and/or via other bacterial antigens expressed by immunogenic bacteria has not been established.

Shaping of lowly abundant bacterial taxa independently of Ig (Figure 3) suggests that other mechanisms contribute to shaping the microbiota of Ggta1-deleted mice. These probably include the modulation of nutritional or spatial niches due to the loss of αGal from complex glycosylated structures present at epithelial barriers, such as the mucus, as demonstrated for other glycans (Pickard et al., 2014).

The selective pressure exerted by the adaptive immune system of Ggta1^-/- mice on the bacterial species present in the microbiota, probably allows for the establishment of a more diverse ecosystem containing pathobionts (Singh et al., 2021), such as Helicobactereaceae (Figure 1—figure supplements 1 and 2). These can elicit the production of antibodies targeting and exerting negative selective pressure on other bacterial symbionts and releasing ecological niches, thus further shaping the microbiota. Expansion of these pathobionts in the microbiota of Ggta1^-/- mice is restrained by Ig, which probably explains the lack of associated pathology (Figure 1—figure supplement 3). This suggests that the loss of GGTA1 function in ancestral primates fostered mutualistic interactions with more diverse bacterial ecosystems, incorporating pathobionts such as Helicobacter pylori, associated with fitness costs (Atherton and Blaser, 2009) and gains (Linz et al., 2007).

Our findings suggest that Ig-shaping of the bacterial species present in the gut microbiota of Ggta1^-/- mice reduces the microbiota pathogenicity, as illustrated when comparing the lethal outcome of systemic infections using the Ig-shaped vs. non-shaped microbiota (Figure 4A, Figure 4—figure supplement 1A and B). This reduction in pathogenicity means that the effector mechanism underlying resistance against systemic infection by the Ig-shaped microbiota no longer relies on the adaptive immune system (Figure 4—figure supplement 1C and E), but instead on cellular components of the innate immune systems, namely, neutrophils (Figure 4G,H).

We propose that Ggta1 deletion in mice increases resistance to bacterial sepsis via two distinct antibody-dependent mechanisms. The first involves a relative increase in antibody effector function, when αGal is not present in the biantennary glycan structures of IgG (Singh et al., 2021). The second relies on shaping and reduction of the microbiota pathogenicity by antibodies, most likely from the IgA isotype. To what extent the lack of αGal from the biantennary glycan structures of Ig also contributes to shape and reduce the microbiota pathogenicity, remains to be established. It is possible however, that similar to IgG (Singh et al., 2021), the absence of αGal from the glycan structures of different Ig isotypes, including IgA, modulates their effector function, when targeting immunogenic bacteria in the microbiota.

The notion of host mechanisms shaping the microbiota composition toward a reduction of its pathogenicity is in keeping with host microbial interactions not being hardwired, but instead shifting between symbiotic to pathogenic depending on host and microbe cooperative behaviors (Ayres, 2016; Vonaesch et al., 2018). For example, when restricted to the microbiota, bacterial pathobionts can behave as commensals, posing no pathogenic threat to the host (Vonaesch et al., 2018), while triggering sepsis (Haak and Wiersinga, 2017) upon translocation across epithelial barriers (Caruso et al., 2020). The high fitness cost imposed to modern humans by sepsis (Rudd et al., 2020) suggests that mutations shaping the composition of the microbiota toward a reduced capacity to elicit sepsis should be associated with major fitness advantages. Our findings suggest that loss-of-function mutations in GGTA1 act in such a manner.

When challenged experimentally with a bacterial inoculum or bacterial lipopolysaccharide (LPS), non-human primates appear to be far more susceptible to develop sepsis or septic shock, respectively, as compared to other mammalian lineages (Chen et al., 2019). This may appear at odds with our interpretation that similar to Ggta1 deletion in mice (Figure 4; Singh et al., 2021), the evolutionary loss of GGTA1 function in Old-World primates might have increased resistance to bacterial sepsis (Singh et al., 2021). One likely explanation for this apparent discrepancy may relate to the intrinsic properties of primate immunity, whereby natural selection of traits enhancing immune-driven resistance mechanisms (Olson, 1999; Wang et al., 2006) might be associated with lower capacity to establish disease tolerance to infection (Martins et al., 2019; Medzhitov et al., 2012). This interpretation is consistent with resistance and disease tolerance to infection being negatively correlated (Råberg et al., 2007), such that traits increasing resistance might be associated with a reduction in disease tolerance, as an evolutionary trade-off.

In conclusion, protective immunity against αGal-expressing pathogens was likely a major driving force in the natural selective events that led to the fixation of loss-of-function mutations in the GGTA1 gene of ancestral Old World primates (Galili, 2016; Soares and Yilmaz, 2016). Moreover, in the absence of αGal, the glycan structures associated with the Fc portion of IgG, can increase IgG-effector function and resistance to bacterial infections, irrespectively of αGal-specific immunity (Singh et al., 2021). The net survival advantage against infection provided by these traits came alongside the emergence of reproductive senescence (Singh et al., 2021), a major fitness cost presumably outweighed by endemic exposure to highly virulent pathogens (Singh et al., 2021). Here we provide experimental evidence for yet another fitness advantage against infection, associated with the loss of GGTA1, driven by Ig-shaping and reduction of microbiota pathogenicity. We infer that ancestral Old World primates carrying loss-of-function mutations in GGTA1 probably shaped their microbiota to minimize its pathogenic effect, providing a major fitness advantage against sepsis.

All data generated during this study are included in the manuscript and supporting files. The 16S sequencing data can be accessed via NCBI Bioproject PRJNA701192.

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Author details

1. Sumnima Singh

   Instituto Gulbenkian de Ciência, Oeiras, Portugal

   Present address

   Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Supervision, Funding acquisition, Investigation, Methodology, Writing - original draft, Project administration, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1826-0180

2. Patricia Bastos-Amador

   Instituto Gulbenkian de Ciência, Oeiras, Portugal

   Present address

   Champalimaud Centre for the Unknown, Lisbon, Portugal

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing - original draft, Writing - review and editing

   Contributed equally with

   Jessica Ann Thompson

   Competing interests

   No competing interests declared

3. Jessica Ann Thompson

   Instituto Gulbenkian de Ciência, Oeiras, Portugal

   Contribution

   Formal analysis, Funding acquisition, Investigation, Methodology, Writing - original draft, Writing - review and editing

   Contributed equally with

   Patricia Bastos-Amador

   Competing interests

   No competing interests declared

4. Mauro Truglio

   Instituto Gulbenkian de Ciência, Oeiras, Portugal

   Contribution

   Data curation, Formal analysis

   Competing interests

   No competing interests declared

5. Bahtiyar Yilmaz

   Instituto Gulbenkian de Ciência, Oeiras, Portugal

   Present address

   Department for Biomedical Research, Inselspital, University of Bern, Bern, Switzerland

   Contribution

   Data curation, Formal analysis, Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

6. Silvia Cardoso

   Instituto Gulbenkian de Ciência, Oeiras, Portugal

   Contribution

   Formal analysis, Investigation, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

7. Daniel Sobral

   Instituto Gulbenkian de Ciência, Oeiras, Portugal

   Present address

   Universidade Nova de Lisboa, Caparica, Portugal

   Contribution

   Data curation, Software, Formal analysis, Investigation, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-3955-0117

8. Miguel P Soares

   Instituto Gulbenkian de Ciência, Oeiras, Portugal

   Contribution

   Conceptualization, Data curation, Formal analysis, Supervision, Funding acquisition, Investigation, Methodology, Writing - original draft, Project administration, Writing - review and editing

   For correspondence

   mpsoares@igc.gulbenkian.pt

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-9314-4833

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